Jiaqi Gao, Balun Li, Hongkai Tian, Chenchen Li, Nikita Merzlikin, Dongyao Han, Zixi Ling, Zengyu Zhang, Wenfeng Zhu, Jianqi Dai, Lydmila Gerunova, Changrong Lv, Na Li, Jinlian Hua
Abstract Introduction Type 1 diabetes (T1D) results from the destruction of pancreatic β-cells, leading to insulin deficiency. As insulin therapy does not affect disease progression, advancements in immune regulation therapies have emerged, including the reconstitution of the insulin secretory system. Cysteine-rich acidic secretory protein ( SPARC ) is an extracellular matrix glycoprotein that regulates cell adhesion, facilitating cell migration, and mediating interactions between cells and their extracellular matrix. SPARC is overexpressed during tissue repair and is involved in β-cells survival. However, the potential of SPARC -modified mesenchymal stem cells (MSCs) to improve insulin secretion has not been thoroughly investigated. This study investigated the therapeutic effects of SPARC -MSCs in vivo and in vitro and assessed whether SPARC enhances survival and insulin secretion after β-cells injury. Methods In vivo, we established T1D models in mice and canine using SPARC -MSCs for cell transplantation. In vitro, MIN6 cells were damaged with STZ, and SPARC -MSC supernatant was co-cultured with MIN6 for various assays. Results Our study demonstrated that SPARC enhanced the regenerative capacity and migratory efficiency of MSCs after H 2 O 2 injury and improved their morphology. In STZ-induced canine and mice diabetes models, SPARC -MSCs therapy significantly reduced hyperglycemia, improved oral glucose tolerance test (OGTT), and reversed weight loss in canine. Biochemical analyses showed improved liver function, and histological examination revealed restored islet area was significantly restored. Transcriptome and proteome sequencing indicated significant enrichment in calcium binding and cell migration pathways. Co-culturing SPARC -MSC supernatant with MIN6 cells after STZ injury restored their regenerative ability, enhancing insulin secretion and ATP content under high glucose stimulation. SPARC treatment also significantly increased intracellular Ca 2+ levels in MIN6 cells. Conclusion SPARC significantly promotes cell regeneration and stimulates insulin secretion by increasing intracellular ATP and Ca 2+ influx. In diabetic canine and mice models, it alleviated hyperglycemia, improved glucose tolerance, and enhanced pancreatic islet area and insulin secretion. Graphical Abstract