The initial fetal human retinal vasculature develops by vasculogenesis

Abstract

There is increasing evidence that the hemangioblast, a common progenitor for hematopoietic cells and endothelial cells, participates in embryonic and extra-embryonic vasculogenesis in some organs. Whether resident angioblasts or endothelial progenitor cells (EPCs) contribute to human retinal vasculogenesis is still a matter of controversy. To address this controversy, fetal human retinas of 6 -23 weeks gestation (WG) were examined using immunohistochemistry and a panel of antibodies against endothelial cell markers (CD34, CD31), a marker for retinal angioblasts and endothelium (CD39/ecto-ADPase), and a marker for precursors and hemangioblasts (CXCR4). Confocal microscopic spectral analysis and double labeling with Ki67 was used to identify the proliferating cell types. In the inner neuroblastic layer of the 6 -8 WG retina and in the putative ganglion cell layer in avascular regions of older eyes (14 WG-20 WG), scattered CD39 ؉ angioblasts were well in advance of forming vasculature. There was a layer of CXCR4 ؉ cells in the inner retina that was reduced in size with development. As blood vessels formed, CD39؉ cells were always well in advance of the vascular front and they expressed CXCR4. This demonstrates that a pool of resident angioblasts express CD39 and CXCR4 as they differentiate and participate in vasculogenesis in the fetal human. They retain expression of CD39 as endothelial cells in the newly formed retinal vasculature but they down-regulate CXCR4 expression. Developmental Dynamics 235:3336 -3347, 2006.

CXCR4 signaling in the regulation of stem cell migration and development

“…A further interesting phenotype identified in SDF-1/CXCR4 knockout mice is a deficiency in blood vessel development, initially observed in the gastrointestinal system (Tachibana et al, 1998). Consistent with such observations, CXCR4 receptors have been shown to be expressed by hemangioblasts, the earliest common precursor to hematopoietic and endothelial stem cells found in yolk sac blood islands (McLeod et al, 2006) and also by endothelial cells that can be derived from embryonic stem cells (ESCs) in culture (Chen et al, 2007). In the latter case these endothelial cells expressed CXCR4 and migrated towards an SDF-1 gradient.…”

The embryonic human choriocapillaris develops by hemo‐vasculogenesis

“…It forms by vasculogenesis, the differentiation and coalescence of CD39 ϩ angioblasts without proliferation of the angioblasts (McLeod et al, 2006). The vascular markers employed in this study, CD34, CD31, and VWf, were only observed in endothelial cells in formed retinal blood vessels, and not associated with angioblasts.…”

“…3H-J). CD39 was also present in retinal angioblasts in the avascular embryonic human retina (data not shown) (Chan-Ling et al, 2004;McLeod et al, 2006). VEGFR-2 was also present in cells in inner retina (data not shown) as well as in the sheet of cells under the RPE layer.…”

“…The lobular pattern of adult choriocapillaris may be a consequence of development from islands of precursors where capillaries are formed independent of flow and without guidance of neurons or matrix. This is as opposed to human retina where a mesh-like capillary system forms initially by vasculogenesis (Chan-Ling et al, 2004;McLeod et al, 2006) but it is remodeled in part by blood flow and in part by neuronal development and tissue needs, resulting in an end-arterial vasculature. There are free CD39 ϩ cells, presumably angioblasts, present during fetal development that may contribute to expansion of the choriocapillaris by vasculogenesis.…”

“…ADPase is now known to be CD39, a marker for vascular precursors (angioblasts) before, during, and after their differentiation and organization into primordial capillaries (McLeod et al, 2006). CD39 is used as an angioblast marker because there are no molecules known to date that are expressed solely by angioblasts.…”