1001 – MAKING BLOOD BEFORE A BLOOD STEM CELL

Abstract

Erythroid cells comprise a critical component of the cardiovascular network, which constitutes the first functional organ system of the mammalian embryo. In the beginning of the last century, it was recognized that distinct “primitive” and “definitive” red cell populations circulate in the embryo. Building on pioneering studies by Metcalf mapping myeloid progenitors in embryonic time and space, we determined that overlapping waves of primitive (EryP-CFC) and definitive (BFU-E) erythroid progenitors emerge in the yolk sac of pre-circulation murine embryos. EryP-CFC generate a synchronous wave of cells that comprises ∼40% of all cells in the mouse embryo, which undergo rapid hemoglobin accumulation, maturational globin switching, complex metabolic reprogramming, and ultimately enucleation, indicating that primitive erythropoiesis is indeed ‘mammalian’ in character. While EPO regulates the terminal maturation of primitive erythroblasts, it has remained unclear what factors regulate their initial emergence. Our recent studies indicate that Stat3 signaling, activated independently of EPO, may serve this function. Unlike EryP-CFC, the BFU-E that arise in the yolk sac are clonally associated with multiple myeloid lineages, and go on to seed the early fetal liver to serve as a critical bridge between primitive hematopoiesis and HSC-derived blood cell production. Interestingly, definitive, but not primitive, erythroblasts can self-renew when cultured ex vivo, through a Bmi1-regulated process. Overexpression of BMI1 in adult murine and human erythroblasts increases their in vitro self-renewal capacity, potentially providing a means of generating sufficient cultured red cells to meet future blood banking and transfusion needs. In summary, survival and growth of the mammalian embryo relies upon a complex and highly regulated process of robust red cell production from 2 distinct erythroid lineages that are initiated independently of HSCs soon after the start of gastrulation. Erythroid cells comprise a critical component of the cardiovascular network, which constitutes the first functional organ system of the mammalian embryo. In the beginning of the last century, it was recognized that distinct “primitive” and “definitive” red cell populations circulate in the embryo. Building on pioneering studies by Metcalf mapping myeloid progenitors in embryonic time and space, we determined that overlapping waves of primitive (EryP-CFC) and definitive (BFU-E) erythroid progenitors emerge in the yolk sac of pre-circulation murine embryos. EryP-CFC generate a synchronous wave of cells that comprises ∼40% of all cells in the mouse embryo, which undergo rapid hemoglobin accumulation, maturational globin switching, complex metabolic reprogramming, and ultimately enucleation, indicating that primitive erythropoiesis is indeed ‘mammalian’ in character. While EPO regulates the terminal maturation of primitive erythroblasts, it has remained unclear what factors regulate their initial emergence. Our recent studies indicate that Stat3 signaling, activated independently of EPO, may serve this function. Unlike EryP-CFC, the BFU-E that arise in the yolk sac are clonally associated with multiple myeloid lineages, and go on to seed the early fetal liver to serve as a critical bridge between primitive hematopoiesis and HSC-derived blood cell production. Interestingly, definitive, but not primitive, erythroblasts can self-renew when cultured ex vivo, through a Bmi1-regulated process. Overexpression of BMI1 in adult murine and human erythroblasts increases their in vitro self-renewal capacity, potentially providing a means of generating sufficient cultured red cells to meet future blood banking and transfusion needs. In summary, survival and growth of the mammalian embryo relies upon a complex and highly regulated process of robust red cell production from 2 distinct erythroid lineages that are initiated independently of HSCs soon after the start of gastrulation.