Abstract
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.
Highlights
Bone can heal itself, but it is exceedingly difficult to reconstitute large bone defects induced by heavy trauma or resection of malignant tumor
Glucose is essential for osteogenic differentiation and survival of human bone marrow stem cells (hBMSCs) Alizarin Red staining was used to confirm the effect of glucose on osteogenic differentiation
METTL7A-transfected hBMSCs (METTL7A) knockout inhibit osteogenic differentiation and glucose supplementation conditions were set to the normal range of reduced cell viability in hBMSCs
Summary
But it is exceedingly difficult to reconstitute large bone defects induced by heavy trauma or resection of malignant tumor. Regenerative medicine, including the implantation of stem cells, has been studied as a novel solution to treat refractory bone defects or diseases [1, 2]. With impaired local vascularity, even the transplanted cells undergo rapid necrosis before differentiating into osteoblasts and regenerating bone. Without enhanced survival of implanted stem cells, regenerative therapy is inefficient [3, 4]. Most of the implanted cells die early due to exposure to hypoxia, inflammation, oxidative stress, and glucose-deficient microenvironments [5,6,7]. While little is known about the survival of osteogenic stem cells in the microenvironment of bone regeneration, e.g., fracture healing, several studies have shown that glucose is one of the key environmental factors necessary for osteogenic differentiation [8, 9]
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