BMP4 regulates the hematopoietic stem cell niche

Goldman, Devorah C.; Bailey, Alexis S.; Pfaffle, Dana L.; Masri, Azzah Al; Christian, Jan L.; Fleming, William H.

doi:10.1182/blood-2009-02-206433

Cited by 100 publications

(81 citation statements)

References 39 publications

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“…40 Recently, Bmp4 hypomorphs were shown to have numerical and functional reductions in HSPCs that emanated from the microenvironment. 41 Interestingly, Bmp4-mediated human HSC proliferation was shown to be downstream of Shh signaling. 32 We find Shh also highly overexpressed in Wif1 osteoblasts.…”

Section: Discussionmentioning

confidence: 99%

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Schaniel

Sirabella²,

Qiu³

et al. 2011

Blood

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The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions. (Blood. 2011; 118(9):2420-2429) IntroductionHematopoietic stem cells (HSCs) are characterized by their ability to self-renew and differentiate, producing blood cells throughout life. In the adult, the balance of self-renewal and differentiation is tightly regulated by cross-talk between HSCs and specialized cells within the bone marrow (BM) constituting the stem cell niche. This molecular dialogue is beginning to be explored, repeatedly implicating the Wnt signaling pathway. Wnt signaling can be mediated through either canonical ␤-catenin-mediated Lef/Tcf transcriptional activity or other noncanonical pathways. 1,2 Signaling is initiated in most all pathways through binding of Wnts to Frizzled (Fzd) receptors. There are multiple Wnts and Fzds allowing for many ligand/receptor combinations. On the other hand, Wnt signaling can be inhibited by several regulatory molecules. The Dickkopf family (Dkk) actively prevents binding of Wnt to Fzd and its coreceptors low-density lipoprotein receptor-related proteins 5 and 6, inhibiting canonical signaling, whereas secreted Fzd-related proteins (Sfrps) and Wnt inhibitory factor 1 (Wif1) bind Wnt proteins and sequester them in the extracellular space thus inhibiting both pathways. 3 Evidence for a role of Wnt proteins in hematopoiesis arose from experiments demonstrating that multiple Wnts could expand hematopoietic stem/progenitor cells (HSPCs) in culture. 4,5 Subsequently, culture of single HSCs, in the presence of purified Wnt3a, resulted in expansion concomitant with maintenance of phenotype and robust repopulating activity. 6 In addition, retroviral expression of constitutively active ␤-catenin in HSCs allowed their expansion in vitro without loss of rec...

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Section: Discussionmentioning

confidence: 99%

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Schaniel

Sirabella²,

Qiu³

et al. 2011

Blood

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“…This family controls stem cell fate by affecting diverse cellular functions, such as growth arrest, apoptosis, migration, and differentiation. BMP4, for example, is required for hematopoiesis and expressed by cells of the microenvironment of hematopoietic stem cells (13). TGF-β signaling is essential to maintain immaturity and quiescence of melanocyte stem cells in their niches within the hair bulge (14).…”

Section: Introductionmentioning

confidence: 99%

Hepatic stem cell niches

Kordes

Häussinger²

2013

J. Clin. Invest.

130

105

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Stem cell niches are special microenvironments that maintain stem cells and control their behavior to ensure tissue homeostasis and regeneration throughout life. The liver has a high regenerative capacity that involves stem/ progenitor cells when the proliferation of hepatocytes is impaired. In recent years progress has been made in the identification of potential hepatic stem cell niches. There is evidence that hepatic progenitor cells can originate from niches in the canals of Hering; in addition, the space of Disse may also serve as a stem cell niche during fetal hematopoiesis and constitute a niche for stellate cells in adults.

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“…Female CD46 transgenic donor bone marrow (1610 6 unfractionated cells or 1000 Lineage 2 c-kit + Sca-1 + cells sorted as described (Goldman et al, 2009) was transplanted into CD45.1 or CD45.1 GFP male recipients following 750 cGy gamma irradiation. For secondary transplant studies, 1610 6 unfractionated bone marrow cells from primary hosts were transplanted into lethally irradiated (1150 cGy), 8-to 12-week-old hosts.…”

Section: Transplantation Studiesmentioning

confidence: 99%

Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system

Skinner

Grompe

Kurre

2012

Journal of Cell Science

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SummaryCell fusion plays a well-recognized, physiological role during development. Bone-marrow-derived hematopoietic cells have been shown to fuse with non-hematopoietic cells in a wide variety of tissues. Some organs appear to resolve the changes in ploidy status, generating functional and mitotically-competent events. However, cell fusion exclusively involving hematopoietic cells has not been reported. Indeed, genomic copy number variation in highly replicative hematopoietic cells is widely considered a hallmark of malignant transformation. Here we show that cell fusion occurs between cells of the hematopoietic system under injury as well as non-injury conditions. Experiments reveal the acquisition of genetic markers in fusion products, their tractable maintenance during hematopoietic differentiation and long-term persistence after serial transplantation. Fusion events were identified in clonogenic progenitors as well as differentiated myeloid and lymphoid cells. These observations provide a new experimental model for the study of non-pathogenic somatic diversity in the hematopoietic system.

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BMP4 regulates the hematopoietic stem cell niche

Cited by 100 publications

References 39 publications

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Hepatic stem cell niches

Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system

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