Abstract
BackgroundMesenchymal stem cells (MSCs) have been considered as ideal cells for the treatment of a variety of diseases. However, aging and spontaneous differentiation of MSCs during culture expansion dampen their effectiveness. Previous studies suggest that ex vivo aging of MSCs is largely caused by epigenetic changes particularly a decline of histone H3 acetylation levels in promoter regions of pluripotent genes due to inappropriate growth environment. Methodology/Principal FindingsIn this study, we examined whether histone deacetylase inhibitor trichostatin A (TSA) could suppress the histone H3 deacetylation thus maintaining the primitive property of MSCs. We found that in regular adherent culture, human MSCs became flatter and larger upon successive passaging, while the expression of pluripotent genes such as Oct4, Sox2, Nanog, Rex-1, CD133 and TERT decreased markedly. Administration of low concentrations of TSA in culture significantly suppressed the morphological changes in MSCs otherwise occurred during culture expansion, increased their proliferation while retaining their cell contact growth inhibition property and multipotent differentiation ability. Moreover, TSA stabilized the expression of the above pluripotent genes and histone H3 acetylation levels in K9 and K14 in promoter regions of Oct4, Sox2 and TERT. Conclusions/SignificanceOur results suggest that TSA may serve as an effective culture additive to maintain the primitive feature of MSCs during culture expansion.
Highlights
Mesenchymal stem cells (MSCs) are multipotent stem cells [1,2]
We found that low concentrations of trichostatin A (TSA) significantly inhibited morphological changes of human MSCs (hMSCs) that otherwise occurred during cell passaging
In accordance with the morphological changes, RealTime PCR analysis showed marked decreases of expression levels of pluripotent genes Oct4, Sox2, CD133, TERT, REX1 and Nanog, and increased levels of osteogenic genes alkaline phasphatase (ALP) and OPN in passage 10 hMSCs compared to hMSCs in passage 1 (Figure 1)
Summary
Mesenchymal stem cells (MSCs) are multipotent stem cells [1,2]. Accumulating evidence suggests that MSCs have profound therapeutic potential for a variety of diseases such as myocardial infarction, neural diseases and wound healing [3,4]. It has been demonstrated that MSCs are present in umbilical cord and placenta [7,8] This profoundly increases the availability of MSCs, but ex vivo expansion remains an indispensable procedure to obtain sufficient amounts of MSCs for cell therapies and tissue engineering. Previous studies suggest that ex vivo aging of MSCs is largely caused by epigenetic changes a decline of histone H3 acetylation levels in promoter regions of pluripotent genes due to inappropriate growth environment. Administration of low concentrations of TSA in culture significantly suppressed the morphological changes in MSCs otherwise occurred during culture expansion, increased their proliferation while retaining their cell contact growth inhibition property and multipotent differentiation ability. Conclusions/Significance: Our results suggest that TSA may serve as an effective culture additive to maintain the primitive feature of MSCs during culture expansion
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