Requests for the pcDNA3-Venus-Akaluc should be submitted to. The pcDNA3-Venus-Akaluc can be provided by RIKEN BioResource Center pending scientific review and a completed material transfer agreement. Data and materials availability: All data pertaining to this study are present in the paper and/or in the Supplementary Materials. All other authors declare that they have no competing interests. The initial filing was assigned the Chinese patent application no. were listed as the inventors on a patent application for MSC-Ex-4 for T2DM therapy. are employees of Beijing CytoNiche Biotechnology Co. All authors read and approved the manuscript. provided overall intellectual guidance, edited the manuscript, and is the principal investigator of the supporting grants. performed scanning electron microscopy characterization of microscaffolds. helped in the production of GMs and cell encapsulation. analyzed and interpreted the data of RNA-seq and secretome analysis. constructed the plasmids and recombinant cells, prepared the figures, and drafted the manuscript. performed experiments, analyzed and interpreted data, and drafted the manuscript. designed and performed experiments, analyzed and interpreted data, drafted the manuscript, and coordinated the project. Funding: This work was financially supported by National Key R&D Program of China (2017YFA0104901), National Natural Science Foundation of China (82061148010), the Beijing Municipal Science and Technology Commission (Z181100001818005), and China Postdoctoral Science Foundation (2019 M650717). We would like to thank all members of Y.D.’s laboratory for great support. Together, our findings provide mechanistic insights into Exendin-4-mediated MSCs self-persistence and antidiabetic activity that offer more effective MSC-based therapy for T2DM. Furthermore, we encapsulated MSC-Ex-4 in 3D gelatin microscaffolds for single-dose administration to extend the therapeutic effect for 3 months. Meanwhile, MSC-Ex-4-secreted Exendin-4 suppressed senescence and apoptosis of pancreatic β cells through endocrine effects, while MSC-Ex-4-secreted bioactive factors (e.g., IGFBP2 and APOM) paracrinely augmented insulin sensitivity and decreased lipid accumulation in hepatocytes through PI3K-Akt activation. Mechanistically, MSC-Ex-4 achieved self-augmentation and improved survival under high glucose stress via autocrine activation of the GLP-1R-mediated AMPK signaling pathway. Here, we genetically engineered MSCs with Exendin-4 (MSC-Ex-4), a glucagon-like peptide-1 (GLP-1) analog, and demonstrated their boosted cellular functions and antidiabetic efficacy in the type 2 diabetes mellitus (T2DM) mouse model. Mesenchymal stem cell (MSC)-based therapy to combat diabetic-associated metabolic disorders is hindered by impoverished cell survival and limited therapeutic effects under high glucose stress.
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