Engineering prosurvival synthetic microenvironments by modulating extrinsic and intrinsic factors in stem cell-derived islet-cells

The use of human pluripotent stem cell (SC)-derived islets holds promise as a therapy for Type 1 diabetes (T1D), but the lack of suitable conditions sustaining cell survival after transplantation represents an obstacle to its clinical application.

The loss in number and functionality of SC-derived islet cells occurs shortly after transplantation, preceding adequate graft neovascularization.

Hence, there is a critical knowledge gap concerning the fate of SC-islet cells upon engraftment and the main challenge remains to hamper such dramatic cell loss after transplantation.

Our research proposal establishes a multi-disciplinary consortium with the ambitious goal of developing an innovative approach for sustaining cell longevity and functionality of SC-islet transplants. Specifically, we will target extrinsic and intrinsic prosurvival factors.

To modulate the extrinsic factors, we will develop an innovative biomaterial platform to closely mimic the in vivo islet microenvironment, including cell-ECM and cell-cell communication, and enhance SC-islets survival.

To engineer a prosurvival cell state, we will use new ways to transiently modify gene expression using non-integrating, RNA-based molecules in SC-islets.

This will enable combinatorial screening of candidate mRNAs and siRNAs to identify optimal therapeutic approaches improving SC-islet survival and establishing ‘immune-protected niches’. The optimal strategies will be then assessed for their functionality in vivo using a self-oxygenating modular device.

We expect that the knowledge and paradigms generated by our research programme will not only yield novel insights into islet cells survival but will also accelerate SC-therapy as a treatment that could significantly enhance the life quality of T1D patients.