No abstract

Oxidative stress, a hallmark of ageing, inhibits the osteogenic differentiation of bone marrow‐derived mesenchymal stem cells in long bone. The dysfunction of the cellular antioxidant defence system is a critical cause of oxidative stress, but the mechanism of the decline of antioxidant defence in senescent stem cells remains elusive. Here, we found that EZH2, an epigenetic regulator of histone methylation, acted as a suppressor of the antioxidative defence system in BMSCs from the femur. The increased EZH2 led to a decrease in the levels of antioxidant enzymes and exaggerated oxidative damage in aged BMSCs, resulting in the defect of bone formation and regeneration. Mechanistically, EZH2 enhanced the modification of H3K27me3 on the promoter of Foxo1 and suppressed its function to activate the downstream genes in antioxidant defence. Moreover, epigenetic therapy targeting EZH2‐mediated H3K27me3 modification largely recovered the antioxidant defence in BMSCs and attenuate oxidative damage, leading to the recovery of the osteogenesis in old BMSCs. Taken together, our findings revealed novel crosstalk between histone epigenetic modification and oxidative stress during stem cell ageing, suggesting a possibility of epigenetic therapy in the recovery of BMSCs senescence and treatment of age‐related bone disease.

Replicative senescence during in vitro augmentation, which is mostly induced by the loss of physiological microenvironment, hinders the application of mesenchymal stem cells (MSCs) in the clinic. Here, we investigated whether MSCs senescence could be prevented by bio‐scaffold mimicking the natural tissue matrix. Human umbilical cord mesenchymal stem cells (hUCMSCs) exhibited a senescent phenotype during a long‐term passage in the conventional culture dish. To fabricate the bone matrix, a naturally based matrix composed of nano‐hydroxyapatite/chitosan/poly lactide‐co‐glycolide (nHA/CS/PLGA) was produced. Long‐term passage resulted in an obvious increase in the expression of senescence markers and a reduction in the expression of master genes involved in tissue regeneration. Functional assay confirmed that nHA/CS/PLGA scaffold preserved the proliferation and differentiation of hUCMSCs even after being passaged 27 times. Moreover, in vivo ectopic bone formation assay revealed that the bone formation of hUCMSCs cultured on the nano‐scaffolds for the long term was as robust as the cells in the early passage. In summary, our results demonstrate that nHA/CS/PLGA scaffold effectively preserves the stemness and youth of hUCMSCs in the long‐term passage. Taken advantage of its compatibility and bioactivity, nHA/CS/PLGA scaffold is of great potential in large‐scale expansion of MSCs for stem cell therapy and tissue engineering.