Epigenetic memory gained by priming with osteogenic induction medium improves osteogenesis and other properties of mesenchymal stem cells

Abstract

Mesenchymal stem cells (MSCs) are highly plastic cells that are able to transdifferentiate or dedifferentiate under appropriate conditions. In the present study, we reported here that after in vitro induction of osteogenic differentiation, MSCs could be reverted to a primitive stem cell population (dedifferentiated osteogenic MSCs, De-Os-MSCs) with improved cell survival, colony formation, osteogenic potential, migratory capacity and increased expression of Nanog, Oct4 and Sox2. Most importantly, our results showed great superiority of the De-Os-MSCs over untreated MSCs in ectopic bone formation in vivo. Furthermore, Nanog-knockdown in MSCs could reverse these enhanced properties in De-Os-MSCs in vitro, indicating a central role of Nanog in the transcriptional network. In addition, epigenetic regulations including DNA methylation and histone modifications may play important roles in regulating the de-osteogenic differentiation process. And we found decreased methylation and promoter accrual of activating histone marks, such as H3K4me3 and H4ac on both Nanog and Oct4 gene promoters. Taken together, our study demonstrated that epigenetic memory in De-Os-MSCs gained by priming with osteogenic induction medium favored their differentiation along osteoblastic lineage with improved cell survival and migratory abilities, which may have application potential in enhancing their regenerative capacity in mammals.

5‐Azacytydine and resveratrol reverse senescence and ageing of adipose stem cells via modulation of mitochondrial dynamics and autophagy

“…It agrees with our previous data regarding the effects of AZA on aged human MSCs, where its beneficial effect on these cells was proved . A study conducted by Rui et al revealed that epigenetic alternations of MSCs could be an attractive way to control their differentiation . Epigenetic regulation, including DNA methylation and histone modification plays a key role in the process of differentiation.…”

The involvement of histone methylation in osteoblastic differentiation of human periosteum‐derived cells cultured in vitro under hypoxic conditions

“…Although many studies have focused on the relationship between extrinsic regulators and corresponding intrinsic target transcription factors that affect the characteristics and functions of MSCs, evidence regarding the importance of epigenetics in regulating MSCs has been limited. Among the various modes of epigenetic regulation, DNA methylation and histone modifications are widely accepted to have the greatest impact on MSC differentiation …”

“…In addition, the hPDCs cultured under hypoxic conditions showed a decrease in the expression of have the greatest impact on MSC differentiation. 10,33,34 In the present study, we examined whether histone methylation is [16][17][18][19] Here, an increased level of H3K27me3 was observed on the promoter region of a key osteogenic factor, BMP-2, in hPDCs cultured in hypoxic conditions compared with those cultured in normoxic conditions. In addition, histone demethylase KDM6B was significantly downregulated in hPDCs cultured in hypoxia.…”

Epigenetic Modification of the CCL5/CCR1/ERK Axis Enhances Glioma Targeting in Dedifferentiation-Reprogrammed BMSCs

“…This result is consistent with the other reports showing that acetylation modification patterns are more responsive to culture condition in MSCs (Fani et al., 2016, Zhu et al., 2015). Moreover, in our previous study, we observed that the expression of multiple histone acetyltransferases was markedly increased in dedifferentiated-reprogrammed BMSCs (Rui et al., 2015). Consistently, in this study, we demonstrated that the expression of H4Ac was also significantly increased in the migrating De-neu-BMSCs toward glioma in vivo (Figure 5D).…”