The Study Of Human Umbilical Cord Mesenchymal Stem Cells Overexpressing JAM-A Promoting Diabetes Wound Healing And Related Mechanisms

With the development of an ageing society and changes in lifestyle,the prevalence of diseases associated with diabetes,varicose veins and various microangiopathies is increasing year on year,as is the incidence of chronic wounds such as diabetic wounds,venous ulcers and pressure sores.In particular,the incidence of diabetic trauma is increasing rapidly,yet there is no effective clinical treatment.Diabetic wounds are responsible for 20-30% of all amputations,making them the number one factor in non-traumatic amputations.Therefore,the treatment of diabetic trauma has become an urgent clinical challenge.Stem cell therapy is a hot topic of research in the field of regenerative medicine and it is widely considered to have greater research potential in the treatment of diabetic wounds.Stem cell therapy is also a new type of therapy in which adult stem cells are injected into damaged tissue to treat disease or injury,the most commonly used cells being mesenchymal stem cells(MSCs).There are numerous clinical studies that have demonstrated the effectiveness of MSCs in the treatment of chronic diabetic wounds,but there are limitations associated with stem cell therapy.Studies have reported that damage to MSCs and their inability to perform physiological functions as a result of transplantation manipulation can lead to inconsistent efficacy in treating wounds.The diabetic trauma microenvironment also accelerates the ageing of MSCs and induces impaired function of MSCs,preventing them from performing their original positive effects.Impairment of the adhesion activity of MSCs,which is a prerequisite for their survival,viability and effective function,can lead to a significant reduction in the survival time of MSCs in the wound and their inability to perform their physiological functions properly.Therefore,we wanted to investigate whether there is a way to improve the adhesion of MSCs in a high-sugar environment,thereby increasing their survival rate and enhancing their contribution to wound healing.In this direction,we used cellular assays to verify that the high glucose environment caused a decrease in the survival rate and corresponding functional impairment of MSCs and examined the possible mechanisms of damage to MSCs in the high glucose environment through multi-omics techniques.The results showed that the high glucose environment significantly impaired the cell adhesion and connectivity of MSCs,resulting in the inability of MSCs to establish good intercellular communication with the microenvironment and receive nutritional support,and causing oxidative stress and other adverse reactions leading to the apoptosis of MSCs.We further found that JAM-A is at the core of the adhesion-linkage related proteins in MSCs and has the ability to regulate cell proliferation and migration,which has a positive effect on MSCs.Thus,we constructed JAM-A MSCs and found that the cell survival rate of the JAM-A MSCs was higher than that of the control group under high glucose conditions and the degree of impairment of cell function was less,indicating that overexpression of JAM-A could effectively reduce the oxidative stress response induced by high glucose stimulation and reduce apoptosis.In addition,we discovered that the levels of secreted cytokines such as VEGF and PDGF were higher in the JAM-A MSCs than in the control group.Co-culture of supernatants from both groups with vascular endothelial cells revealed that supernatants from the JAM-A MSCs group significantly promoted angiogenesis,verifying that JAM-A MSCs could retain higher paracrine activity.Finally,we constructed a diabetic mouse model of total excisional wound and injected a stable strain of JAM-A MSCs in the area.We demonstrated that JAM-A overexpression survived longer in diabetic wounds than in the control group and effectively promoted wound revascularization and accelerated wound healing through paracrine growth factors VEGF and PDGF.In summary,we have explored the molecular pathology of MSCs transplanted into diabetic wounds based on the integration of multi-omics data.We have demonstrated for the first time that overexpression of JAM-A in MSCs can restore the dysfunction and reduce the apoptosis of MSCs under high glucose conditions,allowing MSCs to retain a high paracrine activity,promoting angiogenesis and accelerating the healing of diabetic wounds.In this study,we hope to explore better ways to modify MSCs to reduce the damage caused by the high glucose environment,in order to provide a new research idea for stem cells to treat poor healing of diabetic wounds.