The Characteristics And Biological Functions Of Human Placental Mesenchymal Stem Cells

Mesenchymal stem cells(MSCs)have the potential of self-renewal and multilineage differentiation.MSCs can be derived from a wide range of different tissues.Owning to their properties of immunomodulation and tissue repair,MSCs are considered one of the most promising cell types for therapeutic applications in clinical settings.Although the different sources of MSCs have been investigated so far,human term placentas have drawn increased interest in recent years and become a sort of ideal seed cells for researches in both pre-clinical and clinical settings,due mainly to their non-invasive donor procurement,low immunogenicity,high capability of proliferation and large MSCs supply.At present,only few research groups focus on the characteristics and function of MSCs origin from human placenta derived,especially,there is no extensive research illustrates the difference of MSCs derived from human placental maternal and fetal side.Hence,interrogating the property,biological functions and potential application in a clinical setting of these placental MSCs will expand our understanding of characteristic and prospect of clinical application of MSCs.This will have an important significance in both of theoretical basis and economic benefit.Therefore,our study aimed to isolate MSCs derived from maternal and fetal side of human placentas,four polymorphic STR markers of D2S1399,D10S2325,D18S535 and GATA198B05 were employed for verification of the placental MSCs isolated from the maternal and fetal side are maternal and fetal origins,respectively.In order to find out the discrepancy between two sources of placental MSCs,the expression of functional cytokines were analyzed by flow cytometry and ELISA,and its regulatory relationship relevant to microenvironment,such as inflammation,infection and hypoxia,as well as the functions of tissue repair and immunoregulation was established.Based on above results,we further confirmed MSCs have superior benefit,by analyzing the properties,safety and therapeutic effects in a murine model of pulmonary fibrosis.The main findings of this study are listed as follows:1)Both of the cells derived from maternal and fetal side of human placentas possess a typical characteristic of MSCs,and 4 polymorphic STR markers were used for parent-offspring genetic matching.The results indicate that the MSCs from the fetal side of the placenta carry alleles of maternal and paternal origins,indicative of the fetal genome,while the MSCs from the maternal side of the placenta carry alleles of only maternal origin.These results demonstrate that the MSCs from human placenta of maternal side belong to maternal cells,while the MSCs from fetal side belong to fetal cells,which are designated as mPMSCs and fPMSCs in this study,respectively.2)Although all placental MSCs express typical MSC phenotypes,fetal but not maternal MSCs of placenta express high levels of CD200 and hepatocyte growth factor(HGF).A stress of inflammation,infection or hypoxia could alter the capability of MSCs to express cytokines IL-6,IL-8,IL-10 and HGF,implying that microenvironment might influence the immunomodulatory function of MSCs.Furthermore,compared with HGF and CD200 negative cells(mPMSCs),HGF and CD200 positive cells(fPMSCs)demonstrated significantly high potentials in promoting angiogenesis in vitro andincreasing immunosuppressive function in vivo.These therapeutic potentials were at least in part due to a difference in the ability to produce HGF and CD200.3)fPMSCs could maintain their MSC characteristics before they reached a senescent state under serum-free condition.Furthermore,acetylation modification patterns were changed in fPMSCs along with gradually increased global histone deacetylase(HDAC)activity and expression of HDAC subtypes HDAC4,HDAC5 and HDAC6,as well as a down-regulated global histone H3/H4 acetylation during in vitro culturing.In line with the acetylation alterations,the expression of oncogenes Oct4,Sox2 and TERT were significantly decreased over the propagation period.Of note,the down-regulation of Oct4 was strongly associated with changes in acetylation.Intriguingly,telomere length in fPMSCs did not significantly change during the propagating process.More importantly,fPMSCs can significantly decrease the proliferation of fibrosis as well as the deposition of collagen in Bleomycin induced mouse pulmonary fibrosis.These findings suggest that human fPMSCs may be a safe and reliable resource of MSCs and can be propagated under a serum-free condition with less risk of spontaneous malignancy,and warrants further validation in clinical settings.