On July 2nd, 20021year, Tsinghua University Du Yanan team was in the science department? Advance payment? A research paper entitled "Exendin-4 gene modification and microencapsulation promote the self-persistence and anti-diabetic activity of MSCS" was published online. Exendin-4(MSC-Ex-4), an analogue of glucagon-like peptide 1(GLP- 1), was used in genetically engineered MSC, and their enhanced cellular function and anti-diabetic efficacy were confirmed in a mouse model of type 2 diabetes mellitus (T2DM).
In mechanism, MSC-Ex-4 achieved self-enhancement through the autocrine activation of AMPK signaling pathway mediated by GLP- 1R, and improved the survival rate under high glucose stress. At the same time, Exendin-4 secreted by MSC-Ex-4 inhibits the aging and apoptosis of pancreatic β cells through endocrine action, while bioactive factors secreted by MSC-Ex-4 (such as IGFBP2 and APOM) enhance insulin sensitivity through paracrine and reduce lipid accumulation in hepatocytes through PI3K-Akt activation. In addition, MSC-Ex-4 was encapsulated in 3D gelatin scaffold for single dose administration to prolong the therapeutic effect for 3 months. In a word, the results of this study provide insights into the mechanism of self-maintenance and anti-diabetic activity of mesenchymal stem cells mediated by Exendin-4, and provide more effective treatment based on mesenchymal stem cells for T2DM.
So far, more than 436 million people in the world have diabetes, and it is expected that this number will reach 700 million by 2045. Type 2 diabetes mellitus (T2DM) accounts for about 90% of diabetes cases, which is characterized by insulin resistance and hyperglycemia, which is caused by obesity, lack of exercise, unhealthy diet and heredity. Insulin resistance occurs when cells in liver, muscle and adipose tissue fail to respond to insulin and lead to glucose uptake failure. Pancreatic β cells will compensate insulin resistance by increasing insulin production, which will eventually lead to β cell failure and irreversible hyperglycemia. Therefore, long-term exposure to chronic hyperglycemia will inhibit β cell proliferation, induce β cell apoptosis, lead to β cell decrease and β cell dysfunction.
In addition, T2DM is closely related to abnormal liver function, and more than 90% obese T2DM patients suffer from metabolism-related fatty liver (MAFLD). Hepatocytes store nutrients in the form of glycogen and triglyceride (TG), which plays an important role in the balance between glucose and liposomes. In the case of insulin resistance in liver, insulin can not inhibit gluconeogenesis, but can accelerate the synthesis of fatty acids in liver cells, thus increasing the production of glucose and the accumulation of TG in liver. Despite the dysfunction of β cells and hepatocytes, hyperglycemia and hypertriglyceridemia will aggravate the insulin resistance of muscle and adipose tissue and cause dysfunction of other organs and tissues. Therefore, T2DM is closely related to many complications, including coronary heart disease, stroke and retinopathy.
In addition to lifestyle changes, hypoglycemic agents are needed to better maintain the normal blood sugar level of patients with T2DM. Glucagon-like peptide-1 (GLP- 1) is an incretin hormone, which can increase insulin and inhibit glucagon secretion by interacting with GLP- 1 receptor (GLP- 1R), thus helping to control blood sugar fluctuation. However, GLP- 1 is rarely used in the treatment of T2DM because of its short half-life, and it will be rapidly degraded by dipeptidyl peptidase -4 within a few minutes. Exendin-4 is the first GLP- 1R agonist approved for the treatment of T2DM. It is a 39-amino acid peptide and GLP- 1 analogue with a long half-life of 2.4 hours. It can improve the quality of β cells by inhibiting apoptosis and promoting cell proliferation, thus increasing insulin secretion. In addition, Exendin-4 has been proved to be an effective candidate drug, which can reduce weight and improve diabetes and MAFLD. Although Exendin-4 has improved in regulating blood glucose and insulin response, its plasma half-life is still limited due to the elimination of kidney. Therefore, it needs to be administered twice a day, which will lead to unexpected fluctuations in plasma concentration and intermittent activation of GLP-1R. ?
Although the above-mentioned hypoglycemic drug treatment has brought benefits, some patients still can't return to normal blood sugar or have many side effects such as hypoglycemia, diarrhea, nausea and vomiting. In recent years, cell-based therapy has become an alternative to many refractory diseases, including T2DM. Especially, in some preclinical and clinical trials, mesenchymal stem cells (MSCs) have been proved to be effective in improving hyperglycemia, insulin resistance and systemic inflammation caused by T2DM, thus providing a new scheme for the treatment of T2DM. At the same time, technological progress still urgently needs to successfully transform MSC-based treatment into clinical treatment of T2DM. One of the main obstacles to be overcome is the decrease of proliferation and survival rate of MSC after in vivo administration.
Therefore, many strategies have been studied, such as biomaterial wrapping, genetic engineering and MSC pretreatment, to improve survival rate, delay clearance kinetics and maintain MSC secretion factors in vivo. In addition, it is very important to optimize the route of administration of MSCs, because MSCs administered intravenously mainly stay in the lung and subsequent tissues, resulting in weakened therapeutic effect. In addition, a comprehensive understanding of the therapeutic mechanism of bone marrow mesenchymal stem cells in T2DM is still elusive. MSCs have been proved to promote the production of endogenous insulin and stimulate the proliferation of β cells. In addition, MSC is famous for its ability to regulate immune response, which is very important for improving systemic inflammation caused by T2DM.
In view of the above defects of Exendin-4 and MSCs in the treatment of T2DM, researchers have explored how to coordinate the therapeutic benefits of Exendin-4 and MSCs. MSC has also been genetically modified with GLP- 1, which shows better therapeutic effect than wild-type MSC in the treatment of T2DM. However, it should be emphasized that these combined therapies inherit many defects. For example, when administered with MSC, the therapeutic effect and duration of a single dose of free Exendin-4 are limited. In addition, considering that the half-life of GLP- 1 is only 2 minutes, and the treatment of T2DM requires a higher effective dose, it is expected that it is difficult to significantly improve the therapeutic effect of GLP- 1 modified MSCs.
Here, on the basis of finding that human MSCs express GLP- 1R, we constructed Exendin-4 genetic engineering MSCs(MSC-Ex-4) through lentivirus transduction system, and verified that Exendin-4 secreted by MSC-Ex-4 can activate AMPK signal pathway through GLP- 1R-mediated autocrine, thus prolonging its survival time. This study also discussed the potential mechanism of MSC-Ex-4 in protecting the endocrine of islet β cells and improving the paracrine function of hepatocytes. Except Exendin-4 secreted by MSC-Ex-4, it is speculated that other secretory groups of MSC-Ex-4 can reduce cell senescence and apoptosis, promote pancreatic β cell proliferation, improve insulin sensitivity and reduce lipid accumulation. Finally, the study systematically provided multiple doses of free MSC-Ex-4, and used injectable three-dimensional (3D) gelatin scaffold (GMs) as cell encapsulation and delivery carrier to assist MSC-Ex-4, so as to achieve long-term therapeutic effect and single-dose local administration. ?
In a word, the results of this study provide insights into the mechanism of self-maintenance and anti-diabetic activity of mesenchymal stem cells mediated by Exendin-4, and provide more effective treatment based on mesenchymal stem cells for T2DM.
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