Using Recombinant Human Collagen With Basic Fibroblast Growth Factor to Provide a Simulated Extracellular Matrix Microenvironment for the Revascularization and Attachment of Islets to the Transplantation Region.

Xuan Jiang,Zhiwei Huang,Qing Yao,Yingzheng Zhao,Yina Jiang,Xue Jiang,Qunyan Zhu,Hongxing Fu,Cuitao Lu,Lei Peng

doi:10.3389/fphar.2019.01536

Xuan Jiang, Zhiwei Huang + Show 8 more

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https://doi.org/10.3389/fphar.2019.01536

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Abstract

Islet transplantation is considered a potential therapeutic option to reverse diabetes. The pancreatic basement membrane contains a variety of extracellular matrix (ECM) proteins. The abundant ECM is essential for the survival of transplanted islets. However, the ECM proteins necessary for maintaining islet vascularization and innervation are impaired by enzymatic digestion in the isolation process before islet transplantation, leading to destruction of islet microvessels. These are the primary concern and major barrier for long-term islet survival and function. Thus, it is crucial to create an appropriate microenvironment for improving revascularization and islet function to achieve better transplantation outcome. Given the importance of the presence of ECM proteins for islets, we introduce recombinant human collagen (RHC) to construct a simulated ECM microenvironment. To accelerate revascularization and reduce islet injury, we add basic fibroblast growth factor (bFGF) to RHC, a growth factor that has been shown to promote angiogenesis. In order to verify the outcome, islets were treated with RHC combination containing bFGF and then implanted into kidney capsule in type 1 diabetic mouse models. After transplantation, 30-day-long monitoring displayed that 16 mg–60 ng RHC-bFGF group could serve as superior transplantation outcome. It reversed the hyperglycemia condition in host rapidly, and the OGTT (oral glucose tolerance test) showed a similar pattern with the control group. Histological assessment showed that 16 mg–60 ng RHC-bFGF group attenuated apoptosis, promoted cellular proliferation, triggered vascularization, and inhibited inflammation reaction. In summary, this work demonstrates that application of 16 mg–60 ng RHC-bFGF and islets composite enhance the islet survival, function, and long-term transplantation efficiency.

Highlights

Diabetes is one of the most common serious chronic diseases and is associated with several serious complications, including cardiovascular, kidney, eye, nerve, cerebrovascular, and peripheral vascular diseases (Nathan, 1993; Bader et al, 2016; Wang et al, 2017)
After culturing for 24 h, the viability of both the 1 mg–60 ng recombinant human collagen (RHC)-basic fibroblast growth factor (bFGF) group and the 16 mg–60 ng RHC-bFGF group were over 90%, which was better than the viability of the bFGF-alone or RHC-alone groups
We suspected that simultaneous application bFGF and RHC can improve the viability of islets

Summary

Introduction

Diabetes is one of the most common serious chronic diseases and is associated with several serious complications, including cardiovascular, kidney, eye, nerve, cerebrovascular, and peripheral vascular diseases (Nathan, 1993; Bader et al, 2016; Wang et al, 2017). Type 1 diabetes (T1D) is an autoimmunemediated metabolic disease that is characterized by permanent destruction of insulin-producing beta cells, which results in absolute insulin deficiency (Davis et al, 2012). Most of the time, these treatments fail to control the blood glucose level, which results in severe hypoglycemia and complications (Bogdani et al, 2014). Islet transplantation offers therapeutic potential for patients with T1D to normalize glucose metabolism and prevent the complications of the disease (Davis et al, 2012). The disruption of islet–matrix attachments or the extracellular matrix (ECM) components between endocrine and exocrine cells during isolation decreases islet function and viability before and after transplantation, which severely hinders the efficiency of transplantation (Barrett-Connor and Orchard, 1985). Pre-conditioning in culture prior to islet transplantation, such as the supplementation of angiogenic agents (Uzunalli et al, 2015; Qiu et al, 2017), antioxidant agents, or oxygen carriers in the culture medium, has enabled islets to obtain longer (Emamaullee et al, 2008; Maillard et al, 2011; Brandhorst et al, 2013; Schaschkow et al, 2015), better graft function and greater efficiency (Kin et al, 2008; Schaschkow et al, 2015)

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