San Raffaele Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy.
Università Vita-Salute San Raffaele, Milan, Italy.
Nat Commun. 2023 Feb 16;14(1):878. 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.
肝内胰岛移植是β细胞替代的标准细胞治疗方法。然而，器官供体的短缺和不理想的移植效果限制了其在 1 型糖尿病患者中的应用。因此，迫切需要基于无限来源的胰岛素分泌细胞和创新支架来识别替代策略，以促进细胞相互作用和整合，从而协调生理内分泌功能。我们之前提出使用脱细胞肺作为β细胞替代的支架，最终目标是构建血管化内分泌器官。在这里，我们通过整合新生猪胰岛和健康供体来源的血管内皮细胞，来构建异种血管化内分泌胰腺，对这项技术进行了原型设计。我们验证了体外细胞整合和功能、移植后的功能及其在糖尿病的临床前模型中的性能。结果表明，与各种最先进的临床前模型中 8 周内的正常表现相比，该技术不仅能够促进新生猪胰岛的体外成熟，而且在移植后立即以及 18 周内都能发挥作用。鉴于最近在供体猪基因工程方面的进展，该技术可能能够组装具有免疫保护功能的内分泌器官。
