The Role of the Donor in the Repair of the Marrow Vascular Niche Following Hematopoietic Stem Cell Transplant

Slayton, William B.; Li, Xiaomiao; Butler, Jason M.; Guthrie, Steven M.; Jorgensen, Marda; Wingard, John R.; Scott, Edward W.

doi:10.1634/stemcells.2007-0158

Cited by 60 publications

(47 citation statements)

References 54 publications

(64 reference statements)

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“…53 Interestingly, we found that transplanted ECs did not engraft directly in the BM vasculature, but rather engrafted temporarily in the lungs of recipient mice, suggesting that soluble factors were elaborated by infused ECs, which promoted vascular and HSC regeneration. 53 In keeping with these findings, Slayton et al 54 demonstrated that, following BM transplantation, reconstitution of the BM vasculature derives predominantly from host ECs rather than donor-derived endothelial progenitor cells.…”

Section: Do Ecs Secrete Soluble Growth Factors That Mediate Hsc Self-mentioning

confidence: 85%

The vascular niche: home for normal and malignant hematopoietic stem cells

2011

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Hematopoietic stem cells (HSCs) are uniquely capable of selfrenewal and provision of all of the mature elements of the blood and immune system throughout the lifetime of an individual. HSC self-renewal is regulated by both intrinsic mechanisms and extrinsic signals mediated via specialized microenvironments or 'niches' wherein HSCs reside. HSCs have been shown to reside in close association with bone marrow (BM) osteoblasts in the endosteal niche and also in proximity to BM sinusoidal vessels. An unresolved question surrounds whether the endosteal and vascular niches provide synchronous or redundant regulation of HSC fate or whether these niches provide wholly unique regulatory functions. Furthermore, while some aspects of the mechanisms through which osteoblasts regulate HSC fate have been defined, the mechanisms through which the vascular niche regulates HSC fate remain obscure. Here, we summarize the anatomic and functional basis supporting the concept of an HSC vascular niche as well as the precise function of endothelial cells, perivascular cells and stromal cells within the niche in regulating HSC fate. Lastly, we will highlight the role of the vascular niche in regulating leukemic stem cell fate in vivo. Leukemia (2012) Concept of the hematopoietic stem cell (HSC) nicheThe concept of an instructive role for the bone marrow (BM) microenvironment in regulating hematopoietic cell fate was introduced at least 50 years ago and has been validated over the past decade. 1-9 It has long been postulated that HSCs reside in specialized niches within the adult BM. [8][9][10][11][12][13][14] In addition to HSCs and their progeny, the BM comprises a rich network of osteoblasts, mesenchymal stem cells (MSCs), neuronal cells, adipocytes, sinusoidal vessels and perivascular reticular cells (Figure 1). Recently, genetic knockout studies have begun to demonstrate the functional role of specific cells within the BM microenvironment in regulating hematopoiesis. [3][4][5]7,[15][16][17][18][19][20] Interestingly, certain niches within the BM may uniquely regulate HSC homeostasis in vivo while other niches may be more relevant to HSC regeneration following injury. However, it remains unknown whether there is meaningful 'cross-talk' between distinct microenvironmental cells in regulating HSC fate in vivo. Interestingly, as early as 1961, Fliedner et al. 9 postulated that the recovery of hematopoiesis in rats following 1000 cGy total body irradiation (TBI) required the recovery of an intact vasculature. Similarly, McClugage et al. 14 used a window chamber to visualize dynamic changes in tibial BM cellularity and architecture in live rabbits. Interestingly, both studies suggested a strong association between vasculogenesis in the BM and the hematopoietic response to stress or injury. 9,14 Role of the BM osteoblast With advances in mouse genetics and microscopy, the function of the BM osteoblast in regulating hematopoiesis and HSC homeostasis has been demonstrated. 4,5,14,[21][22][23][24] Human osteoblasts were shown by Taichma...

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Section: Do Ecs Secrete Soluble Growth Factors That Mediate Hsc Self-mentioning

confidence: 85%

The vascular niche: home for normal and malignant hematopoietic stem cells

2011

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“…It was reported previously that the BM sinusoidal system was compromised after 5-FU treatment or irradiation; the transplanted donor stem cells were involved in the reconstruction of a normal sinusoid system. 34,35 Accordingly, in post-5-FU Cxcl12-deficient BM, the preferential localization of HSPCs in the perisinusoidal space might contribute to the quicker rebuild of a vasculaturerelated environment for hematopoiesis. Compared with the wildtype mice, Cxcr4-deficient mice had a low survival rate after serial doses of 5-FU challenge, 8,13 while the same challenge did not result in a significant survival difference in Cxcl12-deficient mice (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression

Tzeng

Kang

et al. 2011

Blood

254

194

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The C-X-C-type chemokine Cxcl12, also known as stromal cell-derived factor-1, plays a critical role in hematopoiesis during fetal development. However, the functional requirement of Cxcl12 in the adult hematopoietic stem/progenitor cell (HSPC) regulation was still unclear. In this report, we developed a murine Cxcl12 conditional deletion model in which the target gene can be deleted at the adult stage. We found that loss of stroma-secreted Cxcl12 in the adult led to expansion of the HSPC population as well as a reduction in longterm quiescent stem cells. In Cxcl12

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“…Some evidence also supports the fact that microenvironmental cells and especially endothelial cells could be transplanted successfully and participate in the repair of the marrow vascular niche following stem cell transplantation. 97,98 Therefore, by participating in the recovery of a physiological regulatory environment, cellsincluding mesenchymal and/or endothelial cells provided by the healthy donor-would favor extinction of the clonal hematopoiesis to the benefit of the normal hematopoiesis.…”

Section: Conclusion and Therapeutic Challengementioning

confidence: 99%

Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence

Lataillade

Pierre-Louis

Hasselbalch

et al. 2008

Blood

125

117

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Primary myelofibrosis (PMF) is the rarest and the most severe Philadelphianegative chronic myeloproliferative syndrome. By associating a clonal proliferation and a mobilization of hematopoietic stem cells from bone marrow to spleen with profound alterations of the stroma, PMF is a remarkable model in which deregulation of the stem cell niche is of utmost importance for the disease development. This paper reviews key data suggesting that an imbalance between en-

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The Role of the Donor in the Repair of the Marrow Vascular Niche Following Hematopoietic Stem Cell Transplant

Abstract: STEM CELLS 2007;25:2945-2955 Disclosure of potential conflicts of interest is found at the end of this article.

Cited by 60 publications

References 54 publications

The vascular niche: home for normal and malignant hematopoietic stem cells

The vascular niche: home for normal and malignant hematopoietic stem cells

Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression

Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence

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