Natural estrogens enhance the engraftment of human hematopoietic stem and progenitor cells in immunodeficient mice

Hematopoietic stem and progenitor cells (HSPC) are crucial in the maintenance of lifelong production of all blood cells. These stem cells are highly regulated to maintain homeostasis through a delicate balance between quiescence, self-renewal and differentiation. However, this balance is altered during the recovery after HSPC transplantation. Transplantation efficacy can be limited by inadequate hematopoietic stem cell number, poor homing, low level of engraftment, or limited self-renewal. As recent evidence indicates that estrogens are involved in regulating hematopoiesis, we sought to examine whether natural estrogens (estrone or E1, estradiol or E2, estriol or E3 and estetrol or E4) modulate human HSPC. Our results show that human HSPC subsets express estrogen receptors, and that signaling is activated by E2 and E4 on these cells. Additionally, these natural estrogens cause different effects on human progenitors in vitro. We found that both E2 and E4 expand human HSPC. However, E4 was the best tolerated estrogen and promoted cell cycling of human hematopoietic progenitors. Furthermore, we found that E2 and, more significantly, E4 doubled human hematopoietic engraftment in immunodeficient mice without altering other HSPC properties. Finally, the impact of E4 on promoting human hematopoietic engraftment in immunodeficient mice might be mediated through the regulation of mesenchymal stromal cells in the bone marrow niche. Collectively, our data demonstrate that E4 is well tolerated and enhances human reconstitution in immunodeficient mice directly, by modulating human hematopoietic progenitor properties, and indirectly, by interacting with the bone marrow niche. This might have particular relevance for improving hematopoietic recovery after myeloablative conditioning, especially when limited numbers of HSPC are available.