Leishman David J, Oppler Scott H, Stone Laura L Hocum, O'Brien Timothy D, Ramachandran Sabarinathan, Willenberg Bradley J, Adams Andrew B, Hering Bernhard J, Graham Melanie L
Preclinical Research Center, Department of Surgery, University of Minnesota, Minneapolis, MN, United States.
Department of Veterinary Population Medicine, University of Minnesota, St. Paul, MN, United States.
Front Transplant. 2024 Jan 26;3:1352777. doi: 10.3389/frtra.2024.1352777. eCollection 2024.
Successful diabetes reversal using pancreatic islet transplantation by various groups illustrates the significant achievements made in cell-based diabetes therapy. While clinically, intraportal islet delivery is almost exclusively used, it is not without obstacles, including instant blood-mediated inflammatory reaction (IBMIR), relative hypoxia, and loss of function over time, therefore hindering long-term success. Here we demonstrate the perihepatic surface of non-human primates (NHPs) as a potential islet delivery site maximizing favorable characteristics, including proximity to a dense vascular network for adequate oxygenation while avoiding IBMIR exposure, maintenance of portal insulin delivery, and relative ease of accessibility through minimally invasive surgery or percutaneous means. In addition, we demonstrate a targeted mapping technique of the perihepatic surface, allowing for the testing of multiple experimental conditions, including a semi-synthetic hydrogel as a possible three-dimensional framework to improve islet viability.
Perihepatic allo-islet cell transplants were performed in immunosuppressed cynomolgus macaques using a targeted mapping technique to test multiple conditions for biocompatibility. Transplant conditions included islets or carriers (including hydrogel, autologous plasma, and media) alone or in various combinations. Necropsy was performed at day 30, and histopathology was performed to assess biocompatibility, immune response, and islet viability. Subsequently, single-injection perihepatic allo-islet transplant was performed in immunosuppressed diabetic cynomolgus macaques. Metabolic assessments were measured frequently (i.e., blood glucose, insulin, C-peptide) until final graft retrieval for histopathology.
Targeted mapping biocompatibility studies demonstrated mild inflammatory changes with islet-plasma constructs; however, significant inflammatory cell infiltration and fibrosis were seen surrounding sites with the hydrogel carrier affecting islet viability. In diabetic NHPs, perihepatic islet transplant using an autologous plasma carrier demonstrated prolonged function up to 6 months with improvements in blood glucose, exogenous insulin requirements, and HbA1c. Histopathology of these islets was associated with mild peri-islet mononuclear cell infiltration without evidence of rejection.
The perihepatic surface serves as a viable site for islet cell transplantation demonstrating sustained islet function through 6 months. The targeted mapping approach allows for the testing of multiple conditions simultaneously to evaluate immune response to biomaterials at this site. Compared to traditional intraportal injection, the perihepatic site is a minimally invasive approach that allows the possibility for graft recovery and avoids IBMIR.
多个研究团队通过胰岛移植成功实现糖尿病逆转，这表明基于细胞的糖尿病治疗取得了重大进展。临床上，几乎仅采用门静脉内胰岛移植，但这并非毫无障碍，包括即时血液介导的炎症反应（IBMIR）、相对缺氧以及功能随时间丧失，因此阻碍了长期成功。在此，我们证明非人灵长类动物（NHP）的肝周表面是一个潜在的胰岛移植部位，具有诸多有利特性，包括靠近密集的血管网络以实现充分氧合，同时避免暴露于IBMIR，维持门静脉胰岛素输送，以及通过微创手术或经皮手段相对容易到达。此外，我们展示了一种肝周表面的靶向映射技术，可用于测试多种实验条件，包括使用半合成水凝胶作为可能的三维框架来提高胰岛活力。
在免疫抑制的食蟹猴中进行肝周同种异体胰岛细胞移植，采用靶向映射技术测试多种生物相容性条件。移植条件包括单独使用胰岛或载体（包括水凝胶、自体血浆和培养基）或各种组合。在第30天进行尸检，并进行组织病理学检查以评估生物相容性、免疫反应和胰岛活力。随后，在免疫抑制的糖尿病食蟹猴中进行单次注射肝周同种异体胰岛移植。频繁测量代谢指标（即血糖、胰岛素、C肽），直至最终取出移植物进行组织病理学检查。
靶向映射生物相容性研究表明，胰岛 - 血浆构建体有轻度炎症变化；然而，在水凝胶载体周围的部位可见大量炎症细胞浸润和纤维化，影响胰岛活力。在糖尿病NHP中，使用自体血浆载体的肝周胰岛移植显示功能延长至6个月，血糖、外源性胰岛素需求和糖化血红蛋白（HbA1c）均有所改善。这些胰岛的组织病理学表现为轻度胰岛周围单核细胞浸润，无排斥迹象。
肝周表面是胰岛细胞移植的可行部位，可证明胰岛功能持续6个月。靶向映射方法允许同时测试多种条件，以评估该部位对生物材料的免疫反应。与传统的门静脉内注射相比，肝周部位是一种微创方法，允许移植物恢复并避免IBMIR。
