Importance of human β and Endothelial cell Cooperation for the maturation, organisation and functionality of islet organoids.

To cure diabetes, functional ß cell mass must be restored. Transplantation of human islets has seen significant progress over the past decades. However, organ donor shortage is a major obstacle.

For transplanted patients, poor graft revascularisation and a recurrent autoimmune attack ultimately result in the loss of the graft.

Human induced pluripotent stem cell (iPSC)-derived ß cells are a promising alternative source of cells that is inexhaustible and allows genetic interventions prior to transplantation to stimulate revascularisation, immunoprotection and ultimately graft survival. iPSC-ß cells retain an immature phenotype in vitro and only in vivo acquire mature function equivalent to that of native human islets.

Intra-islet endothelial cells (ECs) form a necessary niche for pancreatic endocrinogenesis and adult ß-cell function, and they improve islet survival after transplantation.

This proposal aims to test the hypothesis that ECs are crucial to generate mature and functional human iPSC-derived islet organoids in vitro and to promote revascularisation, function, adaptation to metabolic challenges and survival in vivo. To this end, we will generate 'vascularised' islet organoids containing iPSC-derived endocrine and ECs.

By combining genetic interventions and cutting-edge technologies, such as whole tissue three-dimensional analysis and transcriptomics, we will characterise the impact of ECs on islet organoids.

This project will broaden the knowledge on the essential relationship linking structure to function in human islet organoids, paving the way for new human cell therapies.