Sci Transl Med 2022;14(656):eabg9170.PMID: 35921475
Brief summary: In this experimental study, pancreas-derived mesenchymal stem cells (PMSCs) were implanted into the kidney capsule of mice with streptozotocin (STZ)-induced diabetes. PMSCs led to increased levels of IL-6 in T-helper 1 and T-helper 17 cells, which transiently activated tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), which in turn decreased levels of interleukin-17. This was associated with exocrine pancreas regeneration and rescue of β-cells from immune-mediated damage.
Mesenchymal stem cells (MSC) have been used as a therapeutic approach to treat various autoimmune diseases, including diabetes (1). Through a series of elegant studies in mouse models of diabetes and in vitro cell cultures, this study showed the importance of pancreas-specific MSC (PMSC) to regenerate the exocrine pancreas, which in turn was able to protect β-cells, through a network of cytokines. PMSCs were implanted in the mouse kidney capsula and were able to primarily regenerate the exocrine pancreas. In addition, in the STZ-treated mouse model, ectopic pancreas regeneration rescued islet size and insulin producing cells, and corrected hyperglycemia. These effects persisted even after removal of the PMSC implants.
The effects of PMSCs on the endocrine pancreas appeared to be mediated through transient changes in a number of cytokines. In particular there was an increased production of IL-6 in the implants, which transiently activated TNF-α and IFN-γ. The latter had a major role in decreasing levels of IL-17, whose levels were high in this diabetes model, and were believed to drive β-cell apoptosis. The key roles of the changes in IL-6, TNF-α and IFN-γ were confirmed by studying knockout mice, in which PMSC implantation failed to rescue insulin production and hyperglycemia.
These findings are fascinating as they pinpoint the role of specific cytokines in maintaining pancreatic health and highlight their potential role in cell-based therapy. However, there are several aspects to be clarified, including the proposed mechanism through which exocrine pancreas regeneration protects the endocrine pancreas, and the specific actions of changes in cytokines. In addition, it remains to be clarified if the same model and mechanisms found in mice can be translated in humans, as there are differences in our immune systems.
Reference: 1. Cho J, D’Antuono M, Glicksman M, Wang J, Jonklaas J. A review of clinical trials: mesenchymal stem cell transplant therapy in type 1 and type 2 diabetes mellitus. Am J Stem Cells. 2018;7(4):82–93.
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ESPE Yearbook of Paediatric Endocrinology
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