Mechanisms and Drug-Augmenting Strategies of Mesenchymal Stem Cells for Preserving β-Cell in Type 2 Diabetes

Kunlu Wang,1 Jiuwei Li,2 Cong Han,3 Jie Li4– 6 1The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 2The Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 3Department of Nephrology II, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 4Research Office, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 5Key Laboratory of Traditional Chinese Medicine Classical Theory, Ministry of Education, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China; 6Shandong Key Laboratory of Innovation and Application Research in Basic Theory of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of ChinaCorrespondence: Jie Li, Research Office, Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China, Email [email protected] Cong Han, Department of Nephrology II, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong Province, People’s Republic of China, Email [email protected]: Type 2 diabetes (T2D) is closely linked to β-cell dysfunction. Preserving β-cell function has emerged as a critical therapeutic strategy for T2D. Mesenchymal stem cells (MSCs) have demonstrated remarkable potential in achieving this goal. This paper systematically reviews the multifaceted mechanisms by which MSCs protect pancreatic β-cell function in T2D. It integrates eight core mechanisms: modulating the inflammatory microenvironment, regulating the immune system, counteracting oxidative stress, enhancing autophagy levels, alleviating endoplasmic reticulum stress, safeguarding mitochondrial function, promoting β-cell regeneration and repair, and inhibiting ferroptosis. Together, these form a multi-layered, networked intervention system. This framework elucidates MSC protective effects across three functional levels: eliminating injury initiators, maintaining cellular homeostasis, and intervening in cellular fate outcomes. Additionally, this review examines pharmacological strategies to enhance MSC efficacy, including hypoglycemic agents, other drugs, and natural products, with a focus on their mechanisms of action and barriers to clinical translation. Finally, based on MSC advantages and existing research limitations, we propose future research directions, including optimizing MSC source selection and engineering MSC-derived exosomes. These recommendations aim to provide theoretical foundations and strategic references for MSC-based T2D therapies. At the top, the text reads ’Hyperglycemic conditions’. On the left, an image of a medicine pack is labeled ’pharmacological agents’, with arrows indicating ’protect’, ’enhance’ and ’modulate’ effects on ’mesenchymal stem cells’. These cells are depicted as a cluster of circular shapes. From the stem cells, lines extend to the right, connecting to various processes affecting beta-cells, shown as a cluster of smaller circular shapes. The processes listed are ’inflammation’, ’immunity’, ’regeneration and apoptosis’, ’ferroptosis’, ’autophagy’, ’oxidative stress’, ’endoplasmic reticulum stress’ and ’mitochondrial function’.In a hyperglycemic environment, the pharmacological agent can protect MSCs and enhance the protective effects of MSCs on β-cells.Keywords: mesenchymal stem cells, type 2 diabetes, β-cell, hypoglycemic agents, natural products