Meso-Endothelial Bipotent Progenitors from Human Placenta Display Distinct Molecular and Cellular Identity

摘要

class="head no_bottom_margin" id="sec1title">IntroductionVascularization is an essential physiological process that occurs during embryonic and fetal development and in disease (). It is well documented that endothelial cells arise from precursors (, ) of the splanchnopleural or paraxial mesoderm (). Among mesodermal cells, hemangioblasts that differentiate into both hematopoietic and endothelial cells (, ) have received much attention, but they are spatially restricted to the periphery of the endoderm as well as the aorta-gonad-mesonephros region at later stages of development (). Therefore, endothelial cells would be expected to also derive from mesodermal progenitors devoid of hematopoietic potential.Recently, proposed the existence of a mesoderm-derived bipotent progenitor cell, the so-called mesenchymoangioblast, which could be derived and characterized from embryonic stem cells. Although hemangioblast and hemogenic endothelium have been broadly characterized during development (reviewed in ), precursors for mesenchymoangioblasts with both endothelial and mesenchymal potential have seldom been explored in vivo. In this regard, identified vessel-associated progenitors, “mesoangioblasts,” with potential to form both vessel and associated cells in murine models. Mesoangioblasts isolated from dorsal aorta at embryonic day 9.5 demonstrated extensive self-renewal capacity with the potential to form most mesodermal lineages on transplantation (). Moreover, given the similarity of their surface marker profile with mesenchymal stem cells (MSCs), mesoangioblasts were proposed as the ancestors of postnatal MSCs (, , ). Murine experiments reported expression of Flk1 (vascular endothelial growth factor receptor 2) (), CD34, or c-Kit (href="#bib15" rid="bib15" class=" bibr popnode">Minasi et al., 2002) in mesoangioblasts. The existence of mesoangioblasts in postnatal life has also been suggested through isolation from muscle pericytes (href="#bib3" rid="bib3" class=" bibr popnode">Bonfanti et al., 2015). Others have reported mesodermal precursors with endothelial capacity in bone marrow (href="#bib26" rid="bib26" class=" bibr popnode">Reyes et al., 2002, href="#bib27" rid="bib27" class=" bibr popnode">Roobrouck et al., 2011). Despite these various indications in essentially murine studies, the existence of a bipotential population with capacity to give rise to mesenchymal and endothelial progeny in human tissues remains questioned.The recent description of a functional hierarchy in the endothelium based on colony-formation capacity and proliferative potential has allowed to define progenitors, namely highly proliferative endothelial colony-forming cells (ECFCs) as opposed to low proliferative potential ECFCs or endothelial clusters (href="#bib11" rid="bib11" class=" bibr popnode">Ingram et al., 2004). Our group recently demonstrated in vivo the heterogeneity and hierarchy of the endothelial compartment in murine vasculature, allowing a functional definition of endothelial progenitors (href="#bib20" rid="bib20" class=" bibr popnode">Patel et al., 2016a). We have also demonstrated that human ECFCs as well as human MSCs of fetal origin can be isolated from the term placenta (href="#bib19" rid="bib19" class=" bibr popnode">Patel et al., 2013, href="#bib21" rid="bib21" class=" bibr popnode">Patel et al., 2014). Here, we hypothesized that vascularization of the human placenta from mesodermal precursors gives a unique opportunity to prospectively characterize the human mesoangioblast phenotype. Our findings support the existence in vivo of meso-endothelial bipotent progenitors capable of giving rise to both endothelial and mesenchymal progeny. Characterization of this progenitor distinguishes it from both mesenchymal (MSCs) and endothelial progenitors (ECFCs) at the functional and molecular level.