Ontological Differences in First Compared to Third Trimester Human Fetal Placental Chorionic Stem Cells

<div><p>Human mesenchymal stromal/stem cells (MSC) isolated from fetal tissues hold promise for use in tissue engineering applications and cell-based therapies, but their collection is restricted ethically and technically. In contrast, the placenta is a potential source of readily-obtainable stem cells throughout pregnancy. In fetal tissues, early gestational stem cells are known to have advantageous characteristics over neonatal and adult stem cells. Accordingly, we investigated whether early fetal placental chorionic stem cells (e-CSC) were physiologically superior to their late gestation fetal chorionic counterparts (l-CSC). We showed that e-CSC shared a common phenotype with l-CSC, differentiating down the osteogenic, adipogenic and neurogenic pathways, and containing a subset of cells endogenously expressing <em>NANOG</em>, <em>SOX2</em>, <em>c-MYC</em>, and <em>KLF4</em>, as well as an array of genes expressed in pluripotent stem cells and primordial germ cells, including <em>CD24</em>, <em>NANOG</em>, <em>SSEA4</em>, <em>SSEA3</em>, <em>TRA-1-60</em>, <em>TRA-1-81</em>, <em>STELLA</em>, <em>FRAGILIS</em>, <em>NANOS3</em>, <em>DAZL</em> and <em>SSEA1</em>. However, we showed that e-CSC have characteristics of an earlier state of stemness compared to l-CSC, such as smaller size, faster kinetics, uniquely expressing <em>OCT4A</em> variant 1 and showing higher levels of expression of <em>NANOG</em>, <em>SOX2</em>, <em>c-MYC</em> and <em>KLF4</em> than l-CSC. Furthermore e-CSC, but not l-CSC, formed embryoid bodies containing cells from the three germ layer lineages. Finally, we showed that e-CSC demonstrate higher tissue repair <em>in vivo</em>; when transplanted in the <em>osteogenesis imperfecta</em> mice, e-CSC, but not l-CSC increased bone quality and plasticity; and when applied to a skin wound, e-CSC, but not l-CSC, accelerated healing compared to controls. Our results provide insight into the ontogeny of the stemness phenotype during fetal development and suggest that the more primitive characteristics of early compared to late gestation fetal chorionic stem cells may be translationally advantageous.</p>