Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
Department of Cardiovascular Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
J Diabetes Res. 2024 May 17;2024:5574968. doi: 10.1155/2024/5574968. eCollection 2024.
Islet transplantation (ITx) is an established and safe alternative to pancreas transplantation for type 1 diabetes mellitus (T1DM) patients. However, most ITx recipients lose insulin independence by 3 years after ITx due to early graft loss, such that multiple donors are required to achieve insulin independence. In the present study, we investigated whether skeletal myoblast cells could be beneficial for promoting angiogenesis and maintaining the differentiated phenotypes of islets. In vitro experiments showed that the myoblast cells secreted angiogenesis-related cytokines (vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and stromal-derived factor-1 (SDF-1)), contributed to maintenance of differentiated islet phenotypes, and enhanced islet cell insulin secretion capacity. To verify these findings in vivo, we transplanted islets alone or with myoblast cells under the kidney capsule of streptozotocin-induced diabetic mice. Compared with islets alone, the group bearing islets with myoblast cells had a significantly lower average blood glucose level. Histological examination revealed that transplants with islets plus myoblast cells were associated with a significantly larger insulin-positive area and significantly higher number of CD31-positive microvessels compared to islets alone. Furthermore, islets cotransplanted with myoblast cells showed JAK-STAT signaling activation. Our results suggest two possible mechanisms underlying enhancement of islet graft function with myoblast cells cotransplantation: "indirect effects" mediated by angiogenesis and "direct effects" of myoblast cells on islets via the JAK-STAT cascade. Overall, these findings suggest that skeletal myoblast cells enhance the function of transplanted islets, implying clinical potential for a novel ITx procedure involving myoblast cells for patients with diabetes.
胰岛细胞移植（ITx）是治疗 1 型糖尿病（T1DM）患者的一种成熟且安全的替代方案，可用于胰腺移植。然而，由于早期移植物丢失，大多数 ITx 受者在 ITx 后 3 年内失去胰岛素独立性，因此需要多个供体才能实现胰岛素独立性。在本研究中，我们研究了骨骼肌成肌细胞是否有益于促进血管生成和维持胰岛的分化表型。体外实验表明，成肌细胞分泌与血管生成相关的细胞因子（血管内皮生长因子（VEGF）、肝细胞生长因子（HGF）和基质衍生因子-1（SDF-1）），有助于维持胰岛的分化表型，并增强胰岛细胞胰岛素分泌能力。为了在体内验证这些发现，我们将胰岛单独或与成肌细胞一起移植到链脲佐菌素诱导的糖尿病小鼠的肾脏包膜下。与单独胰岛相比，与成肌细胞共移植胰岛的小鼠平均血糖水平显著降低。组织学检查显示，与单独胰岛相比，与成肌细胞共移植的胰岛具有明显更大的胰岛素阳性面积和明显更多的 CD31 阳性微血管。此外，与成肌细胞共移植的胰岛表现出 JAK-STAT 信号通路的激活。我们的结果表明，骨骼肌成肌细胞共移植增强胰岛移植物功能的两种可能机制：“间接效应”通过血管生成介导和“直接效应”通过 JAK-STAT 级联作用对胰岛产生。总的来说，这些发现表明骨骼肌成肌细胞增强了移植胰岛的功能，这意味着涉及糖尿病患者成肌细胞的新型 ITx 程序具有临床潜力。
