Human mesenchymal stem/stromal cell based-therapy in diabetes mellitus: experimental and clinical perspectives

Abstract

Diabetes mellitus (DM), a chronic metabolic disease, poses a significant global health challenge, with current treatments often fail to prevent the long-term disease complications. Mesenchymal stem/stromal cells (MSCs) are, adult progenitors, able to repair injured tissues, exhibiting regenerative effects and immunoregulatory and anti-inflammatory responses, so they have been emerged as a promising therapeutic approach in many immune-related and inflammatory diseases. This review summarizes the therapeutic mechanisms and outcomes of MSCs, derived from different human tissue sources (hMSCs), in the context of DM type 1 and type 2. Animal model studies and clinical trials indicate that hMSCs can facilitate pleiotropic actions in the diabetic milieu for improved metabolic indices. In addition to modulating abnormally active immune system, hMSCs can ameliorate peripheral insulin resistance, halt beta-cell destruction, preserve residual beta-cell mass, promote beta-cell regeneration and insulin production, support islet grafts, and correct lipid metabolism. Moreover, hMSC-free derivatives, importantly extracellular vesicles, have shown potent experimental anti-diabetic efficacy. Moreover, the review discusses the diverse priming strategies that are introduced to enhance the preclinical anti-diabetic actions of hMSCs. Such strategies are recommended to restore the characteristics and functions of MSCs isolated from patients with DM for autologous implications. Finally, limitations and merits for the wide spread clinical applications of MSCs in DM such as the challenge of autologous versus allogeneic MSCs, the optimal MSC tissue source and administration route, the necessity of larger clinical trials for longer evaluation duration to assess safety concerns, are briefly presented.

Keywords: Beta-cell; Clinical; Diabetes; Efficacy; Experimental; Human mesenchymal stem/stromal cells.

Fig. 1

Therapeutic Mechanisms of MSCs in DM management. Abbreviations ANG-1 Angiopoietin 1, ANG-2 Angiopoietin 2, AT Adipose tissue, CXCR4 C-X-C chemokine receptor type 4, DCs Dendritic cells, DLK1 Delta like non-canonical Notch ligand 1, EGF Epidermal growth factor, ERK Extracellular signal-regulated kinase, FGF Fibroblast growth factor, FoxO1 Forkhead box protein O 1, GLUT4 Glucose transporter 4, GM-CSF Granulocyte macrophage colony stimulating factor, HGF Hepatocyte growth factor, HO-1 Heme oxygenase 1, IDO Indoleamine 2,3-dioxygenase, IL-10 Interleukin 10, IL-4 Interleukin 4, IL-6 Interleukin 6, IGF-1 Insulin-like-growth factor, iNOS Inducible-nitric oxide synthase, IRS-1 Insulin receptor substrate 1, M1 Pro-inflammatory macrophages, M2 Anti-inflammatory macrophages, MCP-1 monocyte-chemotactic protein 1, MC4R melanocortin-4 receptor, NK-cells Natural killer cells, Nrf2 Nuclear factor erythroid 2-related factor, PDGF Platelet-derived growth factor, PGE2 Prostaglandin E2, Reg B cells regulatory B cells, Reg DCs Regulatory dendritic cells, ROS Reactive oxygen species, SDF-1α stromal-derived factor 1 alpha, SOD-1 Superoxide dismutase 1, SOD-2 Superoxide dismutase 2, TIMP-1 Tissue inhibitor of metalloproteinase 1, TIMP-2 Tissue inhibitor of metalloproteinase 2, TGF-β1 Transforming growth factor beta 1, Tregs Regulatory T cells, VEGF Vascular endothelial growth factor, (+): promote/support, (-): inhibit or suppress