Abstract
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 NANOG, SOX2, c-MYC, and KLF4, as well as an array of genes expressed in pluripotent stem cells and primordial germ cells, including CD24, NANOG, SSEA4, SSEA3, TRA-1-60, TRA-1-81, STELLA, FRAGILIS, NANOS3, DAZL and SSEA1. 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 OCT4A variant 1 and showing higher levels of expression of NANOG, SOX2, c-MYC and KLF4 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 in vivo; when transplanted in the osteogenesis imperfecta 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.
Highlights
Mesenchymal stromal/stem cells (MSC), isolated from a range of adult and fetal tissues, have generated substantial interest for use in cell therapy and tissue engineering due to their ability to migrate to sites of injury and regenerate and repair damaged tissues [1,2,3]
Kinetic analysis revealed that early fetal placental chorionic stem cells (e-CSC) grew faster than l-CSC over a longer period of time when maintained at sub-confluence (17 vs. 11 passages without reduced growth; Fig. 2d) and generated greater cell numbers when grown beyond confluence (5.0 PD60.6 s.e.m vs. 2.3 PD61.3 over 288 hours, P,0.05; Fig. 2e)
We showed that only e-CSC, but not l-CSC, formed embryoid bodies (EBs) when grown in EB-permissive media, which may be linked to lack of OCT4A variant 1 expression in l-CSC
Summary
Mesenchymal stromal/stem cells (MSC), isolated from a range of adult and fetal tissues, have generated substantial interest for use in cell therapy and tissue engineering due to their ability to migrate to sites of injury and regenerate and repair damaged tissues [1,2,3]. Human fetal blood MSC transplanted in a mouse model of osteogenesis imperfecta substantially reduced long bone fracture rates, with donor cells engrafting at sites of bone formation and differentiating into functional osteoblasts, which modified bone matrix and reduced bone brittleness [8,9]. Transplantation of fetal blood MSC in a mouse model of collagen type 1 deficiency led to improvement of glomerulopathy [10]. Tissue-engineered bone grafts seeded with first trimester bone marrow MSC resulted in closure of critical-sized femoral defects in rats by promoting woven and compact bone formation [11]
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