Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes

• Published in: Nature communications Vol. 14; no. 1; pp. 878 - 15
• Main Authors: Citro, Antonio, Neroni, Alessia, Pignatelli, Cataldo, Campo, Francesco, Policardi, Martina, Monieri, Matteo, Pellegrini, Silvia, Dugnani, Erica, Manenti, Fabio, Maffia, Maria Chiara, Valla, Libera, Kemter, Elisabeth, Marzinotto, Ilaria, Olgasi, Cristina, Cucci, Alessia, Follenzi, Antonia, Lampasona, Vito, Wolf, Eckhard, Piemonti, Lorenzo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/107; 13/31; 14/19; 14/63; 59; 64; 64/60; 692/163/2743/137/1418; 692/308/575; Animal models; Beta cells; Bioengineering; Cell therapy; Diabetes; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - metabolism; Diabetes Mellitus, Type 1 - therapy; Endothelial Cells; Extracellular matrix; Genetic engineering; Humanities and Social Sciences; Humans; Insulin; Insulin-Secreting Cells - metabolism; Integration; Islet cells; Islets of Langerhans - physiology; Islets of Langerhans Transplantation - methods; Maturation; multidisciplinary; Neonates; Organ donors; Pancreas; Pancreas transplantation; Pancreatic islet transplantation; Scaffolds; Science; Science (multidisciplinary); Self-assembly; Swine; Transplantation; Xenografts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36582-1

Intrahepatic islet transplantation is the standard cell therapy for β cell replacement. However, the shortage of organ donors and an unsatisfactory engraftment limit its application to a selected patients with type 1 diabetes. There is an urgent need to identify alternative strategies based on an unlimited source of insulin producing cells and innovative scaffolds to foster cell interaction and integration to orchestrate physiological endocrine function. We previously proposed the use of decellularized lung as a scaffold for β cell replacement with the final goal of engineering a vascularized endocrine organ. Here, we prototyped this technology with the integration of neonatal porcine islet and healthy subject-derived blood outgrowth endothelial cells to engineer a xenogeneic vascularized endocrine pancreas. We validated ex vivo cell integration and function, its engraftment and performance in a preclinical model of diabetes. Results showed that this technology not only is able to foster neonatal pig islet maturation in vitro, but also to perform in vivo immediately upon transplantation and for over 18 weeks, compared to normal performance within 8 weeks in various state of the art preclinical models. Given the recent progress in donor pig genetic engineering, this technology may enable the assembly of immune-protected functional endocrine organs. Cell therapy for diabetes requires the combination of bioengineering and new sources of beta cells. Here, the authors report a self-assembly platform based on neonatal pig islets, human endothelial cells and native organ extracellular matrix, which improves ex vivo islet maturation and in vivo function in a mouse model of diabetes.