title: Ontological differences in first compared to third trimester human fetal placental chorionic stem cells.
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.
authors.affiliation: Institute of Reproductive and Developmental Biology, Imperial College London, London, United Kingdom.
authors.forename: Gemma N
authors.initials: GN
authors.lastname: Jones
authors.forename: Dafni
authors.initials: D
authors.lastname: Moschidou
authors.forename: Tamara-Isabel
authors.initials: TI
authors.lastname: Puga-Iglesias
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kuleszewicz
authors.forename: Maximilien
authors.initials: M
authors.lastname: Vanleene
authors.forename: Sandra J
authors.initials: SJ
authors.lastname: Shefelbine
authors.forename: George
authors.initials: G
authors.lastname: Bou-Gharios
authors.forename: Nicholas M
authors.initials: NM
authors.lastname: Fisk
authors.forename: Anna L
authors.initials: AL
authors.lastname: David
authors.forename: Paolo
authors.initials: P
authors.lastname: De Coppi
authors.forename: Pascale V
authors.initials: PV
authors.lastname: Guillot
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002823:Chorion / Q000166:cytology* / Q000378:metabolism; D005260:Female; D053686:Fetal Stem Cells / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D000090062:Kruppel-Like Factor 4; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010920:Placenta / Q000166:cytology* / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011263:Pregnancy Trimester, Third; D012867:Skin / Q000293:injuries; D055746:Stage-Specific Embryonic Antigens / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation; D013997:Time Factors; D014183:Transplantation, Heterologous; D014945:Wound Healing
chemical_list: D015415:Biomarkers; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D055746:Stage-Specific Embryonic Antigens