Ontogeny of Human Umbilical Cord Perivascular Cells: Molecular and Fate Potential Changes During Gestation

Abstract

Human umbilical cord-derived perivascular cells (PVCs) are a recently characterized source of mesenchymal stromal cells that has gained much interest in the field of cellular therapeutics. However, very little is known about the changes in fate potential and restrictions that these cells undergo during gestational development. This study is the first to examine the phenotypic, molecular, and functional properties of first trimester (FTM)-derived PVCs, outlining properties that are unique to this population when compared to term (TERM) counterparts. FTM- and TERM-PVCs displayed analogous mesenchymal, perivascular, and immunological immunophenotypes. Both PVCs could be maintained in culture without alteration to these phenotypes or mesenchymal lineage differentiation potential. Some unique features of FTM-PVCs were uncovered in this study: (1) while the gene signatures of FTM- and TERM-PVCs were similar, key differences were observed, namely, that the Oct4A and Sox17 proteins were detected in FTM-PVCs, but not in TERM counterparts; (2) FTM-PVCs exhibited a greater proliferative potential; and (3) FTM-PVCs were more efficient in their in vitro differentiation toward selective mesenchymal cell types, including the chondrogenic and adipogenic lineages, as well as toward neuronal- and hepatocyte-like lineages, when compared to TERM-PVCs. Both PVCs were able to generate osteocytes and cardiomyocyte-like cells with similar efficiencies in vitro. Overall, FTM-PVCs show more plasticity than TERM-PVCs with regard to fate acquisition, suggesting that a restriction in multipotentiality is imposed on PVCs as gestation progresses. Taken together, our findings support the idea that PVCs from earlier in gestation may be better than later sources of multipotent stromal cells (MSCs) for some regenerative medicine applications.

Alleviation of streptozotocin-induced diabetes in nude mice by stem cells derived from human first trimester umbilical cord

“…Given the properties of hFTM-PV cells, we hypothesized that they are a favorable source of stem cells for conversion into insulin-producing cells owing to their greater proliferative potential and higher differentiation efficiency in vitro (Librach et al, 2009;Hong et al, 2013), their greater capacity to alleviate diabetes, and the lower risk of rejection they offer compared with other sources of MSCs.…”

“…Moreover, transplantation of the cells with or without differentiation in vitro can alleviate STZ-induced diabetes in nude mice. Since younger sources of adult stem cell populations show a greater proliferative potential and plasticity than their older counterparts (Librach et al, 2009;Choumerianou et al, 2010;Hong et al, 2013), hFTM-PV cells may have more potential as a starting material for the generation of an unlimited supply of insulin-secreting cells.…”

“…To isolate umbilical cord stem cells, we followed a procedure outlined in the references (Librach et al, 2009;Hong et al, 2013).…”

“…Although the hFTM-PV cells per se are mainly a mesenchymal lineage with pericyte-like properties (Hong et al, 2013), the cells can form EB-like aggregations in which a large number of cells can express the endodermal marker AFP ( Figure 1C). We modified a differentiation protocol without the steps of activin A and retinoic acid treatment, and used it to differentiate ES cells into definitive endoderm and pancreatic fates (Jiang et al, 2007;Mayhew and Wells, 2010).…”

“…These hFTM-PV cells exhibit certain features of pluripotent stem cells that include expression of pluripotent stem cell markers and formation of embryoid body (EB)-like cell aggregations (Librach et al, 2009). A research group based in Canada has further discovered that hFTM-PV cells exhibit significantly greater proliferative potential and are more efficient in their in vitro differentiation towards selective mesenchymal cell types including chondrogenic and adipogenic lineages, as well as towards neuronal-and hepatocyte-like lineages when compared with TERM-PV cells (Hong et al, 2013).…”