1509-P: The Mesenchymal Stromal Cells in “Neo-islets,” Islet-Sized 3D Organoids Composed of MSCs and Islet Cells That Functionally Cure Type 1 Diabetes, Actively Preserve Normal ATP Levels and Viability of ICs In Vitro and In Vivo—Applicable to Islet and iPSC-Derived Therapies of Type 1 Diabetes Mellitus

Allotransplants of pancreatic islets in patients with T1DM require their isolation from deceased donor pancreata. This process results in the ischemic loss of up to 50% of islets. Their intraportal administration leads to further islet death due to low oxygen pressure, the Instant Blood-Mediated Inflammatory Reaction and subsequent exposure to high concentrations of orally administered cytotoxic anti-rejection drugs. Despite the use of anti-rejection drugs, a significant percentage of transplanted islets lose their function over time and need to be replaced. The objective of the current study was to determine whether MSCs that are co-aggregated (1:1 ratio) with ICs in “Neo-Islets” protect IC viability by maintaining their ATP levels. This was tested by in vitro exposure x 24 hrs. of cultured human MSCs, ICs and “Neo-Islets” to 1% pO₂. Not unexpectedly, at 24 hrs of hypoxia ATP levels of cultured human ICs (P2) fell from 78±10 to 40±2 pg/cell (p=0.02) and viability decreased to 50%, while ATP levels and viability of identically cultured MSCs remained normal, likely Pasteur effect mediated. Significantly, total ATP levels in freshly formed Neo-Islets remained normal during hypoxia and viability remained close to 99%. Several groups have now demonstrated that MSCs transfer mitochondria though nanotubes into hypoxically stressed neighboring cells, a process that enhances ATP levels and thereby improves their survival.

Conclusion: This ATP-mediated cytoprotective activity of MSCs, combined with their anti-apoptotic, immune-isolating, anti-inflammatory, angiogenic and other trophic actions are exploited in “Neo-islets”. The utility of this co-aggregation technology will be tested to determine whether it can significantly improve islet and novel iPSC-derived transplants that are used to treat patients with T1DM.