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Pancreas Preservation in Modified Histidine-lactobionate Solution Is Superior to That in University of Wisconsin Solution for Porcine Islet Isolation. Transplantation 2022; 106:1770-1776. [PMID: 36001489 DOI: 10.1097/tp.0000000000003636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND We previously reported that modified extracellular-type trehalose-containing Kyoto (MK) solution, which contains a trypsin inhibitor (ulinastatin), significantly improved the islet yield compared with University of Wisconsin (UW) preservation, which is the gold standard for organ preservation for islet isolation. In this study, we evaluated the efficiency of a modified histidine-lactobionate (MHL) solution in addition to UW or MK solution. The MHL solution has a high sodium-low potassium composition with low viscosity compared with the UW solution. Moreover, similar to MK solution, MHL solution also contains ulinastatin. METHODS Porcine pancreata were preserved in UW, MK, or MHL solution, followed by islet isolation. An optimized number (1500 IE) of isolated islets from each group were then transplanted into streptozotocin-induced diabetic mice. RESULTS The islet yield before and after purification was significantly higher in the MHL group than in the UW group. On the contrary, the islet yield before and after purification was not significantly different between the MHL and MK groups. Preserving the porcine pancreata in MHL solution improved the outcome of islet transplantation in streptozotocin-induced diabetic mice compared with that in UW solution. CONCLUSIONS Pancreas preservation with MHL solution preserves islet function better than UW solution. The effect of MHL solution is similar to that of MK solution, suggesting that MHL solution can be used as an alternative to MK solution for pancreatic islet transplantation.
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Pancreas Preservation with a Neutrophil Elastase Inhibitor, Alvelestat, Contributes to Improvement of Porcine Islet Isolation and Transplantation. J Clin Med 2022; 11:jcm11154290. [PMID: 35893379 PMCID: PMC9330829 DOI: 10.3390/jcm11154290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/13/2022] [Accepted: 07/21/2022] [Indexed: 12/14/2022] Open
Abstract
For pancreatic islet transplantation, pancreas procurement, preservation, and islet isolation destroy cellular and non-cellular components and activate components such as resident neutrophils, which play an important role in the impairment of islet survival. It has been reported that inhibitors of neutrophil elastase (NE), such as sivelestat and α1-antitrypsin, could contribute to improvement of islet isolation and transplantation. In this study, we investigated whether pancreatic preservation with alvelestat, a novel NE inhibitor, improves porcine islet yield and function. Porcine pancreata were preserved with or without 5 μM alvelestat for 18 h, and islet isolation was performed. The islet yields before and after purification were significantly higher in the alvelestat (+) group than in the alvelestat (−) group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 55% and 5% of diabetic mice in the alvelestat (+) and alvelestat (−) groups, respectively. These results suggest that pancreas preservation with alvelestat improves islet yield and graft function and could thus serve as a novel clinical strategy for improving the outcome of islet transplantation.
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Nishime K, Miyagi-Shiohira C, Kuwae K, Tamaki Y, Yonaha T, Sakai-Yonaha M, Saitoh I, Watanabe M, Noguchi H. Preservation of pancreas in the University of Wisconsin solution supplemented with AP39 reduces reactive oxygen species production and improves islet graft function. Am J Transplant 2021; 21:2698-2708. [PMID: 33210816 DOI: 10.1111/ajt.16401] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 10/19/2020] [Accepted: 11/15/2020] [Indexed: 01/25/2023]
Abstract
Ischemia-reperfusion injury (IRI) results in increased rates of delayed graft function and early graft loss. It has recently been reported that hydrogen sulfide (H2 S) protects organ grafts against prolonged IRI. Here, we investigated whether the preservation of pancreas in University of Wisconsin (UW) solution supplemented with AP39, which is a mitochondrial-targeted H2 S donor, protected pancreatic islets against IRI and improved islet function. Porcine pancreata were preserved in the UW solution with AP39 (UW + AP39) or the vehicle (UW) for 18 h, followed by islet isolation. The islet yields before and after purification were significantly higher in the UW + AP39 group than in the UW group. The islets isolated from the pancreas preserved in UW + AP39 exhibited significantly decreased levels of reactive oxygen species (ROS) production and a significantly increased mitochondrial membrane potential as compared to the islets isolated from the pancreas preserved in the vehicle. We found that the pancreas preserved in UW + AP39 improved the outcome of islet transplantation in streptozotocin-induced diabetic mice. These results suggest that the preservation of pancreas in UW + AP39 protects the islet grafts against IRI and could thus serve as a novel clinical strategy for improving islet transplantation outcomes.
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Affiliation(s)
- Kai Nishime
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Kazuho Kuwae
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Yoshihito Tamaki
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Tasuku Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Mayuko Sakai-Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Masami Watanabe
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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de Sousa SG, Nascimento da Silva GV, Costa Rodrigues AM, Meireles Fernandes da Silva TM, Costa FC, Freitas Teixeira da Silva A, Santana de Macedo BF, Brito MVH. Organ Preservation Solutions in Transplantation: A Literature Review. EXP CLIN TRANSPLANT 2021; 19:511-521. [PMID: 33797354 DOI: 10.6002/ect.2020.0506] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
OBJECTIVES Renal transplant with ABO-incompatible donors expands the donor pool. Earlier studies have focused the use of protocol biopsies in ABOincompatible transplant patients. Our study described outcomes of indication (for cause) renal biopsies and clinical outcomes in patients with ABO-incompatible renal transplant. MATERIALS AND METHODS This retrospective study included 164 patients from January 2012 to June 2019. Biochemical parameters, serial immunoglobulin G anti-ABO titers, and class I and II donor-specific antibody findings were obtained from hospital records, and renal graft biopsies were reviewed according to the Banff 2017 update. RESULTS We analyzed the results of 65 biopsies from 54 patients. Biopsy-proven acute antibody-mediated rejection (12.8%) was found to be more prevalent than acute cellular rejection (1.8%). Patients with antibodymediated rejection all had microvascular inflammation (g+ptc score of 2 or more, where g+ptc is the sum of the glomerulitis and peritubular capillaritis scores) and were positive for C4d. Acute tubular injury per se was seen in 10.3% of patients; 65% of these patients had C4d positivity in peritubular capillaries, and only 1 patient developed chronic active antibody-mediated rejection on follow-up. Patient and death-censored graft survival rates were 92% and 98% at 1 year after transplant and 88% and 91% at 3 years, respectively. Patients with an episode of antibody-mediated rejection had lower rates of patient (76.5%) and deathcensored graft survival (84.6%) at 1 year. CONCLUSIONS The microvascular inflammation score (g+ptc score of 2 or higher) is more reliable than diffuse C4d positivity to determine antibody-mediated rejection in ABO-incompatible transplants because diffuse C4d positivity may also be seen in etiologies unrelated to antibody-mediated rejection. Acute tubular injury with C4d positivity without microvascular injury does not confirm antibody-mediated rejection. We suggest that Banff classification be updated in ABOincompatible transplants to include diagnostic criteria for the diagnosis of antibody-mediated rejection.
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Sawada S, Miyagi-Shiohira C, Kuwae K, Tamaki Y, Nishime K, Sakai-Yonaha M, Yonaha T, Saitoh I, Watanabe M, Noguchi H. Pancreas preservation with amphotericin B deteriorates islet yield for porcine islet isolation. Xenotransplantation 2021; 28:e12690. [PMID: 33811411 DOI: 10.1111/xen.12690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 03/08/2021] [Accepted: 03/22/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Amphotericin B is a crucial agent in the management of serious systemic fungal infections. It is also known to be cytotoxic. In this study, we evaluated the effect of amphotericin B added to the preservation solution on islet yield during islet isolation. METHODS Porcine pancreata were preserved in the preservation solution with or without amphotericin B (0.25 μg/mL) for approximately 18 hours at 4°C, and then islet isolation was performed. An optimized number (1750 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice. The culture of isolated islets and acinar tissue with amphotericin B was also evaluated. RESULTS The islet yield before and after purification in the amphotericin B (-) group was significantly higher than that in the amphotericin B (+) group. After islet transplantation into diabetic mice, blood glucose levels reached the normoglycemic range, with 50% and 0% of that of the diabetic mice in the amphotericin B (-) and amphotericin B (+) groups, respectively. In the culture study, amphotericin B was found to be cytotoxic to porcine islets and acinar tissue. CONCLUSIONS Amphotericin B added to the preservation solution deteriorates islet yield during porcine islet isolation. Thus, the use of amphotericin B should be considered carefully for the preservation of the pancreas for islet isolation and islet culture before islet transplantation.
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Affiliation(s)
- Sayaka Sawada
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Kazuho Kuwae
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Yoshihito Tamaki
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Kai Nishime
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Mayuko Sakai-Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Tasuku Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Masami Watanabe
- Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
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Yonaha T, Miyagi-Shiohira C, Kuwae K, Tamaki Y, Nishime K, Sakai-Yonaha M, Saitoh I, Watanabe M, Noguchi H. Pancreas preservation in extracellular-type p38 inhibitor-containing solution improves islet yield for porcine islet isolation. Xenotransplantation 2020; 28:e12661. [PMID: 33231337 DOI: 10.1111/xen.12661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Revised: 09/30/2020] [Accepted: 11/09/2020] [Indexed: 01/19/2023]
Abstract
BACKGROUND For islet transplantation, pancreas preservation and islet isolation activate p38, which is a member of the stress-activated group of mitogen-activated protein kinases (MAPKs). In this study, we evaluated an extracellular-type p38 inhibitor-containing (EP) solution with University of Wisconsin (UW) solution, the gold standard for organ preservation. The EP solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EP solution contains a recently developed p38 inhibitor (11R-p38I110 ) from our laboratory. METHODS Porcine pancreata were preserved in UW, EP, or EP-P solution (EP solution without 11R-p38I110 ), and then islet isolation was performed. An optimized number (1500 IE) of isolated islets from each group were transplanted into streptozotocin-induced diabetic mice. RESULTS The islet yield before and after purification was significantly higher in the EP group than in the UW group. The islet yield before and after purification was not significantly different between the EP and EP-P groups; however, the EP solution prevented a reduction in the number of islets during culture. Western blot analysis showed that p38 activation was attenuated by EP solution. For islet transplantation into streptozotocin-induced diabetic mice, pancreas preservation in EP solution improved the outcome of islet transplantation. CONCLUSIONS Pancreas preservation with EP solution preserved islet function better than with UW solution. The advantages of EP solution over UW solution may include the inhibition of p38 activity as well as the composition of the solution.
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Affiliation(s)
- Tasuku Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Kazuho Kuwae
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Yoshihito Tamaki
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Kai Nishime
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Mayuko Sakai-Yonaha
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan
| | - Masami Watanabe
- Department of Urology, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
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Excellent Islet Yields after 18-h Porcine Pancreas Preservation by Ductal Injection, Pancreas Preservation with MK Solution, Bottle Purification, and Islet Purification Using Iodixanol with UW Solution and Iodixanol with MK Solution. J Clin Med 2019; 8:jcm8101561. [PMID: 31574895 PMCID: PMC6832492 DOI: 10.3390/jcm8101561] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Revised: 09/17/2019] [Accepted: 09/26/2019] [Indexed: 11/17/2022] Open
Abstract
Successful islet isolation is the key to successful islet transplantation. Our group recently modified the islet isolation protocol to include pancreatic ductal injection of the preservation solution, pancreas storage in modified extracellular-type trehalose-containing Kyoto (MK) solution, and use of an iodixanol-based purification solution and bottle purification. In this study, we applied these methods to porcine islet isolation after 18-h pancreas preservation and compared two solutions with different compositions in bottle purification. Islet yield before purification was 651,661 ± 157,719 islet equivalents (IE) and 5576 ± 1538 IE/g pancreas weight. An IU solution was made by adding iodixanol to University of Wisconsin solution and an IK solution was made by adding iodixanol to MK solution. The efficacy of the two solutions for islet isolation was compared. There were no significant differences between the two purification methods with regard to islet yield, survival rate, purity, score, or stimulation index. These results indicate that our isolation protocol produces efficient islet yields from prolonged cold-stored pancreas and that IU and IK solutions are equally useful for islet purification.
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A Novel Preservation Solution Containing a JNK Inhibitory Peptide Efficiently Improves Islet Yield for Porcine Islet Isolation. Transplantation 2019; 103:344-352. [DOI: 10.1097/tp.0000000000002555] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
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Nahar S, Nakashima Y, Miyagi-Shiohira C, Kinjo T, Toyoda Z, Kobayashi N, Saitoh I, Watanabe M, Noguchi H, Fujita J. Cytokines in adipose-derived mesenchymal stem cells promote the healing of liver disease. World J Stem Cells 2018; 10:146-159. [PMID: 30631390 PMCID: PMC6325075 DOI: 10.4252/wjsc.v10.i11.146] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 09/07/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023] Open
Abstract
Adipose-derived mesenchymal stem cells (ADSCs) are a treatment cell source for patients with chronic liver injury. ADSCs are characterized by being harvested from the patient's own subcutaneous adipose tissue, a high cell yield (i.e., reduced immune rejection response), accumulation at a disease nidus, suppression of excessive immune response, production of various growth factors and cytokines, angiogenic effects, anti-apoptotic effects, and control of immune cells via cell-cell interaction. We previously showed that conditioned medium of ADSCs promoted hepatocyte proliferation and improved the liver function in a mouse model of acute liver failure. Furthermore, as found by many other groups, the administration of ADSCs improved liver tissue fibrosis in a mouse model of liver cirrhosis. A comprehensive protein expression analysis by liquid chromatography with tandem mass spectrometry showed that the various cytokines and chemokines produced by ADSCs promote the healing of liver disease. In this review, we examine the ability of expressed protein components of ADSCs to promote healing in cell therapy for liver disease. Previous studies demonstrated that ADSCs are a treatment cell source for patients with chronic liver injury. This review describes the various cytokines and chemokines produced by ADSCs that promote the healing of liver disease.
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Affiliation(s)
- Saifun Nahar
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Yoshiki Nakashima
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Chika Miyagi-Shiohira
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Takao Kinjo
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | - Zensei Toyoda
- Department of Basic Laboratory Sciences, School of Health Sciences in the Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
| | | | - Issei Saitoh
- Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata 951-8514, Japan
| | - Masami Watanabe
- Department of Urology, Okayama Univer sity Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hirofumi Noguchi
- Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan.
| | - Jiro Fujita
- Department of Infectious, Respiratory, and Digestive Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan
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