BMP signaling is required for postnatal murine hematopoietic stem cell self-renewal

Abstract

Life-long production of blood from hematopoietic stem cells (HSC) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal – a cardinal feature of HSC. Bone morphogenetic proteins (BMP) have an established role in embryonic hematopoiesis, but less is known about its functions in adulthood. Previously, SMAD-mediated BMP signaling has been proven dispensable for HSC. However, the BMP type-II receptor (BMPR-II) is highly expressed in HSC, leaving the possibility that BMP function via alternative pathways. Here, we establish that BMP signaling is required for selfrenewal of adult HSC. Through conditional knockout we show that BMPR-II deficient HSC have impaired self-renewal and regenerative capacity. BMPR-II deficient cells have reduced p38 activation, implying that non-SMAD pathways operate downstream of BMP in HSC. Indeed, a majority of primitive hematopoietic cells do not engage in SMADmediated responses downstream of BMP in vivo . Furthermore, deficiency of BMPR-II results in increased expression of TJP1 , a known regulator of self-renewal in other stem cells, and knockdown of TJP1 in primitive hematopoietic cells partly rescues the BMPR-II null phenotype. This suggests TJP1 may be a universal stem cell regulator. In conclusion, BMP signaling, in part mediated through TJP1, is required endogenously by adult HSC to maintain self-renewal capacity and proper resilience of the hematopoietic system during regeneration.

Charting epimutation dynamics in human hematopoietic differentiation

“…In particular, several key pathways essential for HSC function were enriched in the BM, including the RHO GTPase cycle signaling, AKT signaling, WNT signaling, BMP pathway, Runx1 pathway, and Notch signaling pathway. 17–20 Regarding PB HSCs, these regions exhibited enrichment in HS-GAG degradation and cell differentiation ( Fig. 5D ).…”

Micro‐environment alterations through time leading to myeloid malignancies

“…Elevated levels of VEGF stimulate angiogenesis and subsequent disease progression. morphogenic protein receptor 2 (BMPR-2) reduces the reconstitutive capacity of long-term repopulating HSCs following transplantation with BmprII À/À bone marrow cells suggesting an important role of BmprII in HSC self-renewal (Singbrant et al, 2010;Warsi et al, 2021). The bone marrow micro-environment has also been shown to influence HSC heterogeneity based on location within cellular networks.…”

“…Whilst the role of the BMP/SMAD (small mothers against decapentaplegic)‐dependant pathway, like other self‐renewal pathways, is well understood in embryonic development, the effect of the canonical pathway in adult and foetal liver haematopoiesis seems dispensable in favour of alternative pathways. Recent work in xenograft mice has however suggested that a deficiency in bone morphogenic protein receptor 2 (BMPR‐2) reduces the reconstitutive capacity of long‐term repopulating HSCs following transplantation with BmprII −/− bone marrow cells suggesting an important role of BmprII in HSC self‐renewal (Singbrant et al, 2010; Warsi et al, 2021). The bone marrow micro‐environment has also been shown to influence HSC heterogeneity based on location within cellular networks.…”