Tgfbr3 is required for the long-term maintenance of self-renewal potential in murine hematopoietic stem cells

Transforming growth factor-β (TGF-β) signaling plays a crucial role in maintaining the quiescence and self-renewal potential of hematopoietic stem cells (HSCs). Despite decades of research, the underlying mechanisms of TGF-β signaling in HSCs remain elusive due to conflicting phenotypes of various knockout (KO) mouse models. Here, we show that HSCs co-express Tgfbr2 , Tgfbr3 , and Endoglin (Eng ) but rarely express Tgfbr1 , whereas lymphocytes co-express Tgfbr1 and Tgfbr2 but rarely express Tgfbr3 or Eng . We also demonstrate that Tgfbr3 is dispensable for the maintenance of immune homeostasis, in contrast to Tgfbr1 and Tgfbr2 , either of which is essential for lymphocyte homeostasis. Serial transplantation assays revealed that deletion of Tgfbr3 in HSCs had little effect on short-term reconstitution but impaired long-term self-renewal potential, a similar phenotype observed in Eng conditional KO mice. Therefore, we propose that lymphocytes rely on the Tgfbr1/Tgfbr2 complex as suggested by the classical model, whereas HSCs require the unique Tgfbr2/Tgfbr3/Eng complex to orchestrate TGF-β signaling. Collectively, this study reveals Tgfbr3 as a critical regulator in the maintenance of HSC self-renewal potential and suggests a novel TGF-β receptor complex specific to HSCs.