Gastrin producing syngeneic mesenchymal stem cells protect non-obese diabetic mice from type 1 diabetes

Abstract

Progressive destruction of pancreatic islet β-cells by immune cells is a primary feature of type 1 diabetes (T1D) and therapies that can restore the functional β-cell mass are needed to alleviate disease progression. Here, we report the use of mesenchymal stromal/stem cells (MSCs) for the production and delivery of Gastrin, a peptide hormone that is produced by intestinal cells and foetal islets and can increase β-Cell mass, to promote protection from T1D. A single injection of syngeneic MSCs that were engineered to express Gastrin (Gastrin-MSCs) caused a significant delay in hyperglycaemia in non-obese diabetic (NOD) mice compared to engineered control-MSCs. Similar treatment of early-hyperglycaemic mice caused the restoration of euglycemia for a considerable duration, and these therapeutic effects were associated with the protection of, and/or higher frequencies of, insulin-producing islets and less severe insulitis. While the overall immune cell phenotype was not affected profoundly upon treatment using Gastrin-MSCs or upon in vitro culture, pancreatic lymph node cells from Gastrin-MSC treated mice, upon ex vivo challenge with self-antigen, showed a Th2 and Th17 bias, and diminished the diabetogenic property in NOD-Rag1 deficient mice suggesting a disease protective immune modulation under Gastrin-MSC treatment associated protection from hyperglycaemia. Overall, this study shows the potential of production and delivery of Gastrin in vivo, by MSCs, in protecting insulin-producing β-cells and ameliorating the disease progression in T1D.

Keywords:

• Mesenchymal stem cells
• type 1 diabetes
• gastrin
• autoimmunity
• insulitis
• immune modulation

Acknowledgements

The authors are thankful to Cell and Molecular Imaging, Pathology, Proteomics, immune monitoring, and discovery, and flow cytometry cores of MUSC and UIC for the histology service, microscopy, FACS, and multiplex assay instrumentation support.

Disclosure statement

The authors report no conflicts of interest.

Data availability statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Resource availability

The cDNA vectors generated during the current study are available from the corresponding author on reasonable request.

Additional information

Funding

This work was supported by unrestricted research funds from MUSC and National Institutes of Health (NIH) grants [R21AI069848, R21AI133798 and R01AI073858] to C.V. C.V. is the guarantor of this work and, as such, has full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.