Improvement of hepatocyte engraftment by co-transplantation with pancreatic islets in hepatocyte transplantation

Yoshikatsu Saitoh, Akiko Inagaki, Ibrahim Fathi, Takehiro Imura, Hiroyasu Nishimaki, Hiroyuki Ogasawara, Muneyuki Matsumura, Shigehito Miyagi, Yohichi Yasunami, Michiaki Unno, Takashi Kamei, Masafumi Goto

Research output: Contribution to journalArticlepeer-review

Abstract

Because of the fragility of isolated hepatocytes, extremely poor engraftment of transplanted hepatocytes remains a severe issue in hepatocyte transplantation. Therefore, improving hepatocyte engraftment is necessary to establish hepatocyte transplantation as a standard therapy. Since the pancreatic islets are known to have favorable autocrine effects, we hypothesized that the transplanted islets might influence not only the islets but also the nearby hepatocytes, subsequently promoting engraftment. We evaluated the effects of islet co-transplantation using an analbuminemic rat model (in vivo model). Furthermore, we established a mimicking in vitro model to investigate the underlying mechanisms. In an in vivo model, the hepatocyte engraftment was significantly improved only when the islets were co-transplanted to the nearby hepatocytes (p < 0.001). Moreover, the transplanted hepatocytes appeared to penetrate the renal parenchyma together with the co-transplanted islets. In an in vitro model, the viability of cultured hepatocytes was also improved by coculture with pancreatic islets. Of particular interest, the coculture supernatant alone could also exert beneficial effects comparable to islet coculture. Although insulin, VEGF, and GLP-1 were selected as candidate crucial factors using the Bio-Plex system, beneficial effects were partially counteracted by anti-insulin receptor antibodies. In conclusion, this study demonstrated that islet co-transplantation improves hepatocyte engraftment, most likely due to continuously secreted crucial factors, such as insulin, in combination with providing favorable circumstances for hepatocyte engraftment. Further refinements of this approach, especially regarding substitutes for islets, could be a promising strategy for improving the outcomes of hepatocyte transplantation.

Original languageEnglish
Pages (from-to)361-374
Number of pages14
JournalJournal of Tissue Engineering and Regenerative Medicine
Volume15
Issue number4
DOIs
Publication statusPublished - 2021 Apr

Keywords

  • cell transplantation
  • coculture techniques
  • exosome
  • hepatocyte engraftment
  • hepatocyte transplantation
  • insulin
  • pancreatic islet transplantation
  • paracrine communication

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biomaterials
  • Biomedical Engineering

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