Endothelial Progenitor Cells of the Human Placenta and Fetoplacental Circulation: A Potential Link to Fetal, Neonatal, and Long-term Health

Abstract

The fetoplacental circulation plays a key role in both short- and long-term outcomes, and aberrant flow indices as manifested by abnormal fetal Doppler velocimetry within this compartment have been associated with significant adverse consequences. These include fetal growth restriction, which often coexists with preeclampsia, and long-lasting medical issues as a result of both the underlying pathology and prematurity such as bronchopulmonary dysplasia, chronic lung disease, and neurodevelopmental delay. Furthermore, it is also clear that exposure to an abnormal in utero environment increases risk for long-term, adulthood issues such as cardiovascular disease. Endothelial progenitor cells (EPCs) have been implicated in vasculogenesis and angiogenesis, and they have been isolated from both human placenta and umbilical cord blood. This review outlines the extensive nomenclature of EPCs, summarizes existing literature surrounding human placental and umbilical cord blood EPCs, explores their potential role in pregnancy complications and adverse perinatal outcome, and highlights key areas where future investigations are needed.

Keywords: circulating progenitor cells; endothelial colony-forming cells; endothelial progenitor cells; placenta; umbilical cord blood.

Figure 1

Isolation of endothelial colony-forming cell schematic. The diagram depicts peripheral blood mononuclear cell separation via a Ficoll gradient, plating on collagen, and the appearance of colonies with cobblestone morphology.

Figure 2

Assessment of endothelial colony-forming cell (ECFC) function. (A) Representative image of a tube formation assay, where ECFCs are capable of forming capillary-like structures with the formation of branches and closed loops. (B) A classic wound migration demonstrates that ECFCs are able to migrate and close the wound. (C) ECFC proliferation is shown with BrdU staining in green (DAPI in blue). (D) Single-cell assay shows that ECFCs are capable of repopulation from a single cell.

Figure 3

Circulating progenitor cell (CPC) flow cytometry gating strategy adapted from Gumina et al. (23). Here, peripheral blood mononuclear cells were analyzed by polychromatic flow cytometry. Live mononuclear cells were selected and then gated for CD14⁻ and glycophorin A⁻ cells to exclude erythrocytes and macrophages. Next, the CD45^dim and CD34⁺ population was selected from which the pro-angiogenic (CD45^dim CD34⁺ CD31⁺ AC133⁺) and non-angiogenic (CD45^dim CD34⁺ CD31⁺ AC133⁻) CPCs were identified.