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.