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

• Published in: Haematologica (Roma) Vol. 106; no. 8; pp. 2203 - 2214
• Main Authors: Warsi, Sarah, Blank, Ulrika, Dahl, Maria, Grahn, Tan Hooi Min, Schmiderer, Ludwig, Andradottir, Silja, Karlsson, Stefan
• Format: Journal Article
• Language: English
• Published: Italy Fondazione Ferrata Storti 01-08-2021; Ferrata Storti Foundation
• Subjects: Basic Medicine; Cell and Molecular Biology; Cell- och molekylärbiologi; Clinical Medicine; Hematologi; Hematology; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Medicinska och farmaceutiska grundvetenskaper; Hematopoietic Stem Cell; Bone morphogenetic protein; Tight junction protein; Hematopoiesis
• ISSN: 0390-6078; 1592-8721
• DOI: 10.3324/haematol.2019.236125

Life-long production of blood from hematopoietic stem cells (HSCs) is a process of strict modulation. Intrinsic and extrinsic signals govern fate options like self-renewal - a cardinal feature of HSCs. 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 HSCs. However, the BMP Type II receptor (BMPR-II) is highly expressed in HSCs, leaving the possibility that BMPs function via alternative pathways. Here, we establish that BMP signaling is required for self-renewal of adult HSCs. Through conditional knockout we show that BMPR-II deficient HSCs have impaired self-renewal and regenerative capacity. BMPR-II deficient cells have reduced p38 activation, implying that non-SMAD pathways operate downstream of BMPs in HSCs. Indeed, a majority of primitive hematopoietic cells do not engage in SMAD-mediated responses downstream of BMPs 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 HSCs to maintain self-renewal capacity and proper resilience of the hematopoietic system during regeneration.