Coculture With Ischemia/Reperfusion-Preconditioned Hepatocytes Improves Islet Function and Survival

Nakamura

et al. 2023

Sci Rep

Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously reported that a recombinant peptide (RCP) enhances subcutaneous islet engraftment. However, it is impractical for clinical use because RCP must be removed when transplanting islets. We herein investigated whether a novel bioabsorbable gelatin hydrogel nonwoven fabric (GHNF) could improve subcutaneous islet engraftment. A silicon spacer with or without GHNF was implanted into the subcutaneous space of diabetic mice. Syngeneic islets were transplanted into the pretreated space or intraportally (Ipo group). Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, CT angiography and gene expression were evaluated. The cure rate and glucose tolerance of the GHNF group were significantly better than in the control and Ipo groups (p < 0.01, p < 0.05, respectively). In the GHNF group, a limited increase of vWF-positive vessels was detected in the islet capsule, whereas laminin (p < 0.05), collagen III and IV were considerably enhanced. TaqMan arrays revealed a significant upregulation of 19 target genes (including insulin-like growth factor-2) in the pretreated space. GHNF markedly improved the subcutaneous islet transplantation outcomes, likely due to ECM compensation and protection of islet function by various growth factors, rather than enhanced neovascularization.

Section: Discussionmentioning

confidence: 99%

A gelatin hydrogel nonwoven fabric improves outcomes of subcutaneous islet transplantation

Kanai

Nakamura

et al. 2023

Sci Rep

“…Interestingly, only a marginal effect was observed by adding the culture supernatant of islets alone; the coculture supernatant was clearly more effective (Figure 4f). This implies that the effect of co‐transplantation is not solely caused by the addition of islets, and that interaction between the hepatocytes and islets may effectively activate the production of key factors, and consequently enhance the beneficial effects (J. G. Lee et al., 2018). The contribution of exosome involvement was estimated to be low in the present in vitro model, but it was also suggested that exosomes might have dose‐dependent effects (Figure 5a).…”

Section: Discussionmentioning

confidence: 99%

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

Saitoh

Fathi

et al. 2021

J Tissue Eng Regen Med

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.

“…In addition, the gene expression of TGF-β1, which is known to closely related to the production of several types of ECM, was also upregulated in the GHNF group. Interestingly, Lee et al previously reported that TGF-β1 in combination with IGF-1, HGF and transforming growth factor alpha (TGF-α), could improve the islet function 32 . In support of this report, in addition to TGF-β1, IGF-1 and HGF were upregulated in the GHNF group in the present study, suggesting that these factors may synergistically act on improving the islet function.…”

Section: Discussionmentioning

confidence: 99%

A Gelatin Hydrogel Nonwoven Fabric Improves Outcomes of Subcutaneous Islet Transplantation

Kanai

Nakamura

et al. 2022

Preprint

Subcutaneous islet transplantation is a promising treatment for severe diabetes; however, poor engraftment hinders its prevalence. We previously reported that a recombinant peptide (RCP) enhances subcutaneous islet engraftment. However, it is impractical for clinical use because RCP must be removed when transplanting islets. We herein investigated whether a novel bioabsorbable gelatin hydrogel nonwoven fabric (GHNF) could improve subcutaneous islet engraftment. A silicon spacer with or without GHNF was implanted into the subcutaneous space of diabetic mice. Syngeneic islets were transplanted into the pretreated space or intraportally (Ipo group). Blood glucose, intraperitoneal glucose tolerance, immunohistochemistry, CT angiography and gene expression were evaluated. The cure rate and glucose tolerance of the GHNF group were significantly better than in the control and Ipo groups (p < 0.01, p < 0.05, respectively). In the GHNF group, a limited increase of vWF-positive vessels was detected in the islet capsule, whereas laminin (p < 0.05), collagen III and IV were considerably enhanced. TaqMan arrays revealed a significant upregulation of 19 target genes (including insulin-like growth factor-2) in the pretreated space. GHNF markedly improved the subcutaneous islet transplantation outcomes in comparison to intraportal islet transplantation, likely due to ECM compensation and protection of islet viability by various growth factors, rather than enhanced neovascularization.