Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets
Modular tissue engineering for the vascularization of subcutaneously transplanted pancreatic islets
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DOI：
10.1073/pnas.1619216114
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发表时间：
2017-08
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影响因子：
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通讯作者：
Alexander E. Vlahos;Nicholas Cober;M. Sefton
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文献类型：
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作者：
Alexander E. Vlahos;Nicholas Cober;M. Sefton
在这项研究中，我们发现嵌入内皮细胞包被模块的胰岛，并在皮肤下注射，使链脲佐菌素诱导的糖尿病SCID/beige小鼠恢复正常血糖。移植的胰岛血管重建，并直接与宿主血管结合，这是以前在皮下空间未见的特征。这些植入物也是可回收的，这是一个重要的临床考虑因素。这里的成功意味着胰岛移植可以从诸如腹膜腔或肝脏等不适合移植的部位移开。胰岛移植，遵循埃德蒙顿协议，是一种有前途的治疗I型糖尿病。然而，需要多个供体来实现胰岛素独立性反映了当胰岛输注到门静脉时发生的大量胰岛损失。寻找一个不太危险的移植部位，既微创又能支持大移植量，是推进这种方法的必要条件。虽然s.c.站点满足这两个标准，但该站点血管化程度较差，妨碍了其实用性。为了解决这个问题，我们证明了模块化组织工程的结果是一个s.c.血管化的床，使胰岛移植成为可能。在链脲佐菌素诱导的糖尿病SCID/beige小鼠中，注射750个嵌入内皮化胶原模块的大鼠胰岛当量足以恢复和维持正常血糖21天；同样数量的游离胰岛无法影响血糖水平。此外，使用CLARITY，我们发现嵌入的胰岛血管重建并与宿主血管系统整合，这是其他s.c.研究中未见的特征。胶原嵌入的胰岛驱动了一个小的（尽管不显著）向促血管生成CD206+MHCII−（m2样）巨噬细胞反应的转变，这是模块相关血管化的一个特征。虽然这些结果打开了使用sc胰岛输送作为1型糖尿病治疗选择的潜力，但更直接的好处可能是探索血管重建的胰岛生物学。
Significance In this study we show that pancreatic islets embedded in modules coated with endothelial cells and injected under the skin return streptozotocin-induced diabetic SCID/beige mice to normoglycemia. The transplanted islets became revascularized and directly integrated with host’s vasculature, a feature not seen previously in the subcutaneous space. These implants were also retrievable, an important clinical consideration. The success here means that islet transplantation can move away from inhospitable sites such as the peritoneal cavity or the liver. The transplantation of pancreatic islets, following the Edmonton Protocol, is a promising treatment for type I diabetics. However, the need for multiple donors to achieve insulin independence reflects the large loss of islets that occurs when islets are infused into the portal vein. Finding a less hostile transplantation site that is both minimally invasive and able to support a large transplant volume is necessary to advance this approach. Although the s.c. site satisfies both these criteria, the site is poorly vascularized, precluding its utility. To address this problem, we demonstrate that modular tissue engineering results in an s.c. vascularized bed that enables the transplantation of pancreatic islets. In streptozotocin-induced diabetic SCID/beige mice, the injection of 750 rat islet equivalents embedded in endothelialized collagen modules was sufficient to restore and maintain normoglycemia for 21 days; the same number of free islets was unable to affect glucose levels. Furthermore, using CLARITY, we showed that embedded islets became revascularized and integrated with the host’s vasculature, a feature not seen in other s.c. studies. Collagen-embedded islets drove a small (albeit not significant) shift toward a proangiogenic CD206+MHCII−(M2-like) macrophage response, which was a feature of module-associated vascularization. While these results open the potential for using s.c. islet delivery as a treatment option for type I diabetes, the more immediate benefit may be for the exploration of revascularized islet biology.