Endochondral ossification is required for haematopoietic stem-cell niche formation

Chan, Charles K.; Chen, Ching-Cheng; Luppen, Cynthia A.; Kim, Jae‐Beom; DeBoer, Anthony; Wei, Kevin; Helms, Jill A.; Kuo, Calvin J.; Kraft, Daniel; Weissman, Irving L.

doi:10.1038/nature07547

Cited by 381 publications

(356 citation statements)

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“…In fact, despite an enrichment in CD146þ cells in NAMP progeny, they could not support BM formation in vivo. Moreover, recent data [51] suggest that endochondral ossification is required for the generation of the HSC niche by a specific population of CD105þ/Thy1.1À murine osteoprogenitors directly implanted under the kidney capsule, while the CD105þ/Thy1.1þ population formed only bone through intramembranous ossification. Our data are in agreement with this report, since NAMP progeny was positive for both CD105 and the human ortholog of murine Thy1.1, CD90 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

et al. 2012

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Bone marrow (BM) mesenchymal stem/stromal cells (MSC) are a heterogeneous population of multipotent progenitors currently under investigation for a variety of applications in regenerative medicine. While self-renewal of stem cells in different tissues has been demonstrated to be regulated by specialized microenvironments called niches, it is still unclear whether a self-renewing niche also exists for MSC. Here, we show that primary human BM cultures contain a population of intrinsically non-adherent mesenchymal progenitors (NAMP) with features of more primitive progenitors than the initially adhering colonyforming units-fibroblast (CFU-f). In fact, NAMP could generate an adherent progeny: (a) enriched with early mesenchymal populations (CD1461, SSEA-11, and SSEA-41); (b) with significantly greater proliferation and multilineage differentiation potential in vitro; and (c) capable of threefold greater bone formation in vivo than the corresponding CFU-f. Upon serial replating, NAMP were able to regenerate and expand in suspension as non-adherent clonogenic progenitors, while also giving rise to an adherent progeny. This took place at the cost of a gradual loss of proliferative potential, shown by a reduction in colony size, which could be completely prevented when NAMP were expanded on the initially adhering BM fraction. Mechanistically, we found that NAMP crucially depend on fibroblast growth factor (FGF)-2 signaling through FGFR2c for their survival and expansion. Furthermore, NAMP maintenance depends at least in part on humoral signals distinct from FGF-2. In conclusion, our data show a niche/progenitor organization in vitro, in which the BM adherent fraction provides a self-renewing microenvironment for primitive NAMP.

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Maintains a Niche-Dependent Population of Self-Renewing Highly Potent Non-adherent Mesenchymal Progenitors Through FGFR2c

et al. 2012

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“…Charles Chan has led our group in finding the mouse skeletal stem cell (SSC) that not only selfrenews but also gives rise at the single-cell level to osteocytes, chondrocytes, and up to four distinct marrow stromal cells (124). Placed under the kidney capsule in large cell numbers, SSCs form bone and cartilage in a morphologically correct manner (124)(125)(126)(127), with a bone marrow cavity containing host-derived HSCs and blood vessels. Of the stromal cell subsets, at least one was in the Whitlock clones (121), and at least three of the stroma support HSCs and hematopoiesis (124-127).…”

Section: Wwwannualreviewsorg • How One Thing Led To Anothermentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

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“…However, a similar primitive side population of HSCs isolated from the bone marrow was shown to be capable of giving rise to osteoblasts through an intermediate mesenchymal phase [71]. Studies have indicated that haematopoietic progenitor cells can be split into CD90-positive and CD90-negative fractions [72]. Both fractions appear capable of osteogenesis; however only the CD90-negative fraction has the capacity to form bone containing a central bone marrow filled cavity.…”

Section: Mesenchymal Progenitor Cellsmentioning

confidence: 99%