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Hematopoiesis
BMP signaling is required for postnatal murine hematopoietic stem cell self-renewal
Ferrata Storti Foundation
Haematologica 2021 Volume 106(8):2203-2214
Sarah Warsi,* Ulrika Blank,* Maria Dahl, Tan Hooi Min Grahn, Ludwig Schmiderer, Silja Andradottir and Stefan Karlsson
Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
*SW and UB contributed equally as co-first authors.
ABSTRACT
Life-long production of blood from hematopoietic stem cells (HSC) is a process of strict modulation. Intrinsic and extrinsic signals gov- ern 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 alterna- tive pathways. Here, we establish that BMP signaling is required for self- renewal 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 SMAD- mediated 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 sug- gests TJP1 may be a universal stem cell regulator. In conclusion, BMP sig- naling, 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.
Introduction
Hematopoietic stem cells (HSC) have dual capacity to self-renew and give rise to differentiating progeny.1,2 Self-renewal pertains to the ability of HSC to duplicate without losing developmental potential. Maintenance of the stem cell pool is dependent on self-renewal and loss thereof leads to erosion of regenerative capacity and hematopoietic failure. In order to ensure homeostasis, HSC are tightly regulated by internal factors and external signaling cues from the bone marrow (BM) niche.3 Although many regulatory mechanisms have been identified, deeper understanding of the self-renewal machinery is required to fully utilize the therapeutic potential of HSC.
Bone morphogenetic proteins (BMP) belong to the TGF-b superfamily of secreted cytokines, which during embryogenesis regulate a wide variety of biological processes.4-7 Mechanistically, BMP signal through cell surface receptors, which acti- vate receptor-regulated SMAD transcription factors (R-SMAD) through phosphory- lation.8 Phosphorylated R-SMAD form complexes with SMAD4 resulting in nuclear accumulation of activated complexes, which together with cofactors regulate target gene transcription.8 Two classes of receptors have been identified; type-I and type- II. BMP bind to and signal via the BMP type-II receptor (BMPR-II), in association with any type-I receptor (ALK2, ALK3, or ALK6).8
The importance of BMP signaling during development is well established and reflected in early embryonic lethality of mice with targeted deletions of components of the pathway.9-12 Similarly, deletion of SMAD1 and SMAD5 results in embryonic lethality.13-16 Beyond development, the TGF-b superfamily regulates tissue home-
Correspondence:
SARAH WARSI
sarah.warsi@med.lu.se
Received: August 28, 2019. Accepted: July 10, 2020. Pre-published: July 16, 2020.
https://doi.org/10.3324/haematol.2019.236125
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