Lee Eugene, Kim Ju-Young, Kim Tae-Kyung, Park Seo-Young, Im Gun-Il
Research Institute for Integrative Regenerative Biomedical Engineering, Dongguk University, Goyang, 10326, Republic of Korea.
Cell Death Discov. 2021 Jun 30;7(1):154. doi: 10.1038/s41420-021-00555-4.
While bone has an inherent capacity to heal itself, it is very difficult to reconstitute large bone defects. Regenerative medicine, including stem cell implantation, has been studied as a novel solution to treat these conditions. However, when the local vascularity is impaired, even the transplanted cells undergo rapid necrosis before differentiating into osteoblasts and regenerating bone. Thus, to increase the effectiveness of stem cell transplantation, it is quintessential to improve the viability of the implanted stem cells. In this study, given that the regulation of glucose may hold the key to stem cell survival and osteogenic differentiation, we investigated the molecules that can replace the effect of glucose under ischemic microenvironment of stem cell transplantation in large bone defects. By analyzing differentially expressed genes under glucose-supplemented and glucose-free conditions, we explored markers such as methyltransferase-like protein 7A (METTL7A) that are potentially related to cell survival and osteogenic differentiation. Overexpression of METTL7A gene enhanced the osteogenic differentiation and viability of human bone marrow stem cells (hBMSCs) in glucose-free conditions. When the in vivo effectiveness of METTL7A-transfected cells in bone regeneration was explored in a rat model of critical-size segmental long-bone defect, METTL7A-transfected hBMSCs showed significantly better regenerative potential than the control vector-transfected hBMSCs. DNA methylation profiles showed a large difference in methylation status of genes related to osteogenesis and cell survival between hBMSCs cultured in glucose-supplemented condition and those cultured in glucose-free condition. Interestingly, METTL7A overexpression altered the methylation status of related genes to favor osteogenic differentiation and cell survival. In conclusion, it is suggested that a novel factor METTL7A enhances osteogenic differentiation and viability of hBMSCs by regulating the methylation status of genes related to osteogenesis or survival.
虽然骨骼具有自我愈合的内在能力，但修复大的骨缺损却非常困难。包括干细胞植入在内的再生医学已被作为治疗这些病症的一种新方法进行研究。然而，当局部血管受损时，即使是移植的细胞在分化为成骨细胞并再生骨骼之前也会迅速坏死。因此，为了提高干细胞移植的有效性，提高植入干细胞的存活率至关重要。在本研究中，鉴于葡萄糖的调节可能是干细胞存活和成骨分化的关键，我们研究了在大骨缺损干细胞移植的缺血微环境下可以替代葡萄糖作用的分子。通过分析在补充葡萄糖和无葡萄糖条件下差异表达的基因，我们探索了诸如甲基转移酶样蛋白7A（METTL7A）等可能与细胞存活和成骨分化相关的标志物。METTL7A基因的过表达增强了无葡萄糖条件下人骨髓干细胞（hBMSCs）的成骨分化和活力。当在临界大小节段性长骨缺损的大鼠模型中探索METTL7A转染细胞在骨再生中的体内有效性时，METTL7A转染的hBMSCs显示出比对照载体转染的hBMSCs明显更好的再生潜力。DNA甲基化谱显示，在补充葡萄糖条件下培养的hBMSCs和在无葡萄糖条件下培养的hBMSCs之间，与成骨和细胞存活相关的基因的甲基化状态存在很大差异。有趣的是，METTL7A过表达改变了相关基因的甲基化状态，有利于成骨分化和细胞存活。总之，提示一种新因子METTL7A通过调节与成骨或存活相关基因的甲基化状态来增强hBMSCs的成骨分化和活力。
