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Research Background
In recent years, the incidence of low bone mineral density and fragility fractures in patients with systemic lupus erythematosus has increased year by year. It is widely believed that systemic lupus erythematosus can increase the risk of fracture, and a large number of clinical studies have found that patients with systemic lupus erythematosus are prone to osteoporosis. Bone marrow mesenchymal stem cell transplantation (BSCT) with self-renewal and differentiation into multiple cell types can effectively increase local bone mass, increase bone density, improve local osteoporosis, correct bone metabolism imbalance, and reduce bone loss. Increased osteogenesis provides a new approach to the treatment of local osteoporosis. However, the molecular mechanism of mesenchymal stem cell transplantation to improve osteoporosis remains unclear. DNA methylation is an important way for the body to regulate gene expression through epigenetic mechanisms. Many studies have shown that DNA methylation can participate in a variety of signaling pathways and play important roles in the development of osteoblasts and osteoporosis. The purpose of this study was to explore the mechanism of transplantation of mesenchymal stem cells to improve osteoporosis caused by systemic lupus erythematosus, especially the regulation of DNA methylation, and provide a theoretical basis for stem cell transplantation therapy.
In this study, the researchers used normal mice, MRL/lpr mice (systemic lupus erythematosus model) and mice treated with bone marrow mesenchymal stem cell transplantation (MSCT) as experimental materials, respectively using DNA methylation chips. The gene promoter methylation level and microRNA expression profile of the three samples were analyzed with the microRNA chip. The promoter region of the Notch signaling pathway-related gene was found to be hypomethylated in the disease group and the corresponding protein level was elevated. The expression of microRNA29b was significantly up-regulated in the disease group. Combined with previous research background, the researchers locked DNMT1 into a microRNA target gene. Further mechanism studies have shown that the increase in microRNA expression in the disease group is due to the lack of Fas protein, which can cause the release of miR-29b, thereby increasing the level of intracellular miR-29b and down-regulating DNA in MRL/lpr BMMSCs. Expression of basal transferase 1 (Dnmt1). This results in hypomethylation of the Notch1 promoter and activation of the Notch signaling pathway, which in turn impairs osteoblast differentiation. Moreover, the experiment also found that exosomes secreted by MSCT will transfer Fas to the receptor MRL/lpr BMMSCs, reducing the level of intracellular miR-29b, which will restore Dnmt1-mediated methylation of the Notch1 promoter. , thereby improving the function of the MRL/lpr BMMSC.
Technical route 
about the author
Shi Songtao, Ph.D., professor. Well-known scientist in the international stomatology field, authoritative researcher in regenerative medicine, special professor of the National Education Minister Jiang Scholar, winner of the National Outstanding Youth Fund, Professor of the University of Southern California Ostrup Dental College, Craniofacial Molecular Organism of the University of Southern California School of Dentistry Professor of the Research Center. He has long been engaged in research work in oral regenerative medicine and its clinical transformation, especially in the field of stem cell basics and applications.
Liu SY, et al. (2015) MSC Transplantation Improves Osteopenia via Epigenetic Regulation of Notch Signaling in Lupus. Cell Metabolism. 22, 1-13.
http://(15)00409-X
Cell Publication: Arraystar DNA Methylation Chip for Stem Cell Transplantation Improves Apparent Mechanism of Osteoporosis
Professor Shi Songtao has worked at the University of Pennsylvania and has long been involved in the research of oral regenerative medicine and its clinical transformation. Recently, the research team used Arraystar DNA methylation chip to study the transplantation of mesenchymal stem cells (MSC) to improve osteoporosis in patients with lupus erythematosus by epigenetic regulation of Notch signaling. This important research finding was published in the journal Cell Metabolism (IF: 17.565) (DNA methylation chip experiments are provided by Kang Cheng Biotech) .
Research ideas
Result display
Figure 1: The left picture shows the osteogenic differentiation of normal mouse MSCs. The red stained area is the new bone formed. The middle picture shows the osteogenic differentiation of MSC in osteoporosis mice. The area of ​​red stained area is significantly lower than that of the left picture. The osteogenic differentiation ability is weak; the right picture shows that the MSC osteogenic differentiation ability of the osteoporosis mice has returned to normal after receiving normal MSC treatment, similar to the left picture.
Figure 2: After 24 hours of intravenous injection of green fluorescently labeled exosomes into diseased mice, observation of mouse bone marrow cells revealed that exosomes were absorbed by bone marrow cells of diseased mice. Red is the cell membrane, green is the exosomes absorbed into the cells, and blue is the nucleus.
Figure 3: Analysis of DNA methylation microarray by MA analysis showed that compared with normal C3H/HeJ mice, MRL/lpr systemic lupus erythematosus disease group mice had decreased methylation in the overall promoter region and were treated with mesenchymal stem cell transplantation. After that, the level of methylation has rebounded significantly.
Figure 4: Schematic diagram of the article mechanism. Increased miR-29b in MRL/lpr mice, down-regulated DNMT1, triggering hypomethylation of Notch1 promoter region, elevated Notch expression, and osteoporosis. After MSCT treatment, exosomes secreted by MSC can carry Fas protein into the recipient mesenchymal stem cells. Fas protein can reduce miR-29b and play a role in the treatment of osteoporosis.
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