Background: Intraportal islet transplantation has been clinically applied for treatment of unstable type 1 diabetes. However, in the liver, systematic assessment of the dispersed islet grafts and the graft-hepatic integration remains difficult, even in animal models. This is due to the lack of global and in-depth analyses of the transplanted islets and their microenvironment. Here, we apply 3-dimensional (3-D) mouse liver histology to investigate the islet graft microstructure, vasculature, and innervation. Methods: Streptozotocin-induced diabetic mice were used in syngeneic intraportal islet transplantation to achieve euglycemia. Optically cleared livers were prepared to enable 3-D morphological and quantitative analyses of the engrafted islets. Results: 3-D image data reveal the clot- and plaque-like islet grafts in the liver: the former are derived from islet emboli and associated with ischemia, whereas the latter (minority) resemble the plaques on the walls of portal vessels (e.g., at the bifurcation) with mild, if any, peri-graft tissue damage. Three weeks after transplantation, both types of grafts are revascularized, yet significantly more lymphatics are associated with the plaque- than clot-like grafts. Regarding the islet reinnervation, both types of grafts connect to the peri-portal nerve plexus and develop peri- and intra-graft innervation. Specifically, the sympathetic axons and varicosities contact the α-cells, highlighting the graft-host neural integration. Conclusion/interpretation: We present the heterogeneity of the intraportally transplanted islets and the graft-host neurovascular integration in mice. Our work provides the technical and morphological foundation for future high-definitional 3-D tissue and cellular analyses of human islet grafts in the liver.

中文翻译：

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3-D 小鼠肝脏组织学揭示门静脉内移植胰岛的异质性和神经血管整合

背景：门静脉内胰岛移植已在临床上用于治疗不稳定的 1 型糖尿病。然而，在肝脏中，即使在动物模型中，对分散的胰岛移植物和移植物-肝脏整合的系统评估仍然很困难。这是由于缺乏对移植胰岛及其微环境的全局和深入分析。在这里，我们应用 3 维 (3-D) 小鼠肝脏组织学来研究胰岛移植物的微观结构、脉管系统和神经支配。方法：将链脲佐菌素诱导的糖尿病小鼠用于同基因门静脉内胰岛移植以实现血糖正常。制备了光学透明的肝脏，以便对移植的胰岛进行 3-D 形态学和定量分析。结果：3-D 图像数据显示肝脏中的凝块和斑块样胰岛移植物：前者源自胰岛栓子并与缺血有关，而后者（少数）类似于门脉血管壁上的斑块（例如，在分叉处），具有轻微的（如果有的话）移植物周围组织损伤。移植后三周，两种类型的移植物都进行了血运重建，但与斑块相关的淋巴管明显多于凝块样移植物。关于胰岛再神经支配，两种类型的移植物都连接到门静脉周围神经丛并形成移植物周围和移植物内神经支配。具体来说，交感神经轴突和静脉曲张与 α 细胞接触，突出了移植物-宿主神经整合。结论/解释：我们展示了小鼠门静脉内移植胰岛和移植物-宿主神经血管整合的异质性。