_:b457511086 . _:b10410020 . _:b10409960 . . _:b10410000 "Thus, as the CD169-driven DTR model was the most restricted, the loss of CD169+ macrophages rather than monocytes appears to be critical for the mobilization of HSCs (Chow et al., >>2011<<)." . _:b457510810 . _:b10410021 . _:b10409963 . . _:b457510727 . _:b10409962 . _:b457510908 . _:b10409967 "Similarly, adult human bone marrow contains a population of self-renewing CD45\u2212CD146+ perivascular osteoprogenitors that can generate bone and marrow when transplanted under the skin of immunodeficient mice (Sacchetti et al., >>2007<<). Moreover, HSCs express the calcium ion receptor, which has been demonstrated to be important for HSC engraftment at the endosteum by enabling HSCs to follow the Ca2+ gradient that results from bone remodeling processes occurring at the" . _:b457510904 . . . . _:b10409959 . . . _:b457510976 . . _:b10410035 . . _:b457510966 . . _:b457511114 . _:b457510736 . _:b457510458 . . _:b457510929 . _:b457511045 . _:b457510514 . _:b457510646 . . _:b10409992 . . _:b10409994 . . _:b457510504 . _:b457510505 . _:b457510506 . _:b457510507 . _:b457510508 . _:b457510509 . _:b457511117 . _:b457510510 . _:b457510511 . _:b457510496 . _:b457510641 . _:b457510497 . _:b457510572 . _:b457510498 . _:b457510499 . _:b457510500 . _:b457510501 . _:b457510502 . _:b457510503 . _:b457510520 . _:b457510521 . _:b457510944 . _:b457510793 . _:b457510661 . _:b457510522 . _:b457510523 . . _:b457510524 . . _:b457510660 . _:b457510525 . _:b457510526 . _:b457510527 . _:b457510512 . . _:b10409996 . . _:b457510663 . _:b457510513 . _:b457510514 . _:b457510418 . _:b457510515 . _:b457510516 . _:b457510517 . _:b457510662 . _:b457510518 . _:b457510519 . . _:b457510472 . . _:b457510657 . _:b457510473 . _:b457510760 . _:b457510474 . _:b457510475 . _:b457511037 . _:b457510476 . _:b457510477 . _:b457510413 . _:b457510656 . _:b457510478 . _:b457510479 . _:b457510464 . _:b457510953 . _:b457510465 . _:b457511218 . . _:b457510659 . _:b457510466 . _:b457510467 . _:b457510815 . _:b457510468 . _:b457510469 . _:b457510658 . _:b457510470 . _:b457510471 . _:b457510488 . _:b457511060 . _:b457510489 . _:b457510669 . _:b457510490 . _:b457510476 . _:b457510491 . _:b457510492 . _:b457510493 . _:b457510668 . _:b457510494 . _:b457510495 . _:b457510855 . . _:b457510480 . _:b457510481 . _:b457510671 . _:b457510482 . _:b457510483 . . _:b457510464 . _:b457510484 . _:b457510430 . _:b457510670 . _:b457510485 . _:b457510486 . _:b457510487 . _:b457510440 . _:b457510441 . _:b457510665 . _:b457510442 . . _:b457510443 . _:b457510444 . _:b457510445 . _:b457510664 . _:b457510446 . _:b10409992 "I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., 2009; Foudi et al., 2009; Schaniel and Moore, 2009; Baldridge et al., 2010; Trumpp et al., >>2010<<; Takizawa et al., 2011). Thus, we postulate the existence of two highly similar niches, one harboring dormant HSCs and one housing self-renewing HSCs (Fig." . _:b457510447 . _:b457510432 . _:b457510898 . . _:b457510433 . _:b457511036 . _:b457510784 . _:b457510667 . _:b457510434 . _:b457510435 . _:b457511224 . . _:b457510436 . _:b457510437 . _:b457510666 . _:b457510438 . _:b457510439 . _:b457510456 . _:b457510457 . _:b457510677 . _:b457510458 . . _:b457510459 . _:b457510460 . . _:b457510676 . _:b457510461 . _:b457510462 . _:b457510463 . _:b457510448 . _:b457510449 . _:b457510679 . _:b457510450 . _:b457510731 . _:b457510451 . _:b457511142 . _:b457510452 . _:b457510583 . _:b457510453 . _:b457510678 . _:b457510454 . . _:b457510455 . _:b457510408 . _:b457510409 . _:b457510673 . _:b457510410 . _:b457510411 . _:b457511145 . _:b457510412 . _:b457510413 . _:b10410003 . . _:b457510672 . _:b457510414 . _:b10409957 . _:b457510415 . _:b457510610 . _:b457510675 . _:b457510402 . _:b10409974 "Conversely, some bone marrow HSCs localized far away from bone surfaces might simply have been caught in histological sections during migration from a niche to a vessel (Wright et al., >>2001<<). Moreover, mobilized HSCs present at extramedullary sites like the spleen have no contact with osteoblastic cells, although whether the splenic environment maintains HSC self-renewal as well as the bone marrow remains questionable." . _:b457510555 . _:b457510643 . _:b457510403 . _:b457510404 . _:b457510405 . _:b10410001 . _:b457510674 . _:b457510406 . . _:b457510407 . _:b457510424 . _:b457510425 . _:b10410006 . _:b457510979 . _:b457510685 . _:b457510426 . _:b457510427 . _:b457510722 . _:b457510428 . _:b457510429 . _:b457510684 . _:b457510430 . . _:b457510431 . _:b457510416 . _:b457511222 . _:b457510417 . _:b457510687 . _:b457510418 . _:b457510419 . . _:b457510420 . _:b457510421 . _:b457510686 . _:b457510422 . _:b457510812 . _:b457510423 . _:b457510632 . _:b457510633 . _:b457510681 . _:b457510634 . _:b457510635 . _:b457510636 . _:b457510637 . . _:b457510680 . _:b457510638 . _:b457511118 . _:b457510639 . _:b457510624 . _:b457510625 . _:b457510683 . _:b457510626 . _:b10409987 "dormant during homeostasis, they can be induced to reenter the cell cycle in response to cytokines like type I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., >>2008<<; Essers et al., 2009; Foudi et al., 2009; Schaniel and Moore, 2009; Baldridge et al., 2010; Trumpp et al., 2010; Takizawa et al., 2011)." . _:b457510627 . _:b457510628 . _:b457510629 . _:b457510468 . _:b457510682 . _:b457510630 . _:b457510631 . . _:b457510648 . _:b457510649 . . _:b457510520 . _:b457510693 . . _:b457510650 . _:b457510651 . _:b457510652 . _:b457510653 . _:b457510692 . _:b457510654 . _:b457510655 . _:b457510981 . _:b457510640 . _:b457510641 . _:b457510695 . _:b457510642 . _:b457510643 . _:b457510644 . _:b457510645 . _:b457510694 . _:b457510646 . _:b457510500 . _:b457510647 . _:b457510600 . _:b457510601 . _:b457510689 . _:b457510602 . _:b457510603 . _:b457510604 . . _:b457510605 . . _:b457510688 . _:b457510606 . _:b457510607 . _:b457510592 . _:b457510870 . _:b457510593 . _:b10409999 "Because CXCL12-mediated activation of the CXCR4 receptor on HSCs is a critical niche retention signal (Lapidot and Petit, 2002; Broxmeyer, >>2008<<), these data provide a plausible explanation for the phenotype observed in these mice." . . _:b457510691 . _:b457510594 . _:b457510595 . _:b457510596 . . . . _:b457510690 . _:b457510597 . _:b457510598 . _:b457510599 . _:b457510616 . _:b457510617 . _:b457510666 . . _:b457510701 . . _:b457510618 . _:b457510619 . _:b457510620 . _:b457510621 . _:b457510700 . _:b457510622 . . _:b457510623 . _:b457510608 . _:b457510609 . _:b457510703 . _:b457510610 . _:b457510611 . _:b457511021 . . _:b457510612 . _:b457510613 . _:b457510702 . _:b457510614 . _:b457510615 . _:b457511056 . _:b457510410 . _:b457510568 . _:b457510569 . _:b457510697 . _:b457510570 . _:b457510571 . _:b457510572 . . _:b457510696 . _:b457510573 . _:b457510574 . _:b457510575 . _:b457510560 . . _:b457510561 . _:b457510699 . _:b457510562 . _:b457510563 . _:b457510564 . . _:b457510698 . _:b457510565 . _:b457510566 . _:b457510567 . _:b457510584 . _:b457510585 . _:b457510709 . _:b457510586 . _:b457510587 . . _:b457510588 . _:b457510589 . _:b457510708 . _:b457510590 . _:b457510591 . _:b457510576 . _:b457510577 . _:b457510711 . _:b457510578 . _:b457511211 . _:b457510579 . _:b457510739 . . _:b457510867 . _:b457510580 . _:b457510581 . _:b457510469 . _:b457510710 . _:b457510582 . _:b457510583 . _:b457510536 . _:b457510537 . _:b457510892 . _:b457510705 . _:b457510538 . _:b457510539 . _:b457510540 . _:b457510447 . _:b457510704 . _:b457510541 . _:b457510542 . . _:b457510543 . _:b457510528 . _:b457510529 . _:b457510707 . _:b457510530 . _:b457510405 . _:b457510531 . _:b457510532 . _:b457510969 . . _:b457510706 . _:b457510533 . _:b457510534 . _:b457511009 . _:b457510535 . _:b457510552 . _:b457510553 . _:b457510717 . _:b457510554 . _:b457510555 . _:b457510753 . . _:b457511108 . _:b457510556 . _:b457510557 . _:b10409996 "studies (including Chow et al. and Christopher et al. in the previous issue of the JEM) add to this complexity by reporting a role for bone marrow mononuclear phagocytes in promoting maintenance and retention of HSCs (Winkler et al., >>2010<<). First, Chow et al. (2011) developed a strategy to subdivide neutrophils, Gr-1hi and Gr-1lo monocytes, and Gr1\u2212F4/80+CD169+ macrophages." . _:b457511144 . _:b457510884 . _:b457510716 . _:b457510558 . _:b457510559 . _:b457510544 . _:b457510545 . _:b457510719 . _:b457510546 . _:b457510547 . _:b457510548 . _:b457510834 . _:b457510549 . . _:b457510718 . _:b457510550 . _:b457510551 . _:b457510942 . _:b457510760 . _:b457510761 . _:b457510713 . _:b457510762 . _:b457510763 . . _:b457510764 . _:b457510765 . . _:b457510712 . _:b457510766 . _:b10409949 "These cells also seem to mediate the capacity of parathyroid hormone to increase HSC numbers, which had previously been correlated with an increase in putative niche OBs (Calvi et al., 2003; Adams et al., >>2007<<). Parathyroid hormone directly stimulated proliferation of nestin+ MSCs while simultaneously promoting their differentiation into OBs (M\u00E9ndez-Ferrer et al., 2010). Collectively, these data support the hypothesis that nestin+ MSCs are a" . _:b457510767 . _:b457510752 . _:b457510753 . _:b457510715 . . _:b457510754 . _:b457510755 . _:b457510756 . _:b457510757 . . _:b457510714 . _:b457510758 . _:b457510759 . _:b457510776 . _:b457511120 . _:b457510822 . _:b457510444 . . _:b457510725 . _:b457510777 . _:b457510778 . _:b457510779 . _:b457510780 . _:b457510781 . _:b457510724 . _:b457510782 . _:b457510977 . . _:b457510567 . _:b457511149 . . _:b457510783 . _:b457510768 . _:b457510769 . _:b457510727 . _:b457510770 . _:b457510771 . _:b457510772 . _:b457511029 . _:b457510773 . _:b457510726 . _:b457510774 . _:b457510775 . _:b457510640 . _:b457510588 . . _:b457510728 . _:b457510729 . _:b457510721 . _:b457510730 . _:b457510731 . _:b457510732 . _:b457510733 . _:b457510720 . _:b457510734 . _:b457510928 . _:b457510735 . _:b457510720 . _:b457510721 . _:b457510723 . _:b457510722 . . . _:b457510723 . _:b457510932 . _:b457510724 . . _:b457510725 . . _:b457510722 . _:b457510726 . _:b457510727 . . . _:b457510744 . _:b457510745 . _:b457510733 . _:b457510746 . . _:b457510747 . _:b457510748 . _:b457510749 . _:b457510732 . _:b457510750 . _:b457511116 . _:b457510751 . _:b457510736 . _:b457510737 . _:b457510735 . _:b457510738 . _:b457510739 . _:b457510740 . _:b457510887 . . _:b457510734 . _:b457510741 . . _:b457510742 . _:b457510743 . _:b457510888 . . _:b457510699 . _:b457510696 . _:b457510697 . _:b457510729 . _:b457510698 . _:b457510698 . _:b457510699 . _:b457510562 . _:b457510700 . . _:b457510728 . _:b457510701 . _:b457510702 . . . _:b457510703 . _:b457510688 . _:b457510689 . _:b457510731 . _:b457510690 . _:b457510691 . . _:b457510692 . _:b457510693 . _:b457510730 . _:b457510694 . _:b457510695 . _:b457510712 . _:b457510713 . _:b457510741 . _:b457510714 . _:b457510715 . _:b457510716 . _:b457510717 . _:b457510740 . _:b457510718 . _:b10410012 . _:b457510719 . _:b10410022 "This effect was apparent within 2 d of G-CSF treatment, preceding the appearance of HSCs in the blood (Winkler et al., >>2010<<). As OBs themselves do not express the G-CSFR, this effect is indirect and likely to be a consequence of G-CSF\u2013mediated depletion of monocytes/macrophages. A positive effect of macrophages on OBs was further supported by data obtained in" . _:b457510704 . _:b457510705 . _:b457511215 . _:b457510743 . _:b457510706 . _:b457510707 . _:b457510708 . . _:b457510527 . _:b457510742 . _:b457510709 . _:b457510710 . _:b457510711 . _:b457510664 . _:b457510886 . . . _:b10409962 "Induced depletion of OBs causes mobilization of HSCs/progenitors to the spleen, and some genetically modified mice with augmented OBs show a simultaneous increase in HSC numbers (Calvi et al., >>2003<<; Zhang et al., 2003; Visnjic et al., 2004; Zhu et al., 2007)." . _:b457510737 . _:b457510665 . _:b457510666 . _:b457510465 . _:b457510667 . _:b457510668 . _:b457510669 . _:b457510736 . . _:b457510670 . _:b457510671 . . _:b457510656 . _:b457510958 . _:b457510657 . . _:b457510739 . . _:b457510658 . _:b457510659 . _:b457510660 . _:b457510661 . _:b457510738 . _:b457510662 . _:b457510663 . _:b457510680 . . _:b457510749 . _:b457510681 . _:b457510682 . _:b457510683 . _:b457510684 . _:b457511094 . . _:b457510685 . _:b457510748 . . _:b457510997 . _:b457510686 . _:b457510687 . _:b457510672 . _:b457510673 . _:b457510865 . _:b457510751 . _:b457510674 . _:b457510675 . . _:b457510676 . _:b457510677 . _:b457510750 . _:b457510678 . _:b457510679 . _:b457510888 . _:b457510889 . _:b457510745 . _:b457510890 . _:b457510891 . _:b457510892 . _:b457510893 . _:b457510744 . _:b457510894 . _:b457510895 . _:b457510880 . _:b457510881 . _:b457510747 . . _:b457510882 . _:b457510883 . _:b457510884 . . _:b457510885 . _:b457510746 . _:b457510886 . _:b457510887 . _:b457510904 . _:b457510905 . _:b457510757 . _:b457510906 . _:b457510907 . _:b457510474 . . . _:b457510908 . _:b457510909 . _:b457510756 . _:b457510910 . _:b457510911 . _:b457510896 . _:b457510897 . _:b457510759 . _:b457510898 . _:b457510899 . _:b457511057 . _:b457510900 . _:b10409982 "although c-MPL\u2212/\u2212 mice are born with normal numbers of HSCs, their frequency progressively declines with age, demonstrating a critical role for OB-derived TPO in adult HSC maintenance in vivo (Qian et al., 2007; Yoshihara et al., >>2007<<)." . _:b457510901 . . _:b457510758 . _:b457510902 . . _:b457510903 . _:b457510856 . _:b457510857 . _:b457510753 . _:b457510858 . _:b457510859 . _:b457510860 . _:b457510861 . _:b457510986 . _:b457510797 . _:b457510752 . _:b457510862 . _:b457510863 . _:b457510848 . _:b457510849 . _:b457510790 . _:b457510755 . _:b457510850 . . _:b457510851 . _:b457510852 . . _:b457510754 . _:b457510853 . _:b457510854 . _:b457510855 . _:b457510872 . _:b457510873 . . _:b457510765 . _:b457510874 . _:b457510875 . _:b457510876 . _:b457510877 . _:b457510764 . _:b457510878 . _:b457510879 . . _:b457510864 . _:b457510865 . _:b457510767 . _:b457510866 . _:b457510867 . _:b457510868 . . . _:b457510766 . _:b457510869 . _:b457510870 . _:b457510871 . _:b457510824 . _:b457510825 . _:b457510779 . _:b457510761 . _:b457510826 . . _:b457511072 . . _:b457510680 . _:b457510827 . _:b457510828 . . _:b457511121 . _:b457510760 . _:b457510829 . _:b457510830 . . _:b457510831 . _:b457510816 . _:b457510817 . _:b457510763 . _:b457510818 . _:b457510819 . . _:b457510820 . _:b457510821 . _:b457510762 . _:b457510822 . _:b457510823 . . _:b457510840 . _:b457510841 . _:b457510773 . _:b457510842 . . _:b457510843 . _:b457510844 . _:b457510845 . _:b457510772 . _:b457510846 . . _:b457510847 . _:b457510781 . _:b457510503 . _:b457510832 . _:b457510833 . _:b457510775 . _:b457510834 . _:b457510835 . _:b457510836 . _:b457510837 . . _:b457510774 . . _:b457510838 . _:b457510839 . _:b457510792 . . _:b457510793 . _:b457510769 . _:b457510794 . _:b457510795 . _:b457510796 . _:b457510797 . _:b457510768 . _:b457510798 . . _:b457510799 . _:b457510784 . _:b457510785 . _:b457510771 . _:b457510786 . . _:b457510787 . _:b457510788 . _:b457510789 . . _:b457510770 . _:b457510790 . . _:b457510791 . _:b457510808 . _:b457510809 . _:b457511050 . _:b457510781 . _:b457510810 . _:b457510811 . _:b457510451 . _:b457510812 . _:b457510813 . _:b457510780 . _:b457510814 . _:b457510815 . _:b457510800 . _:b457511000 . . _:b457510801 . _:b457510783 . _:b457510512 . _:b457510802 . . _:b457510803 . _:b457510804 . _:b457510805 . _:b457510782 . _:b457510806 . _:b457510807 . _:b457510457 . _:b457510777 . _:b457511198 . . _:b457510776 . _:b457511184 . . . _:b457510779 . _:b457511140 . . . _:b457510778 . _:b457510789 . _:b457510541 . _:b457510853 . _:b457510788 . _:b10409976 "Although it has been suggested that the endosteum is not important for HSC function, it may be too early to dismiss OBs as critical niche components (Kiel et al., 2005; M\u00E9ndez-Ferrer et al., >>2010<<). OBs express several factors important for HSC function, including membrane-bound SCF, and they seem to be the exclusive source of TPO (Arai et al., 2009)." . _:b457511202 . . _:b457510791 . . . _:b457510984 . . _:b457511208 . _:b457510790 . . . _:b457510785 . . _:b457510404 . _:b457510784 . _:b457510787 . _:b457510455 . _:b457510786 . _:b457510797 . . _:b457511189 . _:b457510748 . _:b457510796 . . _:b457510632 . _:b457510799 . _:b457510798 . _:b457510956 . _:b457510793 . _:b457510792 . _:b457510795 . _:b457510714 . _:b10409989 . _:b457510794 . _:b457511136 . _:b457511126 . _:b10409955 . _:b457510805 . _:b457511059 . . _:b457510804 . . _:b457510807 . . _:b457510806 . _:b457510479 . _:b457510801 . _:b457511161 . . . _:b457510800 . . _:b457510433 . _:b457511217 . _:b457510604 . _:b457510803 . . _:b457511007 . . _:b457510802 . _:b457510927 . _:b457510813 . . _:b457511214 . . _:b457510812 . _:b457510815 . _:b457511113 . _:b457510762 . _:b457511148 . _:b457510814 . _:b457510426 . _:b457510809 . _:b457510462 . _:b457510717 . _:b457510808 . _:b457510811 . . . _:b457510810 . . _:b457510821 . _:b457511068 . _:b457510422 . _:b457510820 . . _:b457510823 . _:b457511047 . . _:b10410005 "g-csf induces hsc mobilization by targeting monocytes" . _:b457511159 . _:b457510822 . . _:b457511063 . . _:b10410030 "This provides some explanation as to why G-CSF is a much more effective HSC mobilizer than is phagocyte depletion (Chow et al., >>2011<<)." . _:b457510817 . . _:b457510816 . . . _:b457510819 . _:b457511192 . _:b457510818 . _:b457510421 . _:b457510829 . _:b457511210 . _:b457510828 . _:b457510831 . . . _:b457510830 . _:b457511203 . _:b457510825 . _:b457510824 . _:b10410020 "Although it seems unlikely that these two monocyte populations also contain macrophages, the study by Winkler et al. (>>2010<<) showed that F4/80+ osteomacs, which form a structure similar to a canopy around endosteal OBs, were undetectable as early as 2 d after G-CSF stimulation, returning 4 d after cessation of G-CSF treatment." . . _:b457510827 . _:b457510826 . _:b457510837 . _:b457510836 . _:b457510839 . _:b457510663 . _:b457510838 . _:b457511124 . . _:b457510937 . _:b457510833 . . . . _:b457510636 . _:b457510832 . _:b10409952 . _:b457510835 . _:b457510471 . _:b457510834 . _:b10409954 . _:b457510590 . _:b457510434 . _:b457511065 . _:b457510845 . . . _:b457510844 . _:b457511085 . _:b10409984 "cell types have been experimentally ablated using the DTR or thymidine kinase systems, in none of these experiments (MSC, CAR, or OB) did HSCs disappear completely or become mobilized as a whole (Visnjic et al., 2004; Zhu et al., >>2007<<; M\u00E9ndez-Ferrer et al., 2010; Omatsu et al., 2010). This suggests either that the depletion systems are inefficient or that there is some redundancy in the system (or both)." . _:b10410019 "Christopher et al. (>>2011<<) use flow cytometry to show that inflammatory and resident monocytes were reduced up to fivefold 3 d after G-CSF treatment." . _:b457510847 . _:b10410027 "SNS fibers are intermingled with nestin+ MSCs and inhibit HSC retention by negatively affecting nestin+ MSC activity (Katayama et al., >>2006<<; M\u00E9ndez-Ferrer et al., 2008, 2010)." . _:b457510846 . . _:b457510841 . _:b10409975 "Although it has been suggested that the endosteum is not important for HSC function, it may be too early to dismiss OBs as critical niche components (Kiel et al., >>2005<<; M\u00E9ndez-Ferrer et al., 2010). OBs express several factors important for HSC function, including membrane-bound SCF, and they seem to be the exclusive source of TPO (Arai et al., 2009)." . _:b457510840 . _:b457510843 . _:b10409984 . . _:b457510842 . . _:b457510752 . _:b457510853 . _:b457510592 . _:b457510565 . _:b457510791 . _:b457510852 . . _:b457511008 . _:b457510786 . _:b457510855 . _:b457510688 . . _:b457510854 . _:b457510849 . _:b457511098 . _:b457510724 . _:b457510848 . . _:b457510851 . _:b457510913 . . _:b457510850 . . . _:b457510470 . . _:b457510861 . . . _:b10409989 "be induced to reenter the cell cycle in response to cytokines like type I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., 2009; Foudi et al., >>2009<<; Schaniel and Moore, 2009; Baldridge et al., 2010; Trumpp et al., 2010; Takizawa et al., 2011)." . _:b457510860 . _:b10410018 . _:b457510863 . . . . _:b457511097 . _:b457510862 . _:b457511176 . _:b457510857 . _:b457511212 . . _:b457511112 . _:b457510551 . _:b457511070 . _:b457510856 . _:b457510532 . _:b457510859 . . . _:b10410013 . _:b457510858 . . . _:b457510869 . . _:b457510868 . . _:b457510931 . _:b457510871 . _:b457510730 . _:b457510870 . _:b10409958 "This was the first location to be proposed as the putative HSC niche, and HSCs at the endosteum have subsequently been identified by confocal/two-photon intravital imaging (Lord and Hendry, 1972; Nilsson et al., >>2001<<; Calvi et al., 2003; Zhang et al., 2003)." . _:b457510865 . _:b457511190 . _:b457510759 . _:b457510864 . . _:b457510867 . _:b457510467 . _:b457510866 . _:b457510877 . . _:b10410028 . _:b457511039 . . _:b457510876 . _:b457510496 . . . _:b457510879 . _:b457510878 . _:b457511011 . _:b457510828 . _:b457510873 . _:b457510872 . . _:b457510875 . _:b10409985 . _:b457510874 . _:b457510885 . _:b457510579 . _:b457511015 . . _:b457511053 . _:b457510884 . _:b457510630 . _:b457510887 . . _:b457510859 . . _:b457510886 . _:b457510522 . _:b457510701 . . _:b457511004 . _:b457510411 . . _:b457510881 . _:b457510538 . _:b457510920 . _:b457510829 . . _:b457510880 . . _:b457511160 . _:b457510486 . _:b457510883 . . _:b457510683 . _:b457510882 . _:b457511040 . _:b457510764 . _:b457510893 . . _:b457510492 . . . _:b457510892 . _:b457510895 . . . _:b457510894 . . _:b457510889 . . _:b457510888 . _:b457510584 . _:b457510684 . _:b457510891 . _:b457511023 . _:b457510869 . _:b457510890 . . _:b457510608 . . . _:b457510807 . . _:b457510901 . _:b457510900 . . _:b457510903 . _:b457510438 . _:b10410029 . _:b457510602 . _:b457510902 . _:b457510594 . _:b457510897 . _:b457510896 . . _:b10410026 . _:b457510899 . _:b10410025 . _:b457511141 . . _:b457510898 . . _:b457510448 . _:b457510909 . _:b457510504 . _:b457510908 . . _:b457510911 . . _:b457511026 . _:b457510910 . _:b457510905 . _:b457510442 . _:b457510904 . _:b457510907 . _:b457510906 . _:b457510633 . _:b10409945 "Support for the hypothesis that one cell type is present at various sites within the marrow niche was obtained by a recent landmark study by M\u00E9ndez-Ferrer et al. (>>2010<<). This group identified a stromal nestin-expressing MSC population (nestin+ MSC) that is closely associated with putative HSCs." . . _:b457510405 . . _:b457510404 . _:b10409948 "These cells also seem to mediate the capacity of parathyroid hormone to increase HSC numbers, which had previously been correlated with an increase in putative niche OBs (Calvi et al., >>2003<<; Adams et al., 2007)." . . _:b10410001 "A critical role for monocytes/macrophages was also suggested by Winkler et al. (>>2010<<). After phagocyte depletion using clodronate liposomes or the MAFIA model, they also observed mobilization of functional HSCs with repopulating activity." . _:b457510407 . _:b457510416 . . _:b457510406 . . _:b10409971 "maintenance, including CXCL12, OPN, and N-cadherin, in addition to factors that keep HSCs in a quiescent state, including Ang-1, membrane-bound SCF, and thrombopoietin (TPO; Arai et al., 2004; Yoshihara et al., 2007; Thoren et al., >>2008<<)." . _:b457510403 . _:b457510402 . . _:b457510413 . _:b457510963 . _:b457511089 . _:b457510412 . _:b457511174 . _:b457510947 . . _:b457510415 . . _:b457510414 . . _:b457510409 . _:b10410002 "Most strikingly, clodronate depletion was associated with the loss of F4/80+ macrophages specifically associated with the endosteal lining, which have previously been characterized as osteomacs (Chang et al., >>2008<<; Winkler et al., 2010)." . _:b457510408 . . _:b457510411 . . _:b457511079 . _:b457511168 . _:b457511096 . _:b457510410 . _:b457511165 . . _:b457510421 . _:b457510420 . . . _:b457510423 . _:b457510422 . _:b457510417 . _:b457510723 . _:b457510416 . _:b457510419 . . _:b457510418 . _:b10410026 "Most importantly, the expression of CXCL12, which is not produced by macrophages themselves, decreased by approximately fivefold in nestin+ MSCs in response to G-CSF stimulation (M\u00E9ndez-Ferrer et al., >>2010<<)." . _:b457511061 . . . _:b457510429 . _:b457510543 . _:b457510428 . _:b457510431 . _:b457510430 . . _:b457510425 . _:b457510424 . _:b457510472 . _:b457510427 . . _:b457511038 . _:b457510426 . _:b457510437 . _:b457511064 . _:b457510436 . _:b457510439 . _:b457510438 . _:b457510433 . _:b457510432 . _:b457510692 . _:b457510435 . . _:b457510756 . . _:b457510434 . _:b457510445 . _:b457510444 . _:b10409957 "This was the first location to be proposed as the putative HSC niche, and HSCs at the endosteum have subsequently been identified by confocal/two-photon intravital imaging (Lord and Hendry, >>1972<<; Nilsson et al., 2001; Calvi et al., 2003; Zhang et al., 2003)." . . _:b457510447 . . _:b457510446 . _:b457510897 . _:b457510441 . _:b457510912 . _:b457510440 . _:b10409979 "Importantly, TPO signaling via the c-MPL receptor has been shown to mediate HSC quiescence (Qian et al., 2007; Yoshihara et al., >>2007<<), which is a typical feature of the most potent HSCs in steady-state bone marrow (Wilson et al., 2008)." . . . _:b457510443 . . . _:b457510703 . _:b457510442 . . . _:b457510453 . . . _:b457510409 . _:b457510403 . _:b457510452 . _:b457510455 . _:b457511014 . _:b457510454 . _:b457510765 . . _:b457510449 . . _:b457510961 . . . _:b10409997 . _:b457511164 . _:b457510882 . _:b457510448 . _:b457510925 . . . _:b457510451 . _:b457510902 . . _:b457510450 . _:b457510415 . _:b457510461 . _:b457510773 . . _:b457510460 . _:b457510566 . _:b457510498 . _:b457511012 . _:b457510463 . . _:b10410007 . _:b457510462 . . _:b457510457 . _:b457510456 . _:b457510740 . . . _:b457510624 . _:b10410004 . _:b457510459 . _:b457510458 . _:b10409956 _:b10409988 . _:b10409956 _:b10409989 . . _:b10409956 _:b10409990 . _:b10409956 _:b10409991 . _:b457511162 . _:b457510469 . _:b10409956 _:b10409984 . _:b457511154 . _:b10409956 _:b10409985 . _:b10409956 _:b10409986 . _:b10409956 _:b10409987 . _:b457510468 . _:b10410000 . _:b457510471 . _:b10409956 _:b10409992 . _:b457510420 . _:b10409956 _:b10409993 . _:b10409956 _:b10409994 . _:b457510470 . _:b457510769 . _:b457510495 . _:b457510860 . _:b457510465 . . _:b10410015 . _:b457510464 . _:b10409987 . . _:b457510467 . _:b457510466 . _:b10410017 . . . _:b10410010 . _:b457510477 . _:b457510476 . _:b457510408 . _:b10409986 "using the DTR or thymidine kinase systems, in none of these experiments (MSC, CAR, or OB) did HSCs disappear completely or become mobilized as a whole (Visnjic et al., 2004; Zhu et al., 2007; M\u00E9ndez-Ferrer et al., 2010; Omatsu et al., >>2010<<). This suggests either that the depletion systems are inefficient or that there is some redundancy in the system (or both)." . _:b10410008 . _:b457510479 . _:b457510478 . _:b457510487 . _:b457510473 . _:b457511081 . _:b457510472 . _:b457510475 . . _:b457510839 . . _:b457510474 . . _:b457510938 . _:b457510485 . . _:b10410019 . _:b457510484 . _:b10410016 . _:b457510487 . _:b457510486 . _:b10410030 . _:b457510535 . _:b457511052 . _:b457510481 . . _:b457510480 . . _:b457510483 . _:b457511078 . _:b457510482 . _:b457510493 . _:b457510492 . . _:b457511220 . _:b10410024 . _:b457510495 . _:b457511022 . _:b457510494 . _:b457510431 . _:b457510489 . . _:b457510488 . _:b10409977 "OBs express several factors important for HSC function, including membrane-bound SCF, and they seem to be the exclusive source of TPO (Arai et al., >>2009<<). Importantly, TPO signaling via the c-MPL receptor has been shown to mediate HSC quiescence (Qian et al., 2007; Yoshihara et al., 2007), which is a typical feature of the most potent HSCs in steady-state bone marrow (Wilson et al., 2008)." . _:b457510831 . _:b10409953 . _:b457510491 . _:b457510490 . . _:b457510501 . _:b457510749 . _:b457510500 . . _:b457511178 . _:b457510503 . _:b457510814 . _:b457510685 . _:b457510816 . _:b457510502 . _:b457511082 . _:b10409951 . _:b457510497 . . _:b457510496 . _:b457510709 . _:b457510499 . . . _:b457510498 . _:b10409980 "Importantly, TPO signaling via the c-MPL receptor has been shown to mediate HSC quiescence (Qian et al., 2007; Yoshihara et al., 2007), which is a typical feature of the most potent HSCs in steady-state bone marrow (Wilson et al., >>2008<<). Moreover, although c-MPL\u2212/\u2212 mice are born with normal numbers of HSCs, their frequency progressively declines with age, demonstrating a critical role for OB-derived TPO in adult HSC maintenance in vivo (Qian et al., 2007; Yoshihara et" . . . _:b457510509 . _:b457510707 . . _:b457510637 . . _:b457510508 . . _:b457510511 . . _:b457510446 . _:b457510510 . _:b457510450 . _:b457510598 . _:b457510505 . _:b457510429 . _:b457510402 . . _:b457510647 . _:b457511173 . _:b457510504 . . . _:b457510507 . _:b457511172 . . _:b457510506 . _:b457511175 . _:b457511024 . _:b457510682 . _:b457510669 . . _:b457511174 . _:b457510517 . . _:b457510516 . _:b457511169 . _:b457510519 . _:b457511168 . . . . _:b457510518 . _:b457511171 . . . _:b457510513 . _:b457511170 . . _:b457510512 . _:b457511181 . _:b457511083 . _:b457510515 . _:b457511180 . _:b10410033 "endothelial cells have been suggested to play a role, as they produce angiocrine factors such as Notch ligands, which promote HSC self-renewal and regeneration after bone marrow injury (Butler et al., 2010; Kobayashi et al., >>2010<<). Whether sinusoidal endothelial cells also contribute to G-CSF\u2013mediated mobilization remains to be addressed." . _:b457510674 . _:b457511183 . _:b457510514 . . _:b457510763 . _:b457511182 . _:b457510525 . . _:b457510510 . _:b457510524 . _:b457511177 . _:b457510673 . . _:b457510527 . _:b457511176 . . _:b10409969 . . _:b457510526 . _:b457511179 . . . . _:b457511178 . _:b457510521 . _:b457510757 . . _:b457510559 . _:b457510520 . _:b457511189 . _:b457510858 . _:b457510949 . _:b457510523 . _:b457511188 . _:b457511167 . . _:b457511191 . _:b457510522 . _:b457510412 . _:b457511048 . . _:b457511190 . _:b457510533 . _:b457510554 . . . _:b457510532 . _:b457511185 . . _:b457511184 . _:b457510535 . _:b457510534 . _:b457511187 . _:b10410002 . _:b457510745 . _:b457510529 . _:b457511186 . . _:b457511197 . _:b457511129 . _:b457510528 . . _:b457510774 . _:b457511196 . _:b457510531 . _:b457510530 . _:b457511199 . . _:b457510541 . _:b457511216 . _:b457511198 . . _:b457510540 . _:b457511193 . _:b457511020 . _:b457510531 . _:b457510543 . _:b457511192 . _:b457510542 . _:b457511195 . _:b457510537 . _:b457511194 . _:b457510536 . _:b457511205 . _:b457510622 . . _:b457510539 . _:b10409949 . _:b457511204 . _:b457510538 . _:b457511207 . _:b457511091 . . _:b457510549 . _:b457511206 . . . _:b10409983 "various putative niche cell types have been experimentally ablated using the DTR or thymidine kinase systems, in none of these experiments (MSC, CAR, or OB) did HSCs disappear completely or become mobilized as a whole (Visnjic et al., >>2004<<; Zhu et al., 2007; M\u00E9ndez-Ferrer et al., 2010; Omatsu et al., 2010). This suggests either that the depletion systems are inefficient or that there is some redundancy in the system (or both)." . _:b457510548 . _:b457511201 . _:b457510551 . _:b457511200 . _:b457510581 . _:b457510895 . _:b457510550 . _:b457511203 . . _:b457510545 . _:b457511202 . . . . _:b457510544 . _:b457511213 . . _:b457511219 . _:b457510547 . _:b457511212 . . _:b457510734 . _:b457511025 . . _:b457510943 . _:b457510546 . _:b457511215 . . _:b457510557 . _:b457511214 . . _:b10410023 . _:b457510556 . _:b10409972 "Accordingly, a recent study suggests that osterix+ osteoprogenitors rather than mature osteocalcin+ OBs are required for the integrity of the niche (Raaijmakers et al., >>2010<<). In addition, MSCs seem to express much higher levels of some HSC maintenance factors compared with OBs (CXCL12, SCF, IL-7, VCAM1, and OPN; M\u00E9ndez-Ferrer et al., 2010). However, to what degree the expression levels of these factors" . _:b457511209 . _:b457510559 . _:b457511208 . _:b457510702 . . . _:b457510558 . _:b457511211 . _:b10409973 "In addition, MSCs seem to express much higher levels of some HSC maintenance factors compared with OBs (CXCL12, SCF, IL-7, VCAM1, and OPN; M\u00E9ndez-Ferrer et al., >>2010<<). However, to what degree the expression levels of these factors influence niche activity remains unclear. Importantly, sinusoidal endothelium with associated MSC/CAR cells is also found directly at the endosteum. This raises the" . _:b457510553 . _:b457511210 . _:b457510552 . _:b457511221 . _:b457510555 . _:b457511220 . _:b457511105 . . _:b457510554 . _:b457511223 . _:b457510827 . _:b457510599 . _:b457510423 . . _:b457510565 . _:b457511222 . . _:b457510789 . _:b457510564 . _:b457511217 . _:b457510567 . _:b457511216 . . _:b457510566 . _:b457511219 . _:b457510655 . _:b457510914 . _:b457510561 . _:b457511218 . _:b10409988 . _:b457510560 . _:b457511229 . _:b457510933 . _:b10409989 . _:b457510563 . _:b457511228 . _:b457511152 . _:b10409990 . _:b457510562 . _:b457511231 . _:b10409991 . _:b457510573 . _:b457511230 . _:b10409951 "Most interestingly, nestin+ MSCs show several similarities to recently identified mesenchymal progenitors (Sugiyama et al., >>2006<<; Omatsu et al., 2010). These bipotent adipoosteogenic progenitors were identified in a mouse strain in which GFP was expressed from the endogenous CXCL12 locus (Sugiyama et al., 2006; Omatsu et al., 2010)." . _:b10409984 . _:b457510572 . _:b457511225 . _:b10409985 . _:b457510575 . _:b457511224 . . _:b10409986 . _:b457510574 . _:b457511227 . _:b10409987 . _:b457510569 . _:b457511226 . _:b10409996 . _:b457510568 . _:b457510603 . _:b10409997 . _:b457510571 . _:b10409998 . _:b457510570 . _:b10409999 . _:b457510581 . _:b457510585 . _:b457510836 . _:b10409992 . _:b457510580 . . _:b457510534 . _:b457510917 "2"^^ . . _:b457510916 . _:b10409993 . _:b457510583 . _:b457511232 . _:b457510939 . . _:b457510916 "2"^^ . _:b10409994 . _:b457510582 . _:b457510919 "2"^^ . _:b457510575 . _:b457510577 . _:b10409995 . _:b457510918 "2"^^ . _:b457510911 . _:b457511066 . _:b10410004 . _:b457510576 . _:b457510776 . _:b457510913 "2"^^ . _:b457510579 . _:b10410005 . _:b457510912 "2"^^ . _:b457511001 . _:b10410006 . _:b457510578 . _:b457510915 "2"^^ . _:b10410007 . _:b457510589 . _:b457510435 . _:b457510690 . _:b457510914 "2"^^ . _:b10410000 . _:b457510588 . . _:b457510925 "2"^^ . _:b10410014 "(neutrophil elastase, cathepsin G, and MMP9), which were previously thought to be the main drivers of HSC mobilization in response to G-CSF (L\u00E9vesque et al., 2001; Heissig et al., 2002; Petit et al., 2002; Christopherson et al., >>2003<<). Although not excluding a contribution of neutrophils to G-CSF\u2013induced mobilization, Christopher et al. (2011) demonstrate that monocytic cells are the key player in this process, at least in mice." . _:b10410001 . _:b457510591 . _:b457510924 "2"^^ . _:b10410002 . _:b457510590 . _:b457510927 "2"^^ . _:b10410032 . _:b10410003 . . _:b457510811 . _:b457510585 . _:b457510926 "2"^^ . _:b457511087 . _:b10410012 . _:b457510584 . _:b10409947 . . _:b457510921 "2"^^ . _:b10410013 . _:b457510587 . _:b457510920 "2"^^ . _:b10410014 . _:b457510586 . _:b457510923 "2"^^ . . _:b10410015 . _:b457510597 . . . _:b457510552 . _:b457510922 "2"^^ . _:b10410008 . _:b457510596 . _:b457510933 "2"^^ . _:b10410009 . _:b457510599 . _:b457510932 "2"^^ . _:b10410010 . _:b457510598 . _:b457510935 "2"^^ . _:b457511182 . . _:b10410011 . _:b457510593 . _:b457510934 "2"^^ . _:b457510475 . . _:b10410020 . _:b457510592 . _:b457510929 "2"^^ . _:b457511067 . _:b457510668 . _:b10410021 . . . _:b457510595 . _:b457510843 . _:b457510928 "2"^^ . _:b457510519 . _:b457510689 . _:b10410022 . _:b457510594 . _:b457510999 . . _:b457510931 "2"^^ . _:b457510580 . _:b10410023 . _:b457510605 . _:b457510930 "2"^^ . . _:b457511054 . _:b10410016 . _:b457510604 . _:b457511051 . _:b457510941 "2"^^ . _:b10410017 . _:b457510607 . _:b457510652 . _:b457510940 "2"^^ . _:b10410018 . _:b457510606 . _:b457510743 . _:b457510943 "2"^^ . . _:b10410019 . _:b457510601 . _:b457510942 "2"^^ . . _:b457510872 . _:b10410029 "SNS fibers are intermingled with nestin+ MSCs and inhibit HSC retention by negatively affecting nestin+ MSC activity (Katayama et al., 2006; M\u00E9ndez-Ferrer et al., 2008, >>2010<<). The G-CSF\u2013mediated increase in sympathetic tone promotes progenitor cell egress, and thus represents a macrophage/monocyte-independent pathway for G-CSF\u2013mediated mobilization. This provides some explanation as to why G-CSF is a much" . _:b10410028 . _:b457510600 . _:b457510937 "2"^^ . _:b457510930 . _:b10410029 . _:b457511110 . _:b457510603 . _:b457510936 "2"^^ . _:b10409981 "Moreover, although c-MPL\u2212/\u2212 mice are born with normal numbers of HSCs, their frequency progressively declines with age, demonstrating a critical role for OB-derived TPO in adult HSC maintenance in vivo (Qian et al., >>2007<<; Yoshihara et al., 2007)." . _:b10410030 . _:b457510602 . _:b457510439 . . _:b457510939 "2"^^ . . _:b457510613 . _:b10410031 . . _:b10409970 . _:b457510938 "2"^^ . . _:b10410024 . . _:b457510612 . _:b457510894 . _:b457510949 "2"^^ . _:b457510556 . _:b10410025 . _:b457511092 . _:b457510615 . _:b10410031 . _:b457510948 "2"^^ . _:b10410026 . _:b457510614 . _:b10409981 . . _:b457510951 "2"^^ . . _:b10410027 . . _:b457510609 . . _:b10409982 . _:b457510950 "2"^^ . . _:b457510517 . _:b457510608 . _:b457511049 . _:b457510945 "2"^^ . _:b457510611 . _:b457510924 . . _:b457510944 "2"^^ . _:b457510610 . _:b457510947 "2"^^ . _:b10410005 . . _:b457510616 . _:b457510621 . _:b10409978 . _:b457510605 . _:b457510946 "2"^^ . _:b10410032 . _:b457510620 . _:b10409995 . _:b457510957 "2"^^ . _:b10409979 . _:b10410033 . _:b457510623 . _:b457510956 "2"^^ . _:b10410034 . _:b457510622 . _:b457510959 "2"^^ . _:b457510761 . _:b457510618 . _:b10410035 . _:b457510617 . _:b457510958 "2"^^ . _:b457510616 . _:b457510953 "2"^^ . _:b457510619 . _:b457510524 . _:b457510952 "2"^^ . _:b457510618 . _:b457510570 . _:b457510955 "2"^^ . . _:b457510629 . _:b457510909 . _:b457510954 "2"^^ . _:b457510903 . _:b457510628 . _:b457510965 "2"^^ . _:b457510631 . . _:b457510964 "2"^^ . . . _:b457510630 . _:b457510967 "2"^^ . . . _:b457510625 . _:b457510966 "2"^^ . _:b457510624 . . _:b457510961 "2"^^ . _:b457510627 . _:b457510960 "2"^^ . _:b457510626 . . _:b457510963 "2"^^ . . _:b457510637 . _:b457510962 "2"^^ . _:b457510705 . _:b457510636 . _:b457510635 . _:b457510973 "2"^^ . _:b457510639 . _:b457510972 "2"^^ . _:b457510638 . _:b457510975 "2"^^ . _:b457511191 . _:b457510633 . _:b457510974 "2"^^ . _:b457510632 . _:b457510969 "2"^^ . . _:b457510635 . _:b457510968 "2"^^ . _:b457510634 . _:b457510971 "2"^^ . _:b457511137 . _:b457510645 . . _:b457510970 "2"^^ . . "10.1084%2Fjem.20110132" . _:b457510644 . _:b457511207 . _:b457510981 "2"^^ . _:b457510647 . _:b457510980 "2"^^ . _:b457510646 . _:b457510611 . _:b457510983 "2"^^ . _:b10409991 "to cytokines like type I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., 2009; Foudi et al., 2009; Schaniel and Moore, 2009; Baldridge et al., >>2010<<; Trumpp et al., 2010; Takizawa et al., 2011). Thus, we postulate the existence of two highly similar niches, one harboring dormant HSCs and one housing self-renewing HSCs (Fig." . _:b457510641 . _:b457510982 "2"^^ . _:b457510640 . _:b457510977 "2"^^ . _:b457511180 . _:b457510643 . _:b457510629 . _:b457510976 "2"^^ . _:b457510642 . _:b457510948 . _:b457510979 "2"^^ . _:b457510653 . _:b457510978 "2"^^ . _:b457510540 . _:b457510652 . . _:b457510989 "2"^^ . _:b457510923 . _:b457510488 . _:b457510655 . _:b457511055 . _:b457510988 "2"^^ . _:b457510654 . _:b457510820 . _:b457510991 "2"^^ . . . _:b10410034 "A recent study suggested that adipocytes, another cell type produced by MSCs, have an adverse effect on HSC maintenance (Naveiras et al., >>2009<<). Finally, models suggesting the existence of two distinct HSC niches in the bone marrow remain to be experimentally confirmed (Fig. 2; Trumpp et al., 2010). Although such a model would incorporate the currently available data about the" . _:b457510649 . . . _:b457510990 "2"^^ . _:b457510505 . _:b457510648 . _:b457510985 "2"^^ . . . _:b457510651 . _:b457510984 "2"^^ . _:b457510650 . _:b457510987 "2"^^ . _:b457510986 "2"^^ . _:b457510997 "2"^^ . . . _:b457510881 . _:b457510996 "2"^^ . _:b457510631 . _:b457510889 . _:b457510999 "2"^^ . . _:b457511071 . _:b457510998 "2"^^ . . _:b457511227 . _:b457510993 "2"^^ . _:b457510992 "2"^^ . . _:b457510995 "2"^^ . . _:b457510994 "2"^^ . _:b457511005 "2"^^ . _:b457510644 . . _:b457511004 "2"^^ . . . _:b457511007 "2"^^ . . _:b457511006 "2"^^ . _:b457511186 . _:b457510818 . . _:b457510957 . _:b457511001 "2"^^ . . _:b457511000 "2"^^ . _:b10409948 . _:b457510866 . _:b457511003 "2"^^ . . _:b10409949 . . _:b457511002 "2"^^ . _:b457510954 . _:b10409950 . . _:b457511013 "2"^^ . _:b10409951 . _:b457511012 "2"^^ . _:b10409944 . _:b457511015 "2"^^ . _:b10409945 . _:b457511014 "2"^^ . _:b10409946 . _:b457510952 . _:b457511009 "2"^^ . . _:b10409947 . . _:b457511008 "2"^^ . _:b10409956 . _:b457511011 "2"^^ . _:b10409957 . . . _:b457510671 . _:b457511010 "2"^^ . _:b10409958 . _:b457511021 "2"^^ . _:b10409959 . _:b457511223 . _:b457511020 "2"^^ . _:b10409952 . _:b457511023 "2"^^ . _:b10409953 . _:b457511022 "2"^^ . _:b10409954 . . . _:b457511017 "2"^^ . . . _:b457511119 . _:b10409955 . _:b457511016 "2"^^ . _:b457510738 . _:b10409964 . . . . _:b457511019 "2"^^ . . _:b10409965 . _:b457511200 . . _:b457510728 . . _:b457511018 "2"^^ . _:b457511157 . _:b10409966 . . _:b457510809 . _:b457511029 "2"^^ . _:b10409967 . _:b457510697 . _:b457511127 . _:b457511028 "2"^^ . _:b10409960 . _:b457511031 "2"^^ . _:b10409961 . . . _:b457511030 "2"^^ . . . _:b10409962 . . _:b457510612 . . _:b457511025 "2"^^ . _:b10409963 . . _:b457510819 . _:b457511024 "2"^^ . _:b10409972 . _:b457510751 . . _:b457511027 "2"^^ . _:b457511183 . _:b10409973 . . _:b457511026 "2"^^ . _:b10409974 . . _:b457510679 . _:b457511037 "2"^^ . _:b10409975 . . . _:b457511036 "2"^^ . _:b10409968 . . _:b457510805 . _:b457511039 "2"^^ . _:b10409969 . _:b457511038 "2"^^ . _:b10409970 . . . _:b457511033 "2"^^ . . . _:b10409971 . _:b457511032 "2"^^ . _:b10409980 . _:b457511035 "2"^^ . _:b10409981 . _:b457511034 . _:b457511034 "2"^^ . . _:b10409982 . . _:b457511045 "2"^^ . _:b457511031 . . _:b10409983 . _:b457511044 "2"^^ . _:b10409976 . _:b457511047 "2"^^ . _:b457511139 . _:b10409977 . _:b457510767 . . _:b457511046 "2"^^ . _:b457510706 . _:b10409978 . . _:b457511156 . _:b457510653 . _:b457511041 "2"^^ . _:b10409979 . . _:b457511040 "2"^^ . _:b457510833 . _:b457511043 "2"^^ . _:b457511042 "2"^^ . _:b457511053 "2"^^ . . _:b457510955 . _:b457511052 "2"^^ . _:b457511003 . . _:b457511055 "2"^^ . . . _:b457511054 "2"^^ . . . _:b457511049 "2"^^ . _:b457511048 "2"^^ . _:b457511051 "2"^^ . _:b457511050 "2"^^ . _:b10409990 . _:b457511061 "2"^^ . _:b457511226 . _:b457511032 . _:b457511060 "2"^^ . _:b457510875 . _:b457511063 "2"^^ . _:b457511062 "2"^^ . _:b457510402 "29"^^ . _:b457511194 . _:b457511057 "2"^^ . _:b457510403 "20"^^ . _:b457510484 . _:b457511056 "2"^^ . _:b457510440 . _:b457510885 . _:b457511059 "2"^^ . _:b457510544 . _:b457510404 "18"^^ . . _:b457510848 . _:b457511058 "2"^^ . _:b457510405 "16"^^ . _:b457510676 . _:b457510491 . . . _:b457510406 "15"^^ . _:b457511069 "2"^^ . _:b10409967 . _:b457510407 "15"^^ . _:b457511068 "2"^^ . _:b457510741 . . _:b457510959 . _:b457511071 "2"^^ . _:b457510414 "10"^^ . . _:b457511070 "2"^^ . _:b457510978 . _:b457510987 . _:b457510415 "9"^^ . . _:b457510413 "10"^^ . _:b10409968 . _:b457511065 "2"^^ . _:b457510627 . . . _:b457510412 "11"^^ . _:b457511064 "2"^^ . _:b457510411 "11"^^ . _:b457511067 "2"^^ . _:b457510410 "11"^^ . _:b10410009 "This method has been used for many years to harvest functional HSCs for stem cell transplantation (Gertz, >>2010<<), but the cellular and molecular mechanisms for this striking indirect effect (HSCs do not express G-CSF receptor) remain poorly understood." . _:b457511066 "2"^^ . . _:b457511077 "2"^^ . _:b457510409 "12"^^ . _:b457511076 "2"^^ . _:b457510408 "13"^^ . _:b457510993 . . _:b457511079 "2"^^ . _:b457510422 "8"^^ . _:b457510423 "7"^^ . _:b457511078 "2"^^ . . _:b457511073 "2"^^ . _:b457510420 "8"^^ . _:b457511072 "2"^^ . _:b457510421 "8"^^ . _:b457511075 "2"^^ . . _:b457510418 "9"^^ . _:b10410008 "The recent studies also addressed the mechanism of G-CSF\u2013induced mobilization of HSCs into the peripheral blood (Winkler et al., 2010; Chow et al., 2011; Christopher et al., >>2011<<). This method has been used for many years to harvest functional HSCs for stem cell transplantation (Gertz, 2010), but the cellular and molecular mechanisms for this striking indirect effect (HSCs do not express G-CSF receptor) remain" . _:b457511074 "2"^^ . _:b457510466 . _:b457510419 "8"^^ . _:b457510596 . . _:b457511085 "2"^^ . _:b457510416 "9"^^ . _:b457511084 "2"^^ . _:b457511099 . _:b457510417 "9"^^ . _:b457510430 "6"^^ . _:b457510638 . _:b457511087 "2"^^ . _:b10409947 "associated with adrenergic nerve fibers of the sympathetic nervous system (SNS) that regulate HSC mobilization and are responsible for the circadian oscillations in circulating HSC numbers (Katayama et al., 2006; M\u00E9ndez-Ferrer et al., >>2008<<). Strikingly, these MSCs express higher levels of HSC maintenance factor transcripts, including CXCL12, stem cell factor (SCF), angiopoietin-1 (Ang-1), IL-7, vascular cell adhesion molecule 1 (VCAM1), and osteopontin (OPN), compared with" . _:b457511166 . _:b457510431 "6"^^ . . _:b457511086 "2"^^ . _:b457510428 "6"^^ . _:b10410003 "Most strikingly, clodronate depletion was associated with the loss of F4/80+ macrophages specifically associated with the endosteal lining, which have previously been characterized as osteomacs (Chang et al., 2008; Winkler et al., >>2010<<). The loss of phagocytes caused a significant decrease in osteoblastic activity at the bone surface, as the proportion of bone surface lined with OBs and the amount of newly formed bone matrix decreased." . _:b457510693 . _:b457511081 "2"^^ . . _:b457510429 "6"^^ . _:b457510874 . _:b457511080 "2"^^ . . . _:b457510426 "7"^^ . _:b457511083 "2"^^ . _:b457511035 . _:b457510501 . _:b457510425 . _:b457510427 "7"^^ . _:b457511082 "2"^^ . . _:b457510424 "7"^^ . _:b457511093 "2"^^ . _:b457510425 "7"^^ . _:b457511092 "2"^^ . _:b457510991 . _:b457510438 "6"^^ . _:b457511084 . _:b457511095 "2"^^ . _:b457510439 "6"^^ . _:b457511094 "2"^^ . _:b457511179 . _:b457510436 "6"^^ . _:b457511089 "2"^^ . _:b457510437 "6"^^ . _:b457510857 . _:b457511088 "2"^^ . _:b457510434 "6"^^ . . _:b457511091 "2"^^ . _:b457511231 . _:b457510435 "6"^^ . _:b457510726 . . _:b457511090 "2"^^ . _:b457510432 "6"^^ . . _:b457511101 "2"^^ . _:b457510747 . _:b457510433 "6"^^ . _:b457511100 "2"^^ . _:b10409970 "in HSC retention and maintenance, including CXCL12, OPN, and N-cadherin, in addition to factors that keep HSCs in a quiescent state, including Ang-1, membrane-bound SCF, and thrombopoietin (TPO; Arai et al., 2004; Yoshihara et al., >>2007<<; Thoren et al., 2008)." . _:b457511103 "2"^^ . _:b457511201 . _:b10410013 "and neutrophil-derived proteases (neutrophil elastase, cathepsin G, and MMP9), which were previously thought to be the main drivers of HSC mobilization in response to G-CSF (L\u00E9vesque et al., 2001; Heissig et al., 2002; Petit et al., >>2002<<; Christopherson et al., 2003). Although not excluding a contribution of neutrophils to G-CSF\u2013induced mobilization, Christopher et al. (2011) demonstrate that monocytic cells are the key player in this process, at least in mice." . _:b457510445 "5"^^ . _:b457510428 . _:b457511102 "2"^^ . _:b457510444 "5"^^ . _:b457510917 . _:b457511097 "2"^^ . . _:b457510447 "5"^^ . _:b457510916 . _:b457511096 "2"^^ . _:b457510446 "5"^^ . _:b457510919 . . _:b457511099 "2"^^ . _:b457510441 "5"^^ . _:b457510918 . _:b457511098 "2"^^ . . _:b457510440 "5"^^ . _:b457510913 . _:b457511109 "2"^^ . _:b457510443 "5"^^ . _:b457510912 . _:b457511108 "2"^^ . _:b457510456 . _:b457510442 "5"^^ . _:b457510915 . _:b457511111 "2"^^ . _:b457511147 . _:b457510453 "5"^^ . _:b457510914 . . _:b457511110 "2"^^ . . . _:b457510452 "5"^^ . _:b457510925 . _:b10409995 "macrophages join the niche" . _:b457511105 "2"^^ . _:b457510455 "5"^^ . _:b457510924 . _:b457511104 "2"^^ . _:b457510454 "5"^^ . _:b457510927 . _:b457511107 "2"^^ . _:b457510941 . _:b457510449 "5"^^ . _:b457510926 . _:b457510901 . _:b457511106 "2"^^ . _:b457510448 "5"^^ . _:b457510921 . _:b457511117 "2"^^ . _:b457510451 "5"^^ . . . _:b457510920 . _:b457511116 "2"^^ . _:b457510664 . _:b457510450 "5"^^ . _:b457510923 . _:b457511119 "2"^^ . . _:b457510461 "5"^^ . _:b457510922 . _:b457511118 "2"^^ . _:b457510675 . _:b457510460 "5"^^ . . _:b457510933 . _:b457510835 . . _:b457511113 "2"^^ . _:b457510463 "5"^^ . . _:b457510932 . _:b457511112 "2"^^ . _:b457510462 "5"^^ . _:b457510935 . . _:b457511115 "2"^^ . _:b457510457 "5"^^ . . _:b457510934 . _:b457510893 . _:b457511114 "2"^^ . _:b457510456 "5"^^ . _:b457510929 . _:b457511125 "2"^^ . _:b457510459 "5"^^ . _:b457510483 . _:b457510928 . _:b457511124 "2"^^ . _:b457510458 "5"^^ . _:b457510931 . . _:b457511127 "2"^^ . _:b457510469 "5"^^ . . _:b457510930 . _:b457511126 "2"^^ . _:b457510468 "5"^^ . . _:b457510941 . . _:b457511121 "2"^^ . . _:b457510471 "4"^^ . _:b457510940 . _:b457511120 "2"^^ . _:b457510470 "4"^^ . . . _:b457510943 . _:b457511123 "2"^^ . . _:b457510465 "5"^^ . . _:b457510942 . . _:b457511122 "2"^^ . . _:b457510464 "5"^^ . _:b457510452 . _:b457510937 . _:b457511133 "2"^^ . _:b457510794 . _:b457510467 "5"^^ . _:b457510936 . . _:b457511132 "2"^^ . _:b457510466 "5"^^ . _:b457510968 . _:b457510939 . . _:b457511135 "2"^^ . _:b457510477 "4"^^ . . _:b457510938 . _:b457511134 "2"^^ . _:b457510476 "4"^^ . _:b10409961 . _:b457510460 . _:b457510949 . . _:b457511129 "2"^^ . _:b457510479 "4"^^ . _:b457510798 . _:b457510948 . _:b457511128 "2"^^ . _:b457510478 "4"^^ . _:b457510951 . _:b457511131 "2"^^ . _:b457510473 "4"^^ . _:b457510950 . _:b457510660 . _:b457511130 "2"^^ . . _:b457510472 "4"^^ . _:b10409959 "This was the first location to be proposed as the putative HSC niche, and HSCs at the endosteum have subsequently been identified by confocal/two-photon intravital imaging (Lord and Hendry, 1972; Nilsson et al., 2001; Calvi et al., >>2003<<; Zhang et al., 2003). HSCs isolated from endosteal regions by FACS show higher reconstitution activity compared with phenotypically identical cells from the center of the bone marrow (Grassinger et al., 2010)." . _:b457510945 . _:b457511074 . _:b457511141 "2"^^ . _:b457511128 . _:b457510475 "4"^^ . _:b457510944 . _:b457511140 "2"^^ . _:b457510474 "4"^^ . . _:b457511042 . _:b457510947 . _:b457511143 "2"^^ . _:b457510485 "4"^^ . . . _:b457510946 . _:b457511142 "2"^^ . _:b457510484 "4"^^ . _:b457510957 . _:b457511137 "2"^^ . _:b457510487 "4"^^ . _:b10409966 . . . _:b457510956 . _:b457511136 "2"^^ . _:b10410010 "Christopher et al. (>>2011<<) show that G-CSF receptor expression on cells of the monocytic lineage is sufficient for G-CSF\u2013induced mobilization of HSCs (Fig." . _:b457510486 "4"^^ . . . _:b457510959 . _:b457511139 "2"^^ . _:b457510481 "4"^^ . . _:b457510958 . . _:b457511138 "2"^^ . _:b457510480 "4"^^ . _:b457510953 . . _:b457511149 "2"^^ . _:b457510483 "4"^^ . _:b457510952 . . _:b457511148 "2"^^ . _:b457511090 . _:b457510482 "4"^^ . _:b10409969 "are known to be involved in HSC retention and maintenance, including CXCL12, OPN, and N-cadherin, in addition to factors that keep HSCs in a quiescent state, including Ang-1, membrane-bound SCF, and thrombopoietin (TPO; Arai et al., >>2004<<; Yoshihara et al., 2007; Thoren et al., 2008)." . _:b457510955 . _:b457511151 "2"^^ . _:b457510493 "4"^^ . . _:b457510954 . _:b457511150 "2"^^ . _:b457510492 "4"^^ . _:b457511134 . _:b457510965 . _:b457511145 "2"^^ . _:b457510495 "4"^^ . _:b457510964 . _:b457511144 "2"^^ . _:b457510494 "4"^^ . _:b457510967 . . _:b457511147 "2"^^ . . . _:b457510489 "4"^^ . . _:b10409998 "Because CXCL12-mediated activation of the CXCR4 receptor on HSCs is a critical niche retention signal (Lapidot and Petit, >>2002<<; Broxmeyer, 2008), these data provide a plausible explanation for the phenotype observed in these mice." . _:b457510966 . _:b457511146 "2"^^ . _:b457510488 "4"^^ . . _:b457510961 . _:b457511157 "2"^^ . _:b457510491 "4"^^ . _:b457510960 . _:b457511156 "2"^^ . _:b457510490 "4"^^ . _:b457510963 . _:b457510478 . _:b457511159 "2"^^ . . _:b457510715 . _:b457510501 "4"^^ . _:b457510490 . . _:b457510962 . _:b457511158 "2"^^ . _:b457510500 "4"^^ . . _:b457510973 . _:b457511153 "2"^^ . _:b457510503 "4"^^ . . _:b457510972 . _:b457511152 "2"^^ . _:b457510502 "4"^^ . . _:b457510975 . _:b457511155 "2"^^ . _:b457510497 "4"^^ . _:b457510864 . _:b457510974 . _:b457511154 "2"^^ . _:b457510496 "4"^^ . _:b457510539 . _:b457510868 . _:b457510969 . _:b457511165 "2"^^ . _:b457510499 "4"^^ . . _:b10410031 "the hsc niche unit" . _:b457510968 . _:b457511164 "2"^^ . _:b457510498 "4"^^ . _:b457510558 . . . _:b457511150 . . _:b457510971 . _:b457511167 "2"^^ . _:b457510509 "4"^^ . . _:b457510564 . _:b457510970 . _:b457511166 "2"^^ . _:b457510508 "4"^^ . . _:b457510981 . _:b457511135 . _:b457511161 "2"^^ . _:b457510511 "4"^^ . _:b457510980 . _:b457511006 . _:b457511160 "2"^^ . _:b457510510 "4"^^ . _:b457510983 . _:b457511163 "2"^^ . _:b457510505 "4"^^ . . _:b457510982 . . _:b457511162 "2"^^ . _:b457510504 "4"^^ . _:b457510988 . . . _:b457510977 . _:b457511173 "2"^^ . _:b457510507 "4"^^ . _:b457510976 . _:b10410015 "Although not excluding a contribution of neutrophils to G-CSF\u2013induced mobilization, Christopher et al. (>>2011<<) demonstrate that monocytic cells are the key player in this process, at least in mice." . _:b457511172 "2"^^ . _:b457510506 "4"^^ . _:b457510436 . _:b457510733 . _:b457510979 . . _:b457511175 "2"^^ . _:b457510517 "4"^^ . _:b457510978 . _:b457511174 "2"^^ . _:b457510516 "4"^^ . _:b457510989 . _:b457511028 . _:b457511169 "2"^^ . _:b457510519 "4"^^ . _:b457510427 . _:b457511173 . _:b457510988 . . _:b457511168 "2"^^ . _:b457510518 "4"^^ . _:b457510735 . _:b457510862 . . _:b457510991 . . _:b457511171 "2"^^ . _:b457510513 "4"^^ . _:b457510990 . . _:b457511170 "2"^^ . _:b457510512 "4"^^ . . _:b457510985 . _:b457511181 "2"^^ . _:b457510515 "4"^^ . . _:b457510984 . _:b457511180 "2"^^ . _:b457510514 "4"^^ . _:b457510962 . _:b457510987 . _:b457510525 "3"^^ . _:b457511183 "2"^^ . . _:b457510986 . _:b457510524 "3"^^ . _:b457511182 "2"^^ . . _:b457510997 . _:b457510527 "3"^^ . _:b457511177 "2"^^ . _:b457510770 . _:b457510996 . _:b457510526 "3"^^ . _:b457511176 "2"^^ . . _:b457510999 . . _:b457511179 "2"^^ . _:b457510521 "4"^^ . . . _:b457510841 . _:b457510998 . . _:b457511178 "2"^^ . _:b457510520 "4"^^ . _:b457510993 . _:b457510523 "3"^^ . _:b457511189 "2"^^ . _:b457510992 . _:b457511188 "2"^^ . _:b457510522 "4"^^ . _:b457510713 . _:b10409965 "of OBs causes mobilization of HSCs/progenitors to the spleen, and some genetically modified mice with augmented OBs show a simultaneous increase in HSC numbers (Calvi et al., 2003; Zhang et al., 2003; Visnjic et al., 2004; Zhu et al., >>2007<<). Furthermore, a population of CD45\u2212CD105+ osteoprogenitor cells from fetal long bone or calvaria is sufficient to generate an HSC niche when transplanted under the kidney capsule (Chan et al., 2009)." . _:b457510995 . _:b457510533 "3"^^ . _:b457511191 "2"^^ . . _:b457510994 . _:b457510532 "3"^^ . _:b457511190 "2"^^ . _:b457511005 . _:b457510535 "3"^^ . _:b457511185 "2"^^ . _:b457510493 . _:b457511004 . _:b457511205 . _:b457510534 "3"^^ . _:b457511184 "2"^^ . _:b457511007 . _:b457510529 "3"^^ . _:b457511187 "2"^^ . _:b457511006 . _:b457510528 "3"^^ . _:b457511186 "2"^^ . _:b457510449 . _:b457511001 . _:b457510531 "3"^^ . _:b457511197 "2"^^ . _:b457511000 . _:b457510530 "3"^^ . _:b457511199 . _:b457511196 "2"^^ . _:b457510686 . _:b457511003 . _:b457510541 "3"^^ . _:b457511199 "2"^^ . _:b457510750 . _:b10409968 "calcium ion receptor, which has been demonstrated to be important for HSC engraftment at the endosteum by enabling HSCs to follow the Ca2+ gradient that results from bone remodeling processes occurring at the endosteum (Adams et al., >>2006<<). Finally, OBs produce factors that are known to be involved in HSC retention and maintenance, including CXCL12, OPN, and N-cadherin, in addition to factors that keep HSCs in a quiescent state, including Ang-1, membrane-bound SCF, and" . _:b457510846 . . _:b457511002 . . _:b457511198 "2"^^ . _:b457510540 "3"^^ . _:b457511088 . _:b457511013 . _:b457510543 "3"^^ . _:b457511193 "2"^^ . _:b457510513 . . _:b457511012 . . _:b457511192 "2"^^ . _:b457510542 "3"^^ . _:b457510545 . _:b10410009 . _:b457510772 . _:b457511015 . . _:b457511195 "2"^^ . _:b457510537 "3"^^ . _:b457511014 . _:b457510536 "3"^^ . _:b457511194 "2"^^ . . _:b457511009 . _:b10409963 "Induced depletion of OBs causes mobilization of HSCs/progenitors to the spleen, and some genetically modified mice with augmented OBs show a simultaneous increase in HSC numbers (Calvi et al., 2003; Zhang et al., >>2003<<; Visnjic et al., 2004; Zhu et al., 2007)." . _:b457510539 "3"^^ . _:b457511205 "2"^^ . _:b457511008 . _:b457510538 "3"^^ . _:b457511204 "2"^^ . _:b457511011 . _:b10409965 . _:b457510549 "3"^^ . _:b457511207 "2"^^ . . . . . _:b457511010 . _:b457510917 . _:b457510548 "3"^^ . _:b457511206 "2"^^ . . _:b457511021 . _:b457510551 "3"^^ . _:b457511201 "2"^^ . _:b457511020 . _:b457510550 "3"^^ . _:b457511200 "2"^^ . . _:b457510936 . _:b457511023 . _:b457510678 . _:b457511213 . _:b457511203 "2"^^ . . _:b457510545 "3"^^ . _:b457511022 . _:b457510544 "3"^^ . _:b457511202 "2"^^ . _:b457510758 . . _:b457511017 . _:b457510547 "3"^^ . _:b457511213 "2"^^ . _:b457511016 . _:b457511044 . _:b457510546 "3"^^ . _:b457511212 "2"^^ . _:b457510700 . _:b457511019 . . _:b457511215 "2"^^ . . _:b457510557 "3"^^ . _:b457510613 . _:b457510746 . _:b457511018 . _:b457510556 "3"^^ . _:b457511214 "2"^^ . _:b457510985 . . _:b457511029 . _:b457510559 "3"^^ . _:b457511209 "2"^^ . _:b457511028 . _:b457510558 "3"^^ . _:b457511208 "2"^^ . . _:b457511031 . _:b457510553 "3"^^ . _:b457511211 "2"^^ . _:b457510995 . _:b457511030 . _:b457510552 "3"^^ . _:b457511210 "2"^^ . _:b457510744 . _:b457511025 . _:b457510555 "3"^^ . _:b457511221 "2"^^ . _:b457511024 . _:b457510554 "3"^^ . _:b457511220 "2"^^ . _:b457511027 . _:b457510565 "3"^^ . _:b457511223 "2"^^ . _:b457511026 . _:b457510564 "3"^^ . _:b457511222 "2"^^ . . . _:b457511037 . _:b457510567 "3"^^ . _:b457511217 "2"^^ . _:b457510950 . _:b457510915 . _:b457511036 . _:b457510566 "3"^^ . _:b10409954 "These bipotent adipoosteogenic progenitors were identified in a mouse strain in which GFP was expressed from the endogenous CXCL12 locus (Sugiyama et al., 2006; Omatsu et al., >>2010<<). Because of their high CXCL12 expression and their long cellular processes, these cells were named CXCL12-abundant reticular (CAR) cells. The majority of putative HSCs are found in close proximity to CAR cells by immunohistochemistry," . _:b457511216 "2"^^ . _:b10409991 . _:b457511039 . _:b457510561 "3"^^ . _:b457511219 "2"^^ . _:b457510695 . _:b457511038 . _:b457510560 "3"^^ . _:b457511218 "2"^^ . _:b457510801 . _:b457511033 . _:b457510563 "3"^^ . _:b457511229 "2"^^ . . _:b457511032 . _:b457510562 "3"^^ . _:b457511228 "2"^^ . . _:b457510459 . _:b457511035 . _:b457510573 "3"^^ . _:b457511231 "2"^^ . _:b457510417 . . _:b10410024 "of macrophages on OBs was further supported by data obtained in co-culture studies suggesting that macrophages produce factors that support the growth, survival, and mineralization of OBs (Chang et al., 2008; Christopher et al., >>2011<<)." . _:b457510463 . _:b457511069 . . _:b457511034 . _:b457510617 . _:b457511230 "2"^^ . _:b457510572 "3"^^ . _:b457511045 . _:b457510575 "3"^^ . _:b457511225 "2"^^ . . _:b457511044 . _:b457510574 "3"^^ . _:b457511224 "2"^^ . _:b457510883 . _:b457511047 . _:b457510569 "3"^^ . _:b457511227 "2"^^ . _:b457510502 . _:b457511046 . _:b457510568 "3"^^ . _:b10410021 "loss of monocytes/macrophages is similar to the situation in the aforementioned phagocyte depletion models, it is not surprising that G-CSF treatment resulted in the rapid depletion of endosteal osteoblastic activity (Winkler et al., >>2010<<). Histomorphometric methods revealed a 90% reduction of the bone formation rate, specifically at the endosteum." . _:b457511226 "2"^^ . _:b457511041 . _:b457510571 "3"^^ . . _:b457510800 . . . _:b457511040 . _:b457510570 "3"^^ . _:b457510672 . . _:b10409958 . _:b457511043 . _:b457510581 "3"^^ . . _:b10410032 "For example, sinusoidal endothelial cells have been suggested to play a role, as they produce angiocrine factors such as Notch ligands, which promote HSC self-renewal and regeneration after bone marrow injury (Butler et al., >>2010<<; Kobayashi et al., 2010)." . _:b457511042 . _:b457510971 . _:b457510580 "3"^^ . _:b457511053 . _:b457510583 "3"^^ . . _:b10409944 "mesenchymal stem cells (mscs): the main niche players" . _:b457511052 . _:b10410023 "A positive effect of macrophages on OBs was further supported by data obtained in co-culture studies suggesting that macrophages produce factors that support the growth, survival, and mineralization of OBs (Chang et al., >>2008<<; Christopher et al., 2011)." . _:b457510582 "3"^^ . _:b457511232 "2"^^ . _:b457511055 . _:b457510577 "3"^^ . . _:b457511204 . _:b457511054 . _:b457510576 "3"^^ . _:b457511049 . _:b457510579 "3"^^ . _:b457510620 . _:b457511048 . _:b457510578 "3"^^ . _:b457510687 . . _:b457510871 . . _:b457511051 . . _:b457510589 "3"^^ . _:b457511018 . _:b457511050 . . _:b457510918 . _:b457510588 "3"^^ . . . _:b457511061 . _:b457510591 "3"^^ . . _:b457511060 . _:b457510590 "3"^^ . . . _:b457510607 . _:b457511063 . _:b457510585 "3"^^ . . _:b457511062 . _:b457510584 "3"^^ . _:b457511057 . _:b457510587 "3"^^ . _:b457511033 . _:b457510658 . _:b457510934 . _:b457511056 . _:b457510586 "3"^^ . _:b457511175 . _:b457511059 . _:b457510597 "3"^^ . _:b457511058 . _:b457510499 . _:b457510596 "3"^^ . . _:b457511069 . _:b457510599 "3"^^ . _:b457510863 . _:b457511068 . _:b457510598 "3"^^ . . _:b457510582 . . _:b457511071 . _:b457510593 "3"^^ . . _:b457510795 . _:b457511070 . _:b457510592 "3"^^ . _:b457511065 . _:b457510595 "3"^^ . _:b457510587 . _:b457511019 . _:b457511064 . _:b457510594 "3"^^ . . . _:b457511067 . _:b457510605 "3"^^ . _:b457511066 . . _:b457510604 "3"^^ . _:b457511077 . _:b457511143 . _:b457510607 "3"^^ . _:b457510549 . _:b457510732 . _:b457511076 . _:b457510606 "3"^^ . _:b457511079 . _:b457511193 . _:b457510601 "3"^^ . _:b457510625 . _:b457511078 . _:b457510600 "3"^^ . _:b457511062 . . _:b457510508 . _:b457511073 . _:b457510603 "3"^^ . _:b457510742 . _:b457510891 . _:b457511072 . _:b457510602 "3"^^ . _:b457510975 . _:b457510461 . _:b457511075 . _:b457510613 "3"^^ . _:b457510557 . _:b457510511 . . _:b457511074 . _:b457510612 "3"^^ . . _:b457511085 . _:b457510615 "3"^^ . _:b457511177 . . _:b457511084 . _:b457510614 "3"^^ . . . . _:b457511087 . _:b457510609 "3"^^ . . _:b457511086 . _:b457510608 "3"^^ . _:b457510926 . . . _:b457511081 . _:b457510611 "3"^^ . . . _:b457511080 . . _:b457510935 . _:b457510610 "3"^^ . _:b457511083 . _:b457510621 "3"^^ . _:b457510634 . . _:b457511082 . _:b457510620 "3"^^ . _:b457510967 . _:b10410006 "The recent studies also addressed the mechanism of G-CSF\u2013induced mobilization of HSCs into the peripheral blood (Winkler et al., >>2010<<; Chow et al., 2011; Christopher et al., 2011)." . _:b457511093 . . _:b457510623 "3"^^ . _:b10409999 . . _:b457511092 . _:b457510622 "3"^^ . _:b457511095 . _:b457510617 "3"^^ . _:b457511094 . _:b457510616 "3"^^ . _:b457511073 . _:b457511089 . _:b457510619 "3"^^ . . _:b457511088 . _:b457510618 "3"^^ . _:b457511111 . _:b457511091 . _:b457510629 "3"^^ . . _:b457511090 . _:b457510628 "3"^^ . _:b457511101 . _:b457510631 "3"^^ . . _:b457511100 . . _:b457510630 "3"^^ . _:b457510453 . _:b457511103 . _:b457510625 "3"^^ . _:b457510974 . . _:b457511131 . _:b457511102 . _:b457510624 "3"^^ . _:b457510856 . _:b457511097 . _:b457510627 "3"^^ . _:b457511096 . _:b457510626 "3"^^ . . . _:b457511099 . . . _:b457510637 "3"^^ . _:b457511098 . . _:b457510636 "3"^^ . . . _:b457510821 . _:b457511109 . _:b457510639 "3"^^ . _:b457511041 . _:b457511108 . _:b457510638 "3"^^ . _:b457510787 . _:b457511111 . _:b457510633 "3"^^ . _:b457510677 . _:b457510964 . . . _:b457511110 . _:b457510632 "3"^^ . . _:b457511105 . _:b10410028 "SNS fibers are intermingled with nestin+ MSCs and inhibit HSC retention by negatively affecting nestin+ MSC activity (Katayama et al., 2006; M\u00E9ndez-Ferrer et al., >>2008<<, 2010). The G-CSF\u2013mediated increase in sympathetic tone promotes progenitor cell egress, and thus represents a macrophage/monocyte-independent pathway for G-CSF\u2013mediated mobilization. This provides some explanation as to why G-CSF is a" . _:b457510635 "3"^^ . _:b457511104 . _:b457510414 . _:b457510634 "3"^^ . . . _:b457511107 . . _:b457510645 "3"^^ . _:b457510443 . _:b457511106 . . _:b457510644 "3"^^ . _:b10409980 . . _:b457511117 . _:b457510647 "3"^^ . _:b457510586 . . _:b457511116 . _:b457510646 "3"^^ . _:b457511119 . . _:b457510641 "3"^^ . _:b457510873 . _:b457511118 . _:b457510640 "3"^^ . _:b457510482 . _:b457511113 . _:b457510643 "3"^^ . _:b457510542 . . _:b457511112 . _:b457510642 "3"^^ . _:b457510407 . _:b10409961 "HSCs isolated from endosteal regions by FACS show higher reconstitution activity compared with phenotypically identical cells from the center of the bone marrow (Grassinger et al., >>2010<<)." . _:b457511115 . _:b457510653 "3"^^ . _:b457511114 . . _:b457510652 "3"^^ . . _:b457511115 . _:b457511125 . _:b457510655 "3"^^ . _:b457510910 . _:b457510838 . _:b457511124 . _:b10409971 . . _:b457510654 "3"^^ . _:b10410007 "The recent studies also addressed the mechanism of G-CSF\u2013induced mobilization of HSCs into the peripheral blood (Winkler et al., 2010; Chow et al., >>2011<<; Christopher et al., 2011)." . _:b457511127 . _:b457510649 "3"^^ . _:b457510577 . . _:b10409993 . _:b457511126 . _:b457510648 "3"^^ . _:b457510642 . _:b457511121 . _:b457510651 "3"^^ . _:b457510530 . _:b457511120 . . . _:b457510650 "3"^^ . _:b457511123 . _:b457510661 "3"^^ . . . _:b457511122 . _:b457510660 "3"^^ . . _:b457511133 . _:b457510663 "3"^^ . _:b457510591 . _:b457511132 . _:b457511170 . _:b457510662 "3"^^ . . . . _:b457511135 . _:b457510657 "3"^^ . _:b457510560 . _:b457510804 . _:b457511134 . _:b457510656 "3"^^ . _:b457511129 . _:b457510659 "3"^^ . _:b457510651 . . . _:b457511128 . _:b457510658 "3"^^ . . _:b457511122 . . _:b457511131 . _:b457510669 "3"^^ . _:b457510970 . _:b457511130 . _:b457510668 "3"^^ . . _:b457511141 . _:b457510671 "3"^^ . _:b457511140 . _:b457510670 "3"^^ . _:b457510526 . _:b457511107 . . _:b457511143 . . _:b457510665 "3"^^ . . . _:b457511142 . _:b457510664 "3"^^ . _:b10409993 "or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., 2009; Foudi et al., 2009; Schaniel and Moore, 2009; Baldridge et al., 2010; Trumpp et al., 2010; Takizawa et al., >>2011<<). Thus, we postulate the existence of two highly similar niches, one harboring dormant HSCs and one housing self-renewing HSCs (Fig." . _:b457511137 . _:b457510667 "3"^^ . _:b457510992 . . _:b457510980 . _:b457511136 . _:b457510666 "3"^^ . . _:b457510677 "2"^^ . _:b457511139 . . . _:b457511130 . . _:b457511138 . _:b457510676 "2"^^ . . _:b10409944 _:b10409948 . _:b10409944 _:b10409949 . _:b10409944 _:b10409950 . _:b10410012 "role of neutrophils and neutrophil-derived proteases (neutrophil elastase, cathepsin G, and MMP9), which were previously thought to be the main drivers of HSC mobilization in response to G-CSF (L\u00E9vesque et al., 2001; Heissig et al., >>2002<<; Petit et al., 2002; Christopherson et al., 2003)." . _:b457511149 . _:b457510679 "2"^^ . _:b10409944 _:b10409951 . . _:b10409944 _:b10409945 . _:b10409944 _:b10409946 . _:b457511148 . _:b457510678 "2"^^ . . _:b10409944 _:b10409947 . . _:b457510783 . _:b457511151 . _:b457510673 "3"^^ . _:b457511188 . _:b457511132 . _:b10409944 _:b10409952 . . _:b10409944 _:b10409953 . _:b10409944 _:b10409954 . _:b457511150 . _:b10409944 _:b10409955 . _:b457510672 "3"^^ . _:b457510675 "2"^^ . _:b457511145 . _:b457510485 . _:b457511144 . _:b457510563 . _:b457510674 "3"^^ . . . _:b457510685 "2"^^ . _:b457511147 . . _:b457510844 . . _:b457511146 . _:b457510684 "2"^^ . _:b457510687 "2"^^ . _:b457511157 . _:b457510686 "2"^^ . _:b457511156 . _:b10409956 _:b10409972 . _:b10409956 _:b10409973 . _:b10409956 _:b10409974 . _:b457511225 . _:b457511159 . _:b457510681 "2"^^ . _:b10409956 _:b10409975 . _:b10409956 _:b10409968 . _:b457510528 . _:b10409956 _:b10409969 . _:b10409956 _:b10409970 . _:b457511158 . _:b457510680 "2"^^ . _:b10409956 _:b10409971 . _:b10409956 _:b10409980 . _:b10409956 _:b10409981 . _:b457510996 . _:b10409956 _:b10409982 . _:b457511153 . _:b457510683 "2"^^ . _:b10409956 _:b10409983 . _:b457510533 . _:b457511102 . _:b457510945 . _:b10409956 _:b10409976 . _:b10409956 _:b10409977 . _:b10409956 _:b10409978 . _:b457511152 . _:b457510682 "2"^^ . _:b10409956 _:b10409979 . _:b10409956 _:b10409957 . _:b10409956 _:b10409958 . _:b457511155 . _:b457510693 "2"^^ . _:b10409956 _:b10409959 . _:b457510692 "2"^^ . _:b457511154 . _:b457510876 . _:b10409956 _:b10409964 . _:b10409956 _:b10409965 . _:b10409953 "These bipotent adipoosteogenic progenitors were identified in a mouse strain in which GFP was expressed from the endogenous CXCL12 locus (Sugiyama et al., >>2006<<; Omatsu et al., 2010)." . _:b10409956 _:b10409966 . _:b457511165 . _:b457510695 "2"^^ . _:b10409956 _:b10409967 . _:b10409956 _:b10409960 . _:b10409956 _:b10409961 . _:b10409956 _:b10409962 . _:b457511164 . _:b457510694 "2"^^ . _:b10409956 _:b10409963 . _:b10409964 "Induced depletion of OBs causes mobilization of HSCs/progenitors to the spleen, and some genetically modified mice with augmented OBs show a simultaneous increase in HSC numbers (Calvi et al., 2003; Zhang et al., 2003; Visnjic et al., >>2004<<; Zhu et al., 2007). Furthermore, a population of CD45\u2212CD105+ osteoprogenitor cells from fetal long bone or calvaria is sufficient to generate an HSC niche when transplanted under the kidney capsule (Chan et al., 2009)." . _:b457510689 "2"^^ . _:b457511167 . . _:b457510919 . _:b10409983 . _:b457510688 "2"^^ . _:b457511166 . _:b457510576 . _:b457510691 "2"^^ . _:b457511161 . . _:b457510690 "2"^^ . _:b457511160 . . _:b457510701 "2"^^ . _:b457511163 . _:b10409946 "nestin+ MSCs are tightly associated with adrenergic nerve fibers of the sympathetic nervous system (SNS) that regulate HSC mobilization and are responsible for the circadian oscillations in circulating HSC numbers (Katayama et al., >>2006<<; M\u00E9ndez-Ferrer et al., 2008)." . . . _:b457511162 . _:b457510700 "2"^^ . . _:b457510703 "2"^^ . . _:b457510796 . _:b457510702 "2"^^ . _:b457510842 . _:b457510697 "2"^^ . . _:b457510696 "2"^^ . . _:b457510699 "2"^^ . _:b457510698 "2"^^ . . _:b457510709 "2"^^ . _:b457510890 . _:b457510708 "2"^^ . _:b457510830 . . . _:b457510711 "2"^^ . _:b457510710 "2"^^ . _:b457510614 . _:b457510705 "2"^^ . _:b457510704 "2"^^ . . _:b10409964 . _:b457510707 "2"^^ . . _:b457510706 "2"^^ . _:b457511125 . _:b457510717 "2"^^ . _:b457511075 . _:b457510716 "2"^^ . . . _:b457510719 "2"^^ . _:b457511230 . _:b457510983 . _:b457510808 . _:b457510718 "2"^^ . _:b457510691 . _:b457510623 . _:b457510837 . . _:b457510713 "2"^^ . . _:b457510712 "2"^^ . . _:b457510788 . _:b457511002 . _:b457510715 "2"^^ . _:b457511058 . _:b457510714 "2"^^ . . _:b457510725 "2"^^ . _:b10409956 . . _:b457510724 "2"^^ . . _:b10409944 . _:b457510497 . _:b457510727 "2"^^ . . _:b457510726 "2"^^ . _:b457510721 "2"^^ . . _:b457510432 . _:b457510720 "2"^^ . . . _:b457510723 "2"^^ . _:b457510722 "2"^^ . _:b457511206 . _:b457510972 . . _:b457510733 "2"^^ . _:b457510732 "2"^^ . _:b457510536 . _:b457510735 "2"^^ . . . _:b457511169 . _:b10409990 "cell cycle in response to cytokines like type I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., 2009; Foudi et al., 2009; Schaniel and Moore, >>2009<<; Baldridge et al., 2010; Trumpp et al., 2010; Takizawa et al., 2011). Thus, we postulate the existence of two highly similar niches, one harboring dormant HSCs and one housing self-renewing HSCs (Fig." . _:b457510734 "2"^^ . . . _:b457510729 "2"^^ . . _:b457510728 "2"^^ . . _:b457510731 "2"^^ . _:b10409946 . _:b457510730 "2"^^ . _:b457510825 . _:b457510737 . _:b457510775 . _:b457510741 "2"^^ . . . _:b457510740 "2"^^ . . _:b457510743 "2"^^ . . _:b457510742 "2"^^ . . _:b457510737 "2"^^ . _:b457510946 . _:b457510736 "2"^^ . . _:b457510739 "2"^^ . _:b457510738 "2"^^ . _:b457510850 . _:b457510749 "2"^^ . . _:b457510748 "2"^^ . _:b457510751 "2"^^ . . _:b457510750 "2"^^ . _:b457510725 . _:b457511229 . _:b457510441 . _:b457510745 "2"^^ . _:b457510569 . _:b457510744 "2"^^ . _:b457510982 . _:b457510747 "2"^^ . _:b457510899 . _:b10409974 . _:b457510746 "2"^^ . . _:b457510757 "2"^^ . _:b457510756 "2"^^ . _:b457510710 . _:b10409988 "homeostasis, they can be induced to reenter the cell cycle in response to cytokines like type I or II IFN, G-CSF, or injury signals such as those generated by chemotherapy-induced myelosuppression (Wilson et al., 2008; Essers et al., >>2009<<; Foudi et al., 2009; Schaniel and Moore, 2009; Baldridge et al., 2010; Trumpp et al., 2010; Takizawa et al., 2011)." . _:b457510759 "2"^^ . _:b457510758 "2"^^ . _:b457510753 "2"^^ . . _:b457510752 "2"^^ . _:b457510755 "2"^^ . . . _:b457510754 "2"^^ . _:b457510765 "2"^^ . _:b457511123 . . _:b457510764 "2"^^ . . _:b457510767 "2"^^ . _:b457510766 "2"^^ . _:b457511030 . _:b457510761 "2"^^ . . _:b457510760 "2"^^ . _:b457510763 "2"^^ . . _:b457510762 "2"^^ . _:b457510773 "2"^^ . _:b457510772 "2"^^ . . _:b457510654 . _:b457510775 "2"^^ . _:b457511016 . . _:b457510774 "2"^^ . _:b457510729 . _:b457510480 . _:b457510769 "2"^^ . _:b457510768 "2"^^ . . _:b457510771 "2"^^ . _:b457510477 . _:b457510770 "2"^^ . _:b457511076 . _:b457510781 "2"^^ . _:b10409950 "Parathyroid hormone directly stimulated proliferation of nestin+ MSCs while simultaneously promoting their differentiation into OBs (M\u00E9ndez-Ferrer et al., >>2010<<). Collectively, these data support the hypothesis that nestin+ MSCs are a functional component of the bone marrow HSC niche." . . _:b457510780 "2"^^ . _:b457510720 . _:b457510783 "2"^^ . _:b457510861 . _:b457510782 "2"^^ . _:b457510823 . _:b457510777 "2"^^ . _:b457510849 . _:b457510665 . . _:b457510776 "2"^^ . . . _:b457510779 "2"^^ . _:b457510778 "2"^^ . _:b457510789 "2"^^ . . _:b457510788 "2"^^ . _:b457510791 "2"^^ . _:b457510600 . _:b457510790 "2"^^ . . _:b457510785 "2"^^ . . _:b457510784 "2"^^ . _:b457511163 . . _:b457510787 "2"^^ . . _:b457510951 . _:b457510786 "2"^^ . . . _:b457510777 . . _:b10409994 "2; Trumpp et al., >>2010<<). Both niches may rely on perivascular MSCs, but the endosteal niche could maintain a small dormant HSC population via the additional presence of TPO-producing OBs embedded in a calcium-rich microenvironment." . _:b457510797 "2"^^ . _:b457510712 . _:b10409998 . _:b457510796 "2"^^ . _:b457510998 . _:b457511104 . . _:b457510799 "2"^^ . . . _:b457510798 "2"^^ . _:b457510593 . _:b457510793 "2"^^ . _:b457510847 . _:b457511046 . _:b457510792 "2"^^ . . . _:b457510795 "2"^^ . _:b457510716 . . _:b457510794 "2"^^ . _:b457510805 "2"^^ . _:b457510804 "2"^^ . _:b10410027 . _:b457510807 "2"^^ . _:b457510806 "2"^^ . . _:b457510801 "2"^^ . _:b457510800 "2"^^ . _:b10409960 "location to be proposed as the putative HSC niche, and HSCs at the endosteum have subsequently been identified by confocal/two-photon intravital imaging (Lord and Hendry, 1972; Nilsson et al., 2001; Calvi et al., 2003; Zhang et al., >>2003<<). HSCs isolated from endosteal regions by FACS show higher reconstitution activity compared with phenotypically identical cells from the center of the bone marrow (Grassinger et al., 2010)." . _:b10410018 "to an overall decrease of bone marrow and serum CXCL12 levels, which activates the CXCR4 receptor to promote HSC retention\u2014an interaction that is blocked by the mobilizing compound AMD3100 (Broxmeyer et al., 2005; De Clercq, >>2009<<). Macrophages have now been identified as niche components that positively regulate MSCs and OBs, which in turn provide HSCs with the necessary extracellular retention factors, including CXCL12." . _:b457510803 "2"^^ . . _:b457510802 "2"^^ . _:b457510813 "2"^^ . _:b457510812 "2"^^ . _:b457510815 "2"^^ . . . _:b457510814 "2"^^ . . _:b457510809 "2"^^ . _:b457510808 "2"^^ . . _:b457510811 "2"^^ . _:b457510810 "2"^^ . . _:b457510609 . _:b457510650 . _:b457510821 "2"^^ . _:b457511171 . _:b457510820 "2"^^ . _:b457511027 . _:b457510823 "2"^^ . _:b10409975 . _:b457510822 "2"^^ . . _:b10409988 . _:b457510817 "2"^^ . . _:b457511043 . _:b457510816 "2"^^ . . _:b457510819 "2"^^ . . _:b457510818 "2"^^ . _:b457510829 "2"^^ . _:b457510523 . _:b457510828 "2"^^ . . . _:b457510831 "2"^^ . _:b457510830 "2"^^ . _:b457510825 "2"^^ . _:b457510780 . _:b457510824 "2"^^ . _:b457510827 "2"^^ . _:b457510879 . _:b457510826 "2"^^ . _:b457510837 "2"^^ . . _:b457510836 "2"^^ . _:b457510839 "2"^^ . _:b457510838 "2"^^ . . _:b457510833 "2"^^ . _:b457510832 "2"^^ . . . _:b457511133 . _:b457510835 "2"^^ . _:b457511158 . _:b457510834 "2"^^ . _:b457510507 . _:b457510845 "2"^^ . _:b457510844 "2"^^ . _:b10409986 . _:b457510847 "2"^^ . _:b457511013 . _:b457510846 "2"^^ . . _:b457510841 "2"^^ . _:b457510515 . . _:b457510840 "2"^^ . _:b457510639 . . _:b457510843 "2"^^ . _:b10409950 . _:b457510842 "2"^^ . . _:b457510853 "2"^^ . . . . _:b457510852 "2"^^ . . _:b457510855 "2"^^ . . . _:b457510854 "2"^^ . . _:b10409945 . _:b457510806 . . _:b457510817 . _:b457510849 "2"^^ . . _:b457510578 . _:b457510848 "2"^^ . _:b10409977 . _:b457510473 . _:b457510851 "2"^^ . . _:b457510850 "2"^^ . _:b457510896 . _:b457510518 . _:b457510861 "2"^^ . . _:b457510860 "2"^^ . . . _:b10410014 . _:b457510568 . . _:b457510406 . _:b457510863 "2"^^ . _:b457510862 "2"^^ . _:b457511153 . _:b457511080 . _:b457510857 "2"^^ . . _:b457511221 . _:b457510856 "2"^^ . _:b457510859 "2"^^ . _:b457510858 "2"^^ . _:b457511109 . _:b457510521 . . _:b457510869 "2"^^ . _:b457510696 . _:b10410035 "Finally, models suggesting the existence of two distinct HSC niches in the bone marrow remain to be experimentally confirmed (Fig. 2; Trumpp et al., >>2010<<). Although such a model would incorporate the currently available data about the niche components and link it to the finding that dormant and actively self-renewing HSCs coexist in the marrow, it remains very difficult to identify and" . _:b457510868 "2"^^ . _:b10409956 "obs and the endosteal niche" . _:b457510871 "2"^^ . . _:b457510852 . _:b457510870 "2"^^ . _:b457510694 . _:b457510865 "2"^^ . _:b457510864 "2"^^ . _:b457510867 "2"^^ . _:b457510866 "2"^^ . _:b457510755 . . _:b457510877 "2"^^ . . _:b457510876 "2"^^ . _:b457510854 . . _:b457510879 "2"^^ . _:b457510940 . _:b457510878 "2"^^ . _:b457510619 . . _:b457510873 "2"^^ . _:b457510872 "2"^^ . _:b457510875 "2"^^ . _:b457510874 "2"^^ . . . . _:b457510885 "2"^^ . _:b10410011 "debate about the role of neutrophils and neutrophil-derived proteases (neutrophil elastase, cathepsin G, and MMP9), which were previously thought to be the main drivers of HSC mobilization in response to G-CSF (L\u00E9vesque et al., >>2001<<; Heissig et al., 2002; Petit et al., 2002; Christopherson et al., 2003)." . _:b457510884 "2"^^ . . _:b457511106 . . _:b10410034 . . _:b457510887 "2"^^ . . . _:b457510886 "2"^^ . . _:b457510657 . . _:b457510881 "2"^^ . _:b10409976 . _:b457510880 "2"^^ . _:b457510883 "2"^^ . _:b457511010 . _:b457510882 "2"^^ . _:b457510589 . _:b10409973 . _:b457510893 "2"^^ . _:b457510892 "2"^^ . _:b10410011 . . _:b457510799 . _:b457510895 "2"^^ . . _:b457510546 . _:b457510894 "2"^^ . _:b457510792 . _:b457510889 "2"^^ . _:b457510561 . _:b457510888 "2"^^ . _:b457511228 . _:b457510891 "2"^^ . _:b457510537 . _:b457510832 . _:b457510890 "2"^^ . . _:b457510901 "2"^^ . _:b10410031 _:b10410032 . _:b457510548 . _:b457510900 "2"^^ . _:b10410031 _:b10410033 . _:b10410031 _:b10410034 . _:b10410031 _:b10410035 . . _:b457510903 "2"^^ . . _:b457510877 . _:b457510906 . _:b457510902 "2"^^ . _:b457511172 . _:b457510897 "2"^^ . _:b457511187 . _:b457510802 . _:b457510896 "2"^^ . . _:b457510494 . _:b457510899 "2"^^ . _:b10410016 "The data by Christopher et al. (>>2011<<) suggest that G-CSF\u2013stimulated monocytes cause the mobilization of HSCs out of their niche, but how does this work?" . . _:b457511196 . _:b457510898 "2"^^ . . . . _:b457510909 "2"^^ . . _:b457510908 "2"^^ . . _:b457510911 "2"^^ . _:b457510424 . _:b10410005 _:b10410016 . . _:b457510910 "2"^^ . _:b10410005 _:b10410017 . _:b10410005 _:b10410018 . _:b457511005 . _:b10410005 _:b10410019 . _:b10410005 _:b10410020 . _:b10410005 _:b10410021 . _:b457510905 "2"^^ . _:b10410005 _:b10410022 . _:b10410005 _:b10410023 . _:b10410005 _:b10410024 . _:b10410005 _:b10410025 . _:b457511103 . _:b457510904 "2"^^ . _:b10410005 _:b10410026 . _:b457510481 . _:b457510922 . _:b10410005 _:b10410027 . _:b457510437 . _:b10410005 _:b10410028 . _:b10410005 _:b10410029 . _:b457510907 "2"^^ . _:b10410005 _:b10410030 . _:b457510670 . . _:b457510906 "2"^^ . _:b457510574 . . _:b10410005 _:b10410006 . _:b457510990 . . _:b10410005 _:b10410007 . . _:b10410005 _:b10410008 . . _:b10410005 _:b10410009 . _:b10410005 _:b10410010 . _:b10410005 _:b10410011 . _:b10410005 _:b10410012 . . _:b10410005 _:b10410013 . . _:b10410005 _:b10410014 . _:b10410005 _:b10410015 . . _:b10409972 . . _:b457510489 . _:b457511185 . . . . _:b10409995 _:b10409996 . _:b10409995 _:b10409997 . . _:b10409995 _:b10409998 . _:b10409995 _:b10409999 . _:b457510907 . . _:b457510550 . . . . _:b10409995 _:b10410000 . _:b10409995 _:b10410001 . _:b10409995 _:b10410002 . _:b10409995 _:b10410003 . _:b10409995 _:b10410004 . _:b457510525 . _:b457510648 . _:b457510506 . . _:b457510960 . _:b457510659 . _:b457510900 . _:b457511016 . _:b457511017 . _:b457511018 . _:b457511019 . _:b457511020 . _:b457510711 . _:b457511021 . _:b457511017 . . _:b457511022 . _:b457511023 . _:b457511008 . _:b457511095 . _:b457511009 . _:b457511010 . _:b457511011 . . _:b457511012 . _:b457511013 . _:b457511014 . _:b457511015 . _:b457511032 . _:b457511033 . _:b457510721 . _:b457511034 . _:b457511035 . _:b457510573 . _:b457511036 . _:b457511037 . _:b457511038 . _:b457511039 . . _:b457511024 . _:b457511025 . _:b457511026 . _:b457510768 . . _:b457511027 . _:b457511028 . _:b457511029 . _:b457511030 . _:b457511031 . _:b457510984 . _:b457510985 . _:b457511155 . . _:b457510986 . _:b457510987 . _:b457510988 . _:b457510989 . _:b457510990 . _:b457510991 . _:b457510976 . _:b457510977 . _:b457510978 . _:b457510979 . _:b457510980 . _:b457510981 . _:b457510982 . _:b457510983 . _:b457511000 . _:b457511001 . . _:b457511002 . _:b457511003 . . _:b457511004 . _:b457511005 . _:b457511006 . _:b10410033 . _:b457511007 . _:b457510992 . _:b457510993 . _:b457510994 . _:b457510995 . _:b457511151 . _:b457510996 . _:b457510621 . _:b457510997 . . _:b457510998 . _:b457510999 . _:b457510952 . _:b457510953 . _:b457510954 . _:b457510718 . _:b457510955 . _:b457510956 . _:b457510957 . . _:b457510958 . _:b457510959 . _:b457510944 . _:b457510945 . _:b457510946 . _:b457510947 . _:b457510851 . _:b457510948 . _:b457510949 . _:b457510950 . _:b457510951 . _:b457510968 . _:b457510969 . _:b457510970 . _:b457510971 . _:b457510972 . _:b457510973 . _:b457510719 . _:b457510974 . _:b457510975 . _:b457510667 . _:b457510960 . _:b457510961 . . _:b457510962 . _:b457510963 . _:b457510547 . _:b457510964 . . _:b457510965 . _:b457510553 . _:b457510966 . _:b10410017 "been generally attributed to an overall decrease of bone marrow and serum CXCL12 levels, which activates the CXCR4 receptor to promote HSC retention\u2014an interaction that is blocked by the mobilizing compound AMD3100 (Broxmeyer et al., >>2005<<; De Clercq, 2009). Macrophages have now been identified as niche components that positively regulate MSCs and OBs, which in turn provide HSCs with the necessary extracellular retention factors, including CXCL12." . _:b457510967 . _:b10410004 "The latter data conflict with the study by Chow et al. (>>2011<<), who did not observe reduced OB numbers or decreased OB expression of HSC maintenance factors when phagocytes were depleted." . . _:b457510920 . . _:b457510921 . _:b457510922 . . _:b457510923 . _:b457510924 . _:b457510925 . _:b457510708 . _:b457510926 . _:b457510927 . . _:b457510912 . _:b457510913 . _:b457510914 . _:b457510915 . _:b457510916 . _:b457510917 . _:b457510918 . _:b457510919 . _:b457510936 . _:b457510937 . _:b457510938 . _:b457510939 . _:b457510940 . _:b457510778 . _:b457510941 . _:b457511146 . _:b457510942 . _:b457510419 . . _:b457510943 . _:b457510928 . _:b457510845 . _:b457510929 . _:b457510878 . . _:b457510930 . . _:b457510931 . _:b457510932 . _:b457510933 . . . _:b457510934 . _:b457510935 . _:b457511144 . _:b457511145 . _:b457511146 . _:b457511147 . _:b457511148 . "PMC0" . _:b457511149 . _:b457511150 . _:b457510921 . _:b457511151 . _:b457511136 . _:b457511137 . _:b457511138 . _:b457511139 . _:b457511140 . _:b457511141 . _:b457511142 . _:b457511143 . _:b457511160 . _:b457511161 . _:b457511162 . _:b457511163 . _:b457511164 . . _:b457511165 . _:b457511166 . _:b457511167 . _:b457511152 . . _:b457511153 . _:b457511154 . _:b457511155 . _:b457511156 . _:b457511157 . _:b457511158 . _:b457511159 . _:b457511112 . _:b457510615 . _:b457511113 . _:b457510824 . _:b457511114 . _:b457510880 . _:b457511115 . _:b457511116 . _:b457510813 . _:b457511117 . _:b457511118 . . . _:b457511119 . _:b457511104 . _:b457511105 . . _:b457511106 . _:b457511107 . _:b457511108 . _:b457511109 . _:b457511110 . _:b457511111 . _:b457511232 . . _:b457511128 . _:b457511129 . _:b457511130 . _:b457511131 . _:b457511132 . _:b457511133 . _:b457511134 . _:b457511135 . _:b457511120 . _:b457511121 . _:b457511122 . . _:b457511123 . _:b457511124 . _:b457511125 . _:b457511126 . _:b457511127 . _:b457511080 . _:b457510826 . _:b457511081 . _:b457511082 . _:b457511083 . _:b457511084 . _:b10409952 "Most interestingly, nestin+ MSCs show several similarities to recently identified mesenchymal progenitors (Sugiyama et al., 2006; Omatsu et al., >>2010<<). These bipotent adipoosteogenic progenitors were identified in a mouse strain in which GFP was expressed from the endogenous CXCL12 locus (Sugiyama et al., 2006; Omatsu et al., 2010)." . _:b457511085 . _:b457511086 . _:b457511087 . . _:b457511072 . _:b457511073 . _:b457511074 . . _:b457511075 . . _:b457511076 . _:b457511077 . _:b457511078 . _:b457510965 . _:b457511079 . _:b457511138 . _:b457511096 . _:b457511097 . . _:b457511098 . _:b457511099 . _:b457511100 . _:b457511101 . _:b457511102 . _:b457511103 . _:b457511088 . _:b457510973 . _:b457511089 . _:b457510840 . _:b457511090 . _:b457511091 . . _:b457511092 . . _:b457510454 . _:b457511093 . _:b457511094 . _:b457511095 . _:b457510994 . _:b457510803 . _:b457511048 . _:b457510626 . _:b457511049 . _:b457511050 . _:b457511051 . . _:b457511052 . _:b457511053 . . _:b457511054 . . _:b457511055 . _:b457511040 . _:b10409985 "ablated using the DTR or thymidine kinase systems, in none of these experiments (MSC, CAR, or OB) did HSCs disappear completely or become mobilized as a whole (Visnjic et al., 2004; Zhu et al., 2007; M\u00E9ndez-Ferrer et al., >>2010<<; Omatsu et al., 2010). This suggests either that the depletion systems are inefficient or that there is some redundancy in the system (or both)." . _:b457511041 . _:b457511042 . _:b457511043 . _:b457511044 . . _:b457511045 . _:b457511046 . _:b457511047 . _:b457511064 . _:b457510785 . _:b457511065 . . _:b457511066 . _:b457511067 . _:b457511068 . _:b457511069 . _:b457511070 . _:b457511071 . _:b457511181 . _:b457510509 . _:b457511056 . _:b457511057 . _:b457511058 . _:b457511059 . _:b457510782 . _:b457511060 . _:b457511061 . _:b457511062 . _:b457511063 . _:b457510445 . _:b457510905 . _:b457511195 . . . _:b457510628 . . _:b457510766 . . . _:b457511100 . . _:b457510656 . _:b457511232 . . . _:b457511101 . . . . _:b457510595 . _:b457510681 . _:b457510754 . . _:b457511208 . . _:b457511209 . _:b457511210 . _:b457510601 . _:b457511211 . _:b457511212 . _:b457511213 . _:b10409997 "First, Chow et al. (>>2011<<) developed a strategy to subdivide neutrophils, Gr-1hi and Gr-1lo monocytes, and Gr1\u2212F4/80+CD169+ macrophages." . _:b457510529 . _:b457511214 . _:b457511215 . _:b457511200 . _:b457511201 . _:b457511202 . _:b457511203 . _:b457511204 . _:b457511197 . . _:b457511205 . _:b457511077 . _:b457511206 . _:b457511207 . _:b457511224 . _:b457511225 . . _:b457511226 . _:b457511227 . _:b457511228 . . _:b457511229 . _:b457511230 . _:b457511231 . _:b457511216 . . _:b457511217 . _:b457511218 . _:b457511219 . _:b457511220 . _:b457511221 . _:b457511222 . _:b457510661 . _:b457511223 . _:b457511176 . _:b457511177 . _:b457511178 . _:b457511179 . _:b457510516 . _:b457511180 . _:b457511181 . _:b457511093 . _:b457511182 . _:b457511183 . . _:b457511168 . . _:b457511169 . _:b457511170 . _:b457511171 . _:b10409948 . _:b457511172 . _:b457511173 . _:b457511174 . _:b457511175 . . _:b457511192 . . _:b457511193 . _:b457511194 . _:b457511195 . _:b457511196 . . _:b457511197 . _:b457511198 . _:b457511199 . _:b457511184 . _:b10410025 "First, phagocyte depletion inhibited the proliferation of MSCs and their expression of osteoblastic differentiation genes such as osteoglycin, bone morphogenetic protein 4, and adiponectin (M\u00E9ndez-Ferrer et al., >>2010<<). The expression of transcripts encoding HSC maintenance factors including Ang-1, SCF, and VCAM1 by MSCs also decreased. Most importantly, the expression of CXCL12, which is not produced by macrophages themselves, decreased by" . _:b457511185 . _:b457511186 . _:b457511187 . _:b10409955 "These data are in agreement with studies in humans, suggesting that virtually all MSC activity is found within the larger pericyte population that associates closely with the vascular system in the entire body (Crisan et al., >>2008<<)." . _:b457511188 . _:b457511189 . . _:b457511190 . . _:b457511191 . _:b457510597 . _:b10409966 "Furthermore, a population of CD45\u2212CD105+ osteoprogenitor cells from fetal long bone or calvaria is sufficient to generate an HSC niche when transplanted under the kidney capsule (Chan et al., >>2009<<). Similarly, adult human bone marrow contains a population of self-renewing CD45\u2212CD146+ perivascular osteoprogenitors that can generate bone and marrow when transplanted under the skin of immunodeficient mice (Sacchetti et al., 2007)." . . . . _:b457510606 . _:b457510649 . . . _:b457511209 . _:b457510571 . _:b457510771 . _:b457510989 . . . . _:b457510662 . . _:b10409978 "Importantly, TPO signaling via the c-MPL receptor has been shown to mediate HSC quiescence (Qian et al., >>2007<<; Yoshihara et al., 2007), which is a typical feature of the most potent HSCs in steady-state bone marrow (Wilson et al., 2008)." . . . . _:b10410022 . _:b457510704 . _:b457510645 .