Inoue Clinic Diabetes Center

Kyoto, Japan

Inoue Clinic Diabetes Center

Kyoto, Japan
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Sumi S.,Kyoto University | Yanai G.,Kyoto University | Qi M.,City of Hope Medical Center | Sakata N.,Tohoku University | And 7 more authors.
Journal of Medical and Biological Engineering | Year: 2014

Diabetes mellitus (DM) can be cured by adequate insulin secretion from a relatively small volume of cells. Cell encapsulation enables allo- and even xeno-geneic cell therapy without immunosuppression. Micro-encapsulated islets used in recent clinical trials are not fully retrievable after transplantation. This paper summerizes the development of retrievable and theoretically replaceable macro-encapsulated islets using polyvinyl alcohol (PVA) hydrogel. An aqueous solution of PVA becomes a gel through micro crystallization by freezing and thawing. Utilizing this feature, PVA-macro-encapsulated islets (PVA-MEIs) were developed. Rat islets suspended in Euro-Collins solution containing 3% PVA were encapsulated in a mesh-reinforced PVA hydrogel sheet by freezing and thawing. The feasibility of PVA-MEIs for DM therapy was tested in vitro and in vivo. PVA-MEIs showed glucose-responsive insulin secretion in vitro even after 14-day culture. Rat PVA-MEIs cultured in media containing fresh human plasma showed no morphological changes and maintained insulin content. Intra-peritoneal transplantation of PVA-MEIs containing 750 rat islets ameliorated hyperglycemia in streptozotocin (STZ)-induced diabetic mice to nearly normal levels for up to 30 days with a consistent increase in body weight. Transplantation of PVA-MEIs also prevented metabolic and renal disorders in STZ-induced diabetic mice. PVA-MEIs cryo-preserved for 1, 7, and 30 days showed similar function in vitro and corrected hyperglycemia after intra-peritoneal transplantation in STZ-induced diabetic mice. Intra-peritoneal transplantation of PVA-MEIs containing iso- or allo-geneic islets (approx. 2,000 islets) ameliorated hyperglycemia in STZ-induced diabetic rats in a similar manner for almost half a year although the efficacy gradually decreased with time. Transplantation of PVA-MEIs ameliorated hyperglycemia in diabetic mice and rats without immunosupression. Retrievable and theoretically replaceable PVA-MEIs that can secure cell entrapment can mitigate the potential risks associated with xeno-geneic cells and cells made from undifferentiated cells. Therefore, PVA-MEIs are a promising modality for future DM therapy.


Qi Z.,Nankai University | Qi Z.,Kyoto University | Yamamoto C.,Kyoto University | Imori N.,Kyoto University | And 9 more authors.
Cell Transplantation | Year: 2012

Islet transplantation has shown great success in the treatment of type 1 diabetes since the Edmonton protocol was established. However, it still has two major problems to overcome: the lack of organ donors and the side effects of immunosuppression. Encapsulated islets have emerged as a potential option for islet transplantation because it can, at least partly, overcome these two problems. Wistar rat islets suspended in 3% polyvinyl alcohol (PVA) hydrogel were frozen-thawed to make macroencapsulated islets (MEIs). The recovery rate, insulin content, and morphological change in culture medium with/without fresh human plasma (FHP) were measured in MEIs and free islets in vitro. In vivo, MEIs of either Wistar or Lewis rats were transplanted into the peritoneal cavity of streptozotocin (STZ)-induced diabetic Lewis rats and nonfasting blood glucose (NFBG), body weight, and histological evaluations were processed. FHP destroyed rat free islets but did not affect the islet morphology, islet recovery rate, or insulin content of rat MEIs. The transplantation of MEIs decreased the NFBG level and prevented body weight loss without a significant difference between the donor strains. Insulin-positive islets were observed in PVA MEIs 24 weeks after allotransplantation. These results suggest that PVA MEIs may be used as a cure for type 1 diabetes. © 2012 Cognizant Comm. Corp.


Yanai G.,Kyoto University | Hayashi T.,Gakkentoshi Hospital | Zhi Q.,Nankai University | Yang K.-C.,Taipei Medical University | And 5 more authors.
PLoS ONE | Year: 2013

Islet transplantation is a minimally invasive treatment for severe diabetes. However, it often requires multiple donors to accomplish insulin-independence and the long-term results are not yet satisfying. Therefore, novel ways to overcome these problems have been explored. Isolated islets are fragile and susceptible to pro-apoptotic factors and poorly proliferative. In contrast, mesenchymal stem cells (MSCs) are highly proliferative, anti-apoptotic and pluripotent to differentiate toward various cell types, promote angiogenesis and modulate inflammation, thereby studied as an enhancer of islet function and engraftment. Electrofusion is an efficient method of cell fusion and nuclear reprogramming occurs in hybrid cells between different cell types. Therefore, we hypothesized that electrofusion between MSC and islet cells may yield robust islet cells for diabetes therapy. We establish a method of electrofusion between dispersed islet cells and MSCs in rats. The fusion cells maintained glucose-responsive insulin release for 20 days in vitro. Renal subcapsular transplantation of fusion cells prepared from suboptimal islet mass (1,000 islets) that did not correct hyperglycemia even if co-transplanted with MSCs, caused slow but consistent lowering of blood glucose with significant weight gain within the observation period in streptozotocin-induced diabetic rats. In the fusion cells between rat islet cells and mouse MSCs, RT-PCR showed new expression of both rat MSC-related genes and mouse β-cell-related genes, indicating bidirectional reprogramming of both β-cell and MSCs nuclei. Moreover, decreased caspase3 expression and new expression of Ki-67 in the islet cell nuclei suggested alleviated apoptosis and gain of proliferative capability, respectively. These results show that electrofusion between MSCs and islet cells yield special cells with β-cell function and robustness of MSCs and seems feasible for novel therapeutic strategy for diabetes mellitus. © 2013 Yanai et al.

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