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Project
Microvascular remodeling for beta(-like) cell differentiation, regeneration and transplantation (FWOSB94)
Diabetes mellitus is a disease with pandemic dimensions. Diabetes patients depend on oral antidiabetic drugs, GLP-1 analogues or exogenous insulin that comforts but not cures. A potential strategy to cure could involve restoring the endogenous beta cell mass through regeneration or transplantation. We generated a unique mouse model of beta cell mass expansion induced by a transient period of islet hypovascularization. The first part of this proposal aims to dissect the mechanism behind this process using, amongst others, cell tracing and single cell transcriptomics .
Since our model of intraislet hypovascularization is reminiscent of the transplantation of donor islets that are disconnected from their vascular supply during isolation, the second part of our proposal will focus on the islet cell phenotypic changes upon engraftment and revascularization. We recently reported that transfection of islet cell grafts with synthetic, modified mRNA encoding the key angiogenic factor VEGF-A significantly promotes graft revascularization and function. We propose to extend our findings by: (i) employing beta-like cell grafts derived from human induced pluripotent stem cells (iPS-ß) and (ii) assessing the effect of islet cell mRNA transfection in alternative, clinically more relevant transplantation sites including the subcutis and omentum. In this way, we aim to significantly improve the outcome of current islet transplantation protocols.
Since our model of intraislet hypovascularization is reminiscent of the transplantation of donor islets that are disconnected from their vascular supply during isolation, the second part of our proposal will focus on the islet cell phenotypic changes upon engraftment and revascularization. We recently reported that transfection of islet cell grafts with synthetic, modified mRNA encoding the key angiogenic factor VEGF-A significantly promotes graft revascularization and function. We propose to extend our findings by: (i) employing beta-like cell grafts derived from human induced pluripotent stem cells (iPS-ß) and (ii) assessing the effect of islet cell mRNA transfection in alternative, clinically more relevant transplantation sites including the subcutis and omentum. In this way, we aim to significantly improve the outcome of current islet transplantation protocols.
Date:1 Nov 2020 → Today
Keywords:Beta cell regeneration, beta cell transplantation, mRNA-VEGF-A transfection
Disciplines:Cell signalling, Endocrinology, Cell therapy, Regenerative medicine not elsewhere classified, Cell growth and development