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Inhibition of mitochondrial reactive oxygen species (ROS) and subsequent damage‐associated molecular patterns (DAMPs)‐induced inflammatory responses could be a novel target in clinical islet transplantation. We investigated the protective effects of NecroX‐7, a novel clinical‐grade necrosis inhibitor that specifically targets mitochondrial ROS, against primary islet graft failure. Islets from heterozygote human islet amyloid polypeptide transgenic (hIAPP+/−) mice and nonhuman primates (NHPs) were isolated or cultured with or without NecroX‐7 in serum‐deprived medium. Supplementation with NecroX‐7 during hIAPP+/−mouse islet isolation markedly increased islet viability and adenosine triphosphate content, and attenuated ROS, transcription of c‐Jun N‐terminal kinases, high mobility group box 1, interleukin‐1beta (IL‐1 β), IL‐6, and tumor necrosis factor‐alpha. Supplementation of NecroX‐7 during serum‐deprived culture also protected hIAPP+/−mouse and NHP islets against impaired viability, serum deprivation‐induced ROS, proinflammatory response, and accumulation of toxic IAPP oligomer. Supplementation with NecroX‐7 during isolation or serum‐deprived culture of hIAPP+/−mouse and NHP islets also improved posttransplant glycemia in the recipient streptozotocin‐induced diabetic hIAPP−/−mice and BALB/c‐nu/numice, respectively. In conclusion, pretransplant administration of NecroX‐7 during islet isolation and serum‐deprived culture suppressed mitochondrial ROS injury, generation of DAMPs‐induced proinflammatory responses, and accumulation of toxic IAPP oligomers ex vivo, and improved posttransplant glycemia in vivo. NecroX‐7, a novel clinical‐grade necrosis inhibitor, protects against primary islet graft failure in murine and nonhuman primate models through inhibition of mitochondrial reactive oxygen species and subsequent inflammatory responses induced by damage‐associated molecular patterns.

Islet transplantation is the most effective treatment strategy for type 1 diabetes. Long-term storage at ultralow temperatures can be used to prepare sufficient islets of good quality for transplantation. For freezing islets, dimethyl sulfoxide (DMSO) is a commonly used penetrating cryoprotective agent (CPA). However, the toxicity of DMSO is a major obstacle to cell cryopreservation. Hydroxyethyl starch (HES) has been proposed as an alternative CPA. To investigate the effects of two types of nonpermeating CPA, we compared 4 % HES 130 and HES 200 to 10 % DMSO in terms of mouse islet yield, viability, and glucose-stimulated insulin secretion (GSIS). After one day of culture, islets were cryopreserved in each solution. After three days of cryopreservation, islet recovery was significantly higher in the HES 130 and HES 200 groups than in the DMSO group. Islet viability in the HES 200 group was also significantly higher than that in the DMSO group on Day 1 and Day 3. Stimulation indices determined by GSIS were higher in the HES 130 and 200 groups than in the DMSO group on Day 3. After three days of cryopreservation, HES 130 and HES 200 both reduced the expression of apoptosis- and necrosis-associated proteins and promoted the survival of islets. In conclusion, the use of HES as a CPA improved the survival and insulin secretion of cryopreserved islets compared with the use of a conventional CPA.

Yan et al compare the effects of the macrophage inhibitors CD200 and CD47, and report that human CD200 expression by pig endothelial cell inhibited the activation of human macrophages in vitro and improved their survival when transplanted into humanized mice. Supplemental digital content is available in the text.