C-type lectin-like receptor 2 specifies a functionally distinct subpopulation within phenotypically defined hematopoietic stem cell population that contribute to emergent megakaryopoiesis

概要

C-type lectin-like receptor 2 (CLEC-2) expressed on megakaryocytes plays important roles in megakaryopoiesis. We found that CLEC-2 was expressed in about 20% of phenotypical long-term hematopoietic stem cells (LT-HSCs), which expressed lower levels of HSC-specific genes and higher levels of megakaryocyte-related molecules compared with CLEC-2low LT-HSCs. Although CLEC-2high LT-HSCs displayed immature clonogenic activities, cultured CLEC-2high LT-HSCs preferentially differentiated into megakaryocytes. CLEC-2high HSCs yielded 6.8-fold megakaryocytes progenitors (MkPs) and 6.0-fold platelets 2 and 1 week after transplantation compared with CLEC-2low LT-HSCs, respectively. However, platelets yielded from CLEC-2high HSCs gradually declined with the loss of MkPs, while CLEC-2low HSCs revealed long-term self-renewal activities, indicating that CLEC-2high LT-HSCs mainly contribute to the early phase of megakaryopoiesis. Treatment with pI:C and LPS increased the proportion of CLEC-2high LT-HSCs within LT-HSCs. Almost all of CLEC-2low LT-HSCs were in G0 phase and scarcely responded to pI:C. In contrast, 54% of CLEC-2high LT-HSCs were in G0 and pI:C treatment obliged CLEC-2high LT-HSCs to enter cell cycle and differentiated into megakaryocytes, indicating that CLEC-2high LT-HSCs are primed for cell cycle entry and rapidly yield platelets in response to inflammatory stresses. In conclusion, CLEC-2high LT-HSCs are supposed to act as a reserve for emergent platelet production under stress conditions.