Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Abstract

A previously unidentified modulator of vertebrate haematopoietic stem cell (HSC) number has been discovered using a chemical genetic screen in zebrafish. Prostaglandin E2 (PGE2) increases HSCs in the embryo and enhances marrow recovery following irradiation of adult fish. These effects of PGE2 on stem and progenitor cell number are conserved across vertebrate species. This suggests that modulation of this pathway could be used to treat patients undergoing bone marrow transplant and for some forms of anaemia. This study identifies Prostaglandin E2 (PGE2) as an important modulator of vertebrate haematopoietic stem cell (HSC) number. Chemicals that enhance PGE2 synthesis increase the number of HSCs whereas the opposite effect is achieved by blocking PGE2 synthesis. Haematopoietic stem cell (HSC) homeostasis is tightly controlled by growth factors, signalling molecules and transcription factors. Definitive HSCs derived during embryogenesis in the aorta–gonad–mesonephros region subsequently colonize fetal and adult haematopoietic organs1,2. To identify new modulators of HSC formation and homeostasis, a panel of biologically active compounds was screened for effects on stem cell induction in the zebrafish aorta–gonad–mesonephros region. Here, we show that chemicals that enhance prostaglandin (PG) E2 synthesis increased HSC numbers, and those that block prostaglandin synthesis decreased stem cell numbers. The cyclooxygenases responsible for PGE2 synthesis were required for HSC formation. A stable derivative of PGE2 improved kidney marrow recovery following irradiation injury in the adult zebrafish. In murine embryonic stem cell differentiation assays, PGE2 caused amplification of multipotent progenitors. Furthermore, ex vivo exposure to stabilized PGE2 enhanced spleen colony forming units at day 12 post transplant and increased the frequency of long-term repopulating HSCs present in murine bone marrow after limiting dilution competitive transplantation. The conserved role for PGE2 in the regulation of vertebrate HSC homeostasis indicates that modulation of the prostaglandin pathway may facilitate expansion of HSC number for therapeutic purposes.