Nakano Kenta, Goto Motohito, Fukuda Satsuki, Yanobu-Takanashi Rieko, Yabe Shigeharu G, Shimizu Yukiko, Sakuma Tetsushi, Yamamoto Takashi, Shimoda Masayuki, Okochi Hitoshi, Takahashi Riichi, Okamura Tadashi
Department of Laboratory Animal Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.
Animal Resource Technical Research Center, Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan.
Transplantation. 2025 Feb 1;109(2):e81-e91. doi: 10.1097/TP.0000000000005152. Epub 2024 Aug 6.
For patients who have difficulty controlling blood glucose even with insulin administration, xenogeneic islet cells, including human stem cell-derived pancreatic islets (hSC-islet) and porcine islets, have garnered attention as potential solutions to challenges associated with donor shortages. For the development of diabetes treatment modalities that use cell transplantation therapy, it is essential to evaluate the efficacy and safety of transplanted cells using experimental animals over the long term.
We developed permanent diabetic immune-deficient mice by introducing the Akita (C96Y) mutation into the rodent-specific Insulin1 gene of NOD/Shi-scid IL2rγc null (NOG) mice ( Ins1 C96Y/C96Y NOG). Their body weight, nonfasting blood glucose, and survival were measured from 4 wk of age. Insulin sensitivity was assessed via tolerance tests. To elucidate the utility of these mice in xenotransplantation experiments, we transplanted hSC-islet cells or porcine islets under the kidney capsules of these mice.
All male and female homozygous mice exhibited persistent severe hyperglycemia associated with β-cell depletion as early as 4 wk of age and exhibited normal insulin sensitivity. These mice could be stably engrafted with hSC-islets, and the mice that received porcine islet grafts promptly exhibited lowered blood glucose levels, maintaining blood glucose levels below the normal glucose range for at least 52 wk posttransplantation.
The Ins1C96Y/C96Y NOG mouse model provides an effective platform to assess both the efficacy and safety of long-term xenograft engraftment without the interference of their immune responses. This study is expected to contribute essential basic information for the clinical application of islet cell transplantation.
对于即使使用胰岛素治疗仍难以控制血糖的患者，异种胰岛细胞，包括人干细胞衍生的胰岛（hSC-胰岛）和猪胰岛，作为解决供体短缺相关挑战的潜在方案而受到关注。对于使用细胞移植疗法的糖尿病治疗方式的开发，使用实验动物长期评估移植细胞的疗效和安全性至关重要。
我们通过将秋田（C96Y）突变引入NOD/Shi-scid IL2rγc基因敲除（NOG）小鼠的啮齿动物特异性胰岛素1基因中，培育出永久性糖尿病免疫缺陷小鼠（Ins1 C96Y/C96Y NOG）。从4周龄开始测量它们的体重、非空腹血糖和存活率。通过耐受性试验评估胰岛素敏感性。为了阐明这些小鼠在异种移植实验中的实用性，我们将hSC-胰岛细胞或猪胰岛移植到这些小鼠的肾包膜下。
所有雄性和雌性纯合小鼠早在4周龄时就表现出与β细胞耗竭相关的持续性严重高血糖，并且表现出正常的胰岛素敏感性。这些小鼠可以稳定地植入hSC-胰岛，接受猪胰岛移植的小鼠血糖水平迅速降低，移植后至少52周血糖水平维持在正常血糖范围以下。
Ins1C96Y/C96Y NOG小鼠模型提供了一个有效的平台，可在不受免疫反应干扰的情况下评估长期异种移植物植入的疗效和安全性。本研究有望为胰岛细胞移植的临床应用提供重要的基础信息。
