Determinants of Embryonic Hematopoietic Stem Cell Emergence and Maturation

Abstract

Advances in understanding the developmental origins of hematopoietic stem cell (HSCs)—precisely the molecular mechanisms promoting their emergence and maturation—may lead to derivation of personalized HSCs, circumventing issues of immune mismatch during bone marrow transplantation. In mouse, it is widely accepted that HSCs emerge during mid-gestation from the caudal region of the embryo containing the dorsal aorta, which is called the aorta-gonad-mesonephros (AGM). The emergence occurs through an endothelial intermediate via a phenomenon called the endothelial-to-hematopoietic transition (EHT), whereby endothelial cells round up to become HSCs. AGM HSCs subsequently seed the fetal liver and bone marrow near birth. In our first work, we have identified a novel inflammatory signaling axis PKA/CREB-BMP acting downstream of shear stress that regulates HSC emergence in the AGM via the EHT. In our second work, we have identified the inflammatory interferon-alpha/Jak-Stat pathway in the developmental maturation of these AGM HSCs, whose manipulation may lead to increased potency of reprogrammed HSCs for transplantation. Both signaling axes are novel inflammatory signals regulating normal HSC development, which have important applications in the derivation of HSCs from pluripotent stem cells.