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Adult long‐term hematopoiesis depends on sustaining hematopoietic stem/progenitor cells ( HSPC ) in bone marrow ( BM ) niches, where their balance of quiescence, self‐renewal, and hematopoietic differentiation is tightly regulated. Although various  BM  stroma cells that produce niche factors have been identified, regulation of the intrinsic responsiveness of  HSPC  to the niche factors remains elusive. We previously reported that mice deficient for  Sipa1 , a Rap1  GTP ase‐activating protein, develop diverse hematopoietic disorders of late onset. Here we showed that transplantation of  BM  cells expressing membrane‐targeted  C3G (C3G‐F) , a Rap1  GTP / GDP  exchanger, resulted in the progressive decline of the numbers of  HSPC  repopulated in  BM  with time and impaired long‐term hematopoiesis of all cell lineages.  C3G‐F / HSPC  were sustained for months in spleen retaining hematopoietic potential, but these cells inefficiently contributed to overall hematopoietic reconstitution.  C3G‐F / HSPC  showed enhanced proliferation and differentiation with accelerated progenitor cell exhaustion in response to stem cell factor ( SCF ). Using a Ba/F3 cell line, we confirmed that the increased basal Rap1 GTP  levels with  C3G‐F  expression caused a markedly prolonged activation of c‐Kit receptor and downstream signaling through  SCF  ligation. A minor population of  C3G‐F / HSPC  also showed enhanced proliferation in the presence of thrombopoietin ( TPO ) compared to  Vect / HSPC . Current results suggest an important role of basal Rap1 activation status of  HSPC  in their maintenance in  BM  for sustaining long‐term adult hematopoiesis.

Rap1 signal modulators control the maintenance of hematopoietic progenitors in bone marrow and adult long‐term hematopoiesis