Essential Function of PDGF-B Signaling In the Placental Microenvironment In Protecting Hematopoietic Progenitors From Erythroid Differentiation.

Abstract 1559

The goals of hematopoiesis during embryogenesis are two-fold, to rapidly produce red blood cells to support the survival and development of the embryo, and to establish a pool of undifferentiated hematopoietic stem cells (HSC) for postnatal life. These goals are achieved by segregation of fetal hematopoiesis in multiple waves that are executed in distinct anatomical sites and microenvironmental niches. However, the microenvironmental cues that promote “stemness” vs. differentiation remain poorly understood. The placenta is a recently discovered hematopoietic organ that supports HSC generation and expansion without promoting their differentiation. The placental HSC pool is thought to reside in the placental labyrinth, which is comprised of an intricate vascular network surrounded by trophoblasts. So far, it has been unknown how a disruption of the integrity of the placental vascular labyrinth affects fetal hematopoiesis. The structure of the placental labyrinth is compromised in embryos that lack components of PDGF-B signaling. PDGF-B^-/- and PDGF-Rβ^-/- (receptor for PDGF-B) embryos display dilation of fetal blood vessels and reduction of trophoblast cells in the placental labyrinth. Our studies revealed that loss of PDGF-B signaling alters the unique placental hematopoietic microenvironment, resulting in active erythropoiesis in the placenta. The unexpected erythropoiesis in the placenta exhibited the same hallmarks of normal definitive erythropoiesis observed in the fetal liver as confirmed by flow cytometry for erythroid markers, morphological analysis and association of erythroblasts with macrophages. Interestingly, deletion of PDGF-Rβ in hematopoietic cells by using a Tie2-Cre strain did not induce the differentiation of placental hematopoietic progenitors into erythroid cells, implying that the ectopic definitive erythropoiesis results from the lack of PDGF-B signaling in the placental microenvironment rather than in the hematopoietic cells themselves. Our studies revealed that the erythroid differentiation in placentas of PDGF-B^-/- embryos was induced by marked upregulation of Epo in placental trophoblasts. Strikingly, lentiviral overexpression of Epo specifically in the placental trophoblasts was sufficient to convert the placenta into an ectopic erythropoietic organ. These data reveal a critical function of PDGF-B signaling in protecting the integrity of the placental microenvironment that is required for preventing hematopoietic progenitors from differentiation during their residence in the placenta. Furthermore, these studies highlight the placenta as a versatile hematopoietic organ that supports HSC development during normal pregnancy but can be recruited as a site for definitive erythropoiesis during pathological conditions.