The advanced mechanisms of islet-engraftment onto white adipose tissue
Naoaki Sakata1,2, Gumpei Yoshimatsu1,2, Tomoko Tanaka1,2, Teppei Yamada1, Ryo Kawakami1,2, Shohta Kodama1,2.
1Department of Regenerative Medicine and Transplantation, Fukuoka University, Fukuoka, Japan; 2Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka, Japan
Islet transplantation is recognized as a promising therapeutic option for severe diabetes mellitus, however it still has a lot of unresolved problems, especially the difficulty of engraftment. Establishment of the optimal transplant site for islets is one of the challenges to overcome this problem. While liver is known as the representative clinical transplant site, it harbors a tough environment for transplanted islets in the point of inflammation, immunity and ischemia. Therefore, various organs instead of the liver have been examined for overcoming the difficulty in engraftment. In previous World Congress of International Pancreas and Islet Transplant Association (IPITA 2019, Lyon, France), we demonstrated the therapeutic effect of islet transplantation into visceral white adipose tissue (epididymal adipose tissue) and showed that the transplant efficacy was superior to intraperitoneal transplantation and almost equal to renal subcapsular transplantation. And now the aim of this study is to clarify the mechanism of islet engraftment into white adipose tissue. First, we performed transplantation of 200 islets into epididymal white adipose tissue and evaluated the condition of engrafted islets comparing with those in renal subcapsular transplantation using the same number of islets. There was no significant difference between the two transplant models in the area of transplanted islets at postoperative day 56. Interestingly, more microvessels were detected in and around islets engrafted into white adipose tissue than in renal subcapsular space (p = 0.0011). That means white adipose tissue markedly promoted angiogenesis of transplanted islets comparing with kidney. Next, we focused on the adhesion factors in islets and adipose tissue because initial adhesion process is essential for achievement of engraftment. Quantitative PCR revealed that expression of fibronectin gene (Fn1) in white adipose tissue was prominent comparing with kidney and islet (p = 0.010 and 0.0007, respectively). On the other hand, Itgb1, gene of integrin β1 which is known as a fibronectin receptor, was expressed strongly in islets (p = 0.0013 vs. white adipose tissue). Histological assessment showed that fibronectin was detected in cell membrane and cytoplasm of adipocytes in white adipose tissue and integrin β1 in the cytoplasm of endocrine cells of islets, respectively. Finally, we assessed the roles of adiponectin, a cytokine released from adipocytes, for engraftment of islets. Various angiogeneic (Vegfa-c) and adhesion factors (Fn1, Itgb1 and 2) were significantly expressed on recombinant adiponectin-incubated islets (10 µg/mL). It is considered that the mechanism of islet-engraftment into white adipose tissue is classified into three steps: 1) trapping islets into white adipose tissue, 2) adhesion of islets into white adipose tissue via combination of adhesion factors (fibronectin and integrin) and 3) promotion of angiogenesis in transplanted islets via adiponectin.
Grant-in-Aid for Scientific Research (C) (19K09839, NS) from the Ministry of Education, Culture, Sports, Science and Technology of Japan .
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