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Dive into the research topics where Kazuya Ise is active.

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Featured researches published by Kazuya Ise.


Biomaterials | 2009

Bioengineering of a functional sheet of islet cells for the treatment of diabetes mellitus

Hirofumi Shimizu; Kazuo Ohashi; Rie Utoh; Kazuya Ise; Mitsukazu Gotoh; Masayuki Yamato; Teruo Okano

The present study was designed to establish a novel tissue engineering approach for diabetes mellitus (DM) by fabricating a tissue sheet composed of pancreatic islet cells for in vivo transplantation. Pancreatic islet cell suspensions were obtained from Lewis rats, and plated onto temperature-responsive culture dishes coated with extracellular matrix (ECM) proteins. After the cells reached confluency, islet cells cultured on laminin-5 coated dishes were successfully harvested as a uniformly spread tissue sheet by lowering the culture temperature to 20 degrees C for 20 min. The functional activity of the islet cell sheets was confirmed by histological examination and Insulin secretion assay prior to in vivo transplantation. Histological examination revealed that the harvested islet cell sheet was comprised of insulin- (76%) and glucagon- (19%) positive cells, respectively. In vivo functionality of the islet cell sheet was maintained even 7 days after transplantation into the subcutaneous space of Lewis rats. The present study describes an approach to generate a functional sheet of pancreatic islet cells on laminin-5 coated temperature-responsive dishes, which can be subsequently transplanted in vivo. This study serves as the foundation for the creation of a novel cell-based therapy for DM to provide patients an alternative method.


Transplantation | 2011

Reversal of diabetes by the creation of neo-islet tissues into a subcutaneous site using islet cell sheets.

Takahiro Saito; Kazuo Ohashi; Rie Utoh; Hirofumi Shimizu; Kazuya Ise; Hiroyuki Suzuki; Masayuki Yamato; Teruo Okano; Mitsukazu Gotoh

Background. There remains a paucity of therapeutic approaches to completely treat diabetes mellitus. This study was designed to develop a dispersed islet cell-based tissue engineering approach to engineer functional neo-islet tissues in the absence of traditional bioabsorbable scaffold matrices. Methods. Specialized coated plastic dishes were prepared by covalently immobilizing a temperature-responsive polymer, poly(N-isopropylacrylamide), onto the plastic followed by coating with laminin-5. Dispersed rat islet cells were plated on the laminin-5-poly(N-isopropylacrylamide) dishes. After 2 days of culturing, islet cells were harvested as a uniformly connected tissue sheet by lowering the culture temperature from 37°C to 20°C for 30 min. Two harvested islet cell sheets were transplanted into the subcutaneous space of streptozotocin-induced diabetic severe combined immunodeficiency (SCID) mice to engineer neo-islet tissues in vivo. Therapeutic effects were investigated after the tissue engineering procedures. Results. In all of the diabetic SCID mice transplanted with the islet sheets, serum hyperglycemia was successfully reverted to a steady normoglycemic level. The recipient SCID mice demonstrated positive for serum rat C-peptide and elevated serum insulin levels. Moreover, the islet cell sheet-transplanted SCID mice demonstrated rapid glucose clearance and return of serum glucose levels after intraperitoneal glucose tolerance test. Histological examination revealed that the transplanted islet cell sheets were structured as flat clusters of islet tissues in which an active vascular network manifested within and surrounding the newly formed tissues. Conclusions. This study describes a new proof-of-concept therapeutic approach to engineer functional neo-islet tissues for the treatment of type 1 diabetes mellitus.


Journal of Pediatric Surgery | 2008

Congenital esophageal stenosis because of tracheobronchial remnant and treated by circular myectomy: a case report

Takahiro Saito; Kazuya Ise; Yoshinori Kawahara; Michitoshi Yamashita; Hirofumi Shimizu; Hiroyuki Suzuki; Mitsukazu Gotoh

Congenital esophageal stenosis (CES) is a rare anomaly, and appropriate management is not well established. We performed myectomy of the esophageal wall in a child with critical esophageal stenosis caused by tracheobronchial remnant (TBR). An 18-month-old boy was admitted to our hospital having frequent vomiting and failure to thrive. Esophagography and esophagoscopy showed abrupt stenosis at the lower esophageal wall. Balloon dilatation was performed but was ineffective. Surgery was performed under a diagnosis of CES because of TBR. Cartilage was palpable in the stenotic esophageal wall, and extirpation of the muscular layer of the stenotic portion was performed, leaving the mucosal layer intact. The muscular layer was closed loosely using interrupted 5-0 absorbable sutures to match the oral and anal sides together. Postoperatively, the esophageal passage was improved to the point that the patient was able to take solid foods without vomiting. This successful outcome suggests that circular myectomy of the TBR is worth recommending as a surgical procedure for short segment and stenosis of patients with CES because of TBR.


Cell Transplantation | 2008

Mitomycin-C treatment followed by culture produces long-term survival of islet xenografts in a rat-to mouse model.

Takashi Gunji; Takuro Saito; Yoshihiro Sato; Shinichi Matsuyama; Kazuya Ise; Takashi Kimura; Takayuki Anazawa; Mitsukazu Gotoh

One of the goals of islet transplantation is to transplant viable islets without host immunosuppression. The present study was designed to determine whether pretreatment of islets with mitomycin-C (MMC) followed by culture enhances islet survival in a rat-to-mouse xenogeneic combination. WS(RT1k) rat islets pretreated with various concentrations of MMC (0, 3.2, 10, 32, 100, 320, and 1000 μg/ml) were tested for viability by in vitro insulin secretory capacity and vital staining of islets. The MMC-treated islets (10 μg/ml) cultured for various periods (4, 20, or 40 h, 3 or 7 days) were transplanted into the renal subcapsular space of STZ-induced diabetic C57BL/6 (B6: H-2b) mice. MMC-treated or nontreated islets were subjected to microarray gene analysis and immunohistological study. Evaluation of in vitro insulin secretory capacity and vital staining of islets indicated that MMC at a dose ≤32 μg/ml is nontoxic and preserves islet function. Marked prolongation of graft survival was noted with half of islet grafts surviving indefinitely (>100 days) when 10 μg/ml of MMC-treated islets was transplanted after 40 h or 3 days in culture, but not when they were transplanted within 4 h following treatment or at 7 days following treatment, indicating that there is a critical culture period necessary for successful islet graft survival. Microarray analysis suggested possible genes for this prolongation with TGF-β highly expressed in MMC-treated islets subjected to culture for 3 days. Our results indicate that MMC treatment followed by a critical culture period induces marked prolongation of rat islet xenograft survival in nonimmunosuppressed recipient mice, offering a strategy for islet transplantation without immunosuppression.


Transplantation Proceedings | 2013

Topographical Arrangement of α- and β-Cells Within Neo-islet Tissues Engineered by Islet Cell Sheet Transplantation in Mice

Hirofumi Shimizu; Kazuo Ohashi; Takuro Saito; Rie Utoh; Kazuya Ise; Masayuki Yamato; Teruo Okano; Mitsukazu Gotoh

BACKGROUND We established a procedure to engineer therapeutic neo-islets in subcutaneous spaces in mice by transplanting contiguous layers of islet cell sheets. In this study, we investigated the cellular arrangements of α and β within these engineered neo-islets in vivo as a function of time after sheet transplantation. METHODS AND RESULTS Temperature-responsive culture dishes optimized for dispersed islet cell culture were prepared by covalently immobilizing a temperature-responsive polymer poly(N-isopropylacrylamide) (PIPAAm) on plastic dishes followed by laminin-5 coating. Dispersed islet cells obtained from Lewis rats were plated onto the PIPAAm dishes. After reaching confluence at day 2, islet cells were harvested as uniformly spread islet cell sheets by lowering the culture temperature from 37°C to 20°C for 20 minutes. Islet sheet transplantation was performed to creat neo-islet tissues in the subcutaneous spaces of SCID mice with streptozotocin-induced diabetes. This neo-islet engineering approach successfully lowered mouse blood glucose levels, achieving euglycemia at day 5 and thereafter. Histologic analyses of samples obtained at day 4 revealed that neo-islet tissues in the subcutaneous spaces showed heterogeneous cellular alignment of α and β cells. In contrast, analyses of samples at days 14 and 60 revealed α and β cells predominantly located at the peripheral and central parts of the engineered tissues, respectively. CONCLUSIONS Reassembly of α and β cells occurred in neo-islet tissues engineered by sheet transplantation. The unique cellular arrangements in neo-islet tissues, which were similar to those in naïve pancreatic islets, may contribute to their longevity and long-term function.


Cell Transplantation | 2012

A model to evaluate toxic factors influencing islets during collagenase digestion: the role of serine protease inhibitor in the protection of islets.

Manabu Tsukada; Takuro Saito; Kazuya Ise; Akira Kenjo; Takashi Kimura; Yoshihiro Satoh; Takaharu Saito; Takayuki Anazawa; Ikuro Oshibe; Shigeya Suzuki; Yasuhiro Hashimoto; Mitsukazu Gotoh

The recovery of all of the islets contained in a pancreas is the goal of islet isolation for transplantation. This study reveals an environment that injures the isolated islets during digestion and proposes a new model for optimal islet isolation. Islets were isolated from Wistar rat pancreases by stationary collagenase digestion while the digestion time was varied at 15, 30, 60, and 120 min. The digested pancreas and islets were analyzed histologically and adenosine nucleotides were measured. Overnight cultured islets (40 islets) were cocultured for 30 min with the supernatants obtained from pancreatic collagenase digestion at different digestion periods in order to assess the toxic environment. The peak yields of islets were obtained at 30 min of digestion. The histological study of digested pancreas showed that the exocrine cells lost their cellular integrity at 120 min of digestion, but the islet cells were left intact. Accordingly, the ATP levels of the pancreatic tissue decreased during the digestion period. The coculture experiment demonstrated that the islets cultured with the supernatants from the collagenase digestion showed digestion time-dependent disruption of the cellular integrity of islets in accordance with a rapid decrease of ATP levels in the islets. The addition of serine protease inhibitors into this coculture clearly showed protection of islets, which maintained high ATP levels in association with intact membrane integrity as assessed by AO/PI staining. Morphological deterioration of islets as well as a marked ATP decrease was evident in the entire digested pancreas as well as in islets cocultured in the supernatants from the collagenase digestion. Various factors toxic to the islets can therefore be analyzed in future experiments using this coculture model for obtaining a good yield of viable islets.


Transplantation | 2003

Permanent acceptance of mitomycin C-treated islet allograft.

Shinichi Matsuyama; Takashi Gunji; Kazuya Ise; Yoshihiro Sato; Takuro Saito; Mitsukazu Gotoh

Background. Mitomycin C (MMC) treatment produces genotoxic stress and exerts various biologic effects on cell function. This study determines the feasibility of MMC pretreatment of islet grafts as a sole immunomodulatory regimen to protect murine crudedigested islet allografts. Methods. Collagenase‐digested BALB/c (H‐2d) islets were incubated for 30 min with MMC at different doses (0, 3.2, 10, 32, and 100 μg/mL; n = 20, 15, 55, 15, 15, respectively), cultured for 20 hr, and transplanted into the renal subcapsular space of streptozotocin‐induced diabetic C57BL/6 (B6; H‐2b) mice. Results. All mice that received MMC‐treated islets showed restoration of normoglycemia within 5 days postgrafting, which was maintained until rejection. All untreated islets were acutely rejected with a mean survival time of 15.1 ±3.5 days. Significant prolongation of graft survival was noted in mice undergoing transplantation with islets treated with 10 μg/mL MMC compared with untreated islets (58.9±37.7 days, P<0.01). Notably, the grafts of 24 of 55 animals (43%) that received islets treated with 10 μg/mL MMC survived more than 100 days without any other treatment. Furthermore, antigen‐specific prolongation of graft survival of secondary untreated islets was observed in mice bearing long‐term functioning islet grafts. Conclusions. Our results indicate that pretreatment of islets with MMC alone protects the graft against rejection and produces long‐term graft survival with normal blood glucose levels, and that pretreatment with MMC offers a new strategy for allogeneic islet transplantation.


Cell Transplantation | 2000

Grafting of mitomycin C-treated islet xenograft under the kidney capsule produces a clear bleb.

Yoshihiro Sato; Tadeusz Grochowiecki; Yutaka Takeda; Keizo Dono; Kazuya Ise; Yukio Kanazawa; Takuro Saito; Tsuyoshi Abe; Mitsukazu Gotoh

We have previously shown that mitomycin C (MMC) treatment of donor tissue resulted in significant prolongation of graft survival in allo- and xenotransplantation models. However, the mechanisms involved in this prolongation are not clearly understood. This study aims to shed light on the immune responses to MMC-treated islet xenografting under the kidney capsule. Collagenase-digested WS (RT1k) rat islets incubated for 30 min with MMC and subsequently cultured for 20 h were transplanted into the renal subcapsular space of streptozotocin-induced diabetic C57BL/6 (B6;H-2b) mice. The grafts were harvested on postgrafting day 7 and sections were prepared and stained by hematoxylin and eosin (H&E). Histological study of the grafts in a group not treated with MMC showed marked cellular infiltration and destruction of islet clusters, whereas that of MMC-treated grafts demonstrated a bleb formation under the kidney capsule, in which islet cell clusters were reorganized, creating a layer of cells fixed to the interior of the bleb. Minimal invasion by inflammatory cells was observed only at the edge of the bleb, and most islet cells were protected from these infiltrating cells. In conclusion, MMC treatment induces remodeling of islet structure and forms a bleb under the kidney capsule, where no inflammatory cell infiltration occurs, suggesting that this site is a kind of immunologically privileged environment for xenografted islets.


Islets | 2012

Preservation of pancreatic islets in cold UW solution before transplantation

S Ishii; Takuro Saito; Kazuya Ise; Michitoshi Yamashita; Yoshihiro Sato; Takaharu Saito; Manabu Tsukada; Ikuro Oshibe; Akira Kenjo; Takashi Kimura; Takayuki Anazawa; Shigeya Suzuki; Mitsukazu Gotoh

Culture of islets prior to transplantation needs to be revisited for maintaining functional islet capacity. This study was conducted to compare cold UW (University of Wisconsin) preservation with conventional culture based on insulin secretory capacity in vitro and in vivo. Islets isolated from Wistar rats were either cultured for 24 h at 37°C in RPMI1640 medium or DMEM containing various concentrations of glucose or preserved for the same period in UW solution or in DMEM solution at 4°C. The islet yield in UW group, but not in other groups, was maintained as comparable with that of fresh islets. Insulin secretory capacity in response to glucose was maintained only in the islets of UW group, but not in other groups. SCID mice given 300 IEQ islets of UW group showed gradual restoration of normoglycemia as found in the mice given freshly isolated islets. Meanwhile, those mice given cultured islets for 24 h at 37°C in RPMI1640 medium showed rapid decrease of blood glucose levels on day 1 followed by relatively elevated levels on day 2, suggesting unstable insulin secretory capacity of islets. Morphological staining with anti-HMGB1 (high mobility group B1) antibody revealed central damage of islets in all culture groups regardless of glucose concentration and in islets of cold DMEM group, whereas those in the UW group were quite intact. These results suggest that cold preservation in UW solution is simple and beneficial in protecting islets morphologically and functionally before transplantation.


Cell Transplantation | 2012

Mizoribine as sole immunosuppressive agent in islet xenotransplantation models: a candidate immunosuppressant causing no adverse effects on islets.

Michitoshi Yamashita; Takuro Saito; Kazuya Ise; S Ishii; Yoshihiro Satoh; Takaharu Saito; Ikuro Oshibe; Hirofumi Shimizu; Akira Kenjo; Takashi Kimura; Mitsukazu Gotoh

Mizoribine (MZ) inhibits the differentiation and proliferation of helper T and B cells after antigen recognition by suppressing the purine biosynthesis pathway and nucleic acid synthesis. MZ has been used in kidney transplantation, but distinct data are unavailable for islet transplantation. The present study investigated the efficacy of MZ for islet xenotransplantation. Immunosuppressive effects of MZ were determined by mixed lymphocyte reaction (MLR) assay in vitro. Toxicities for Wistar rat islets were determined by adenosine triphosphate (ATP) contents of islets during 3-day culture and stimulation index in response to glucose after culture. Immunosuppressive effects in vivo were tested in a Wistar-to-B6 islet xenotransplantation model. MZ was administered continuously for 28 days subcutaneously or intramuscularly. MZ inhibited MLR response by approximately 50% at 0.1 μg/ml. ATP contents decreased with MZ >100 μg/ml, while stimulation index was maintained. Continuous infusion of MZ at 10 mg/kg maintained blood concentrations at 0.13–0.19 μg/ml, while intramuscular injection of MZ at 100 mg/kg/day (peak 520 μg/ml at 1 h postinjection) resulted in below measurable levels (<0.03 μg/ml) within 24 h. Graft survival was significantly prolonged following continuous infusion of 10 mg/kg/day compared to controls (31.0 ± 9.5 vs. 13.2 ± 5.2 days; p = 0.002). Furthermore, animals with intramuscular injection at doses of 3.2, 10, or 100 mg/kg/day showed significantly longer graft survival (20.0 ± 7.5, 22.0 ± 7.31, and 24.5 ± 8.1 days, respectively; p < 0.05 each). Histological examination showed significant suppression of lymphocyte infiltration by MZ administration. MZ showed immunosuppressive effects in an experimental islet xenotransplantation model without adverse effects on endocrine function of islet grafts.

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Mitsukazu Gotoh

Fukushima Medical University

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Takuro Saito

Fukushima Medical University

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Yoshihiro Sato

Fukushima Medical University

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Hirofumi Shimizu

Fukushima Medical University

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Takayuki Anazawa

Fukushima Medical University

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Akira Kenjo

Fukushima Medical University

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Michitoshi Yamashita

Fukushima Medical University

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Rie Utoh

Hiroshima University

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