Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury

Hematopoietic stem cells (HSCs) possess the great self-renewal and multidirectional differentiation ability, which contributes to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, how to precisely regulate hematopoiesis under stress conditions is poorly understood. In this study, we show that Melanocortin Receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using a MC5R knockout (MC5R-/-) mouse model, we observe that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important sub-type of melanocortin, are elevated in serum and bone marrow, and the expression of MC5R is upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression due to the impairment in the proliferation and reconstitution function of HSCs. Further investigations exhibit that melanocortin/MC5R axis regulates the proliferation of HSCs through activating the PI3K/Akt and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate the hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.