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A Novel Preservation Solution Containing a JNK Inhibitory Peptide Efficiently Improves Islet Yield for Porcine Islet Isolation

Noguchi, Hirofumi, MD, PhD1; Miyagi-Shiohira, Chika, MS1; Nakashima, Yoshiki, DD, PhD1; Ebi, Nana, MS1; Hamada, Eri, MS1; Tamaki, Yoshihito, MS1; Kuwae, Kazuho, MS1; Kitamura, Shinji, MD, PhD2; Kobayashi, Naoya, MD, PhD3; Saitoh, Issei, DD, PhD4; Watanabe, Masami, MD, PhD5

doi: 10.1097/TP.0000000000002555
Original Basic Science—General

Background For islet transplantation, pancreas preservation in University of Wisconsin (UW) solution is associated with disadvantages, such as collagenase inhibition, resulting in poor islet yield and islets with poor viability. In this study, we evaluated a novel preservation solution, the extracellular-type c-Jun N-terminal kinase (JNK) inhibitor-containing (EJ) solution.

Methods The EJ solution has high sodium-low potassium composition with low viscosity compared to UW solution. Moreover, EJ solution contains a recently developed JNK inhibitor from our laboratory.

Results We first compared the performance of EJ solution with that of UW solution. Islet yield before and after purification was significantly higher in the EJ group than in the UW group. Second, we compared the performance of EJ solution with that of EJ solution without the JNK inhibitor (EJ-J solution). After pancreas preservation in EJ solution, JNK activity was maintained at a relatively low level during islet isolation. Islet yield before and after purification was significantly higher in the EJ group than in the EJ-J group. After islet transplantation into streptozotocin-induced diabetic mice, blood glucose levels reached the normoglycemic range in 61.5% and 7.7% of diabetic mice in the EJ and EJ-J groups, respectively. Moreover, EJ solution exhibited reduced inhibition of collagenase digestion compared with UW solution.

Conclusions Advantages of EJ solution over UW solution were inhibition of JNK activity and reduced collagenase inhibition. EJ solution may therefore be more suitable for islet isolation than UW solution.

C-Jun N-terminal kinase (JNK) is activated during pancreatic islet isolation. Porcine pancreas preservation in a solution containing an inhibitor of JNK yields significantly higher islet purification than using UW solution. Islets isolated with this new solution efficiently normalize glycemia in diabetic mice.

1 Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan.

2 Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

3 Department of Surgery, Okayama Saidaiji Hospital, Okayama, Japan.

4 Division of Pediatric Dentistry, Graduate School of Medical and Dental Science, Niigata University, Niigata, Japan.

5 Department of Urology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.

Received 4 September 2018. Revision received 24 October 2018.

Accepted 19 November 2018.

Correspondence: Hirofumi Noguchi, MD, PhD, Department of Regenerative Medicine, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan. (noguchih@med.u-ryukyu.ac.jp).

H.N. designed the experiments and analyzed the data. H.N. carried out most of the experimental work with the help of C.M-S., Y.N. N.E., E.H., Y.T., and K.K. S.K., N.K., I.S., and M.W. provided materials and discussion. H.N. wrote the article. All authors discussed and commented on the article.

The authors declare no conflicts of interest.

This work was supported in part by JSPS KAKENHI grant numbers JP16H05404, JP16K10435, and JP18K08545, Japan Agency for Medical Research and Development, Okinawa Science and Technology Innovation System Construction Project, the Waksman Foundation of Japan, Inc., and The Naito Foundation.

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