Role of STAT3 and SDF-1/CXCL 12 in mitochondrial function in hematopoietic stem and progenitor cells

Abstract

Mitochondria are the major ATP producing source within cells. There is increasing data supporting a direct involvement of mitochondria and mitochondrial function in regulating stem cell pluripotency. Mitochondria have also been shown to be important for hematopoietic stem and progenitor cell function. Hematopoietic stem cells have lower numbers of mitochondria (mass), lower mitochondrial membrane potential, and lower ATP levels as compared to other blood cell types. Mitochondria play an important role in hematopoietic stem and progenitor cells, thus we investigated the role of the chemokine, SDF-1/CXCL12, in mitochondrial function in hematopoietic stem and progenitor cells using an SDF-1/CXCL12 transgenic mouse model. We found increased mitochondrial mass is linked to CD34 surface expression in hematopoietic stem and progenitor cells, suggesting that mitochondrial biogenesis is linked to loss of pluripotency. Interestingly these hematopoietic progenitor cells have low mitochondrial membrane potential and these mitochondrial become active prior to leaving the progenitor cell compartment. We also tested the ability of SDF-1/CXL12 to modulate mitochondrial function in vitro by treating the human leukemia cell line, HL-60, and primary mouse lineage- bone marrow cells with SDF-1/CXCL12. We found significantly reduced mitochondrial function at two hours while mitochondrial function was significantly increased at 24 hours. This suggests that SDF1/CXCL12 regulates mitochondrial function in a biphasic manner in a model of hematopoietic progenitors and immature blood cells. This suggests SDF1/CXCL12 may play a role in regulating mitochondrial function in hematopoiesis. We also investigated STAT3 in hematopoietic stem and progenitor cells. Mitochondrial STAT3 plays an essential role in regulating mitochondrial function. By using a knockout (Stat3-/-) mouse model we found that Stat3-/- hematopoietic progenitor cells had reduced colony forming ability, slower cell cycling status, and loss of proliferation in response to multi-cytokine synergy. We also found mitochondrial dysfunction in Stat3-/- hematopoietic stem and progenitor cells. Our results suggest an essential role for mitochondria in HSC function and a novel role for SDF-1/CXCL12 and STAT3 in regulating mitochondrial function in hematopoietic stem and progenitor cells.