Total pancreatectomy with islet autotransplantation (TP-IAT) is currently being performed to treat intractable pain and to prevent """"""""brittle"""""""" diabetes in well-selected patients with chronic pancreatitis. A major problem associated with TP-IAT is that the number of islets available for transplantation is compromised by a severely diseased and fibrotic pancreas. Moreover, as many as 50-60% of islet cells undergo apoptosis immediately after intraportal infusion when transplantation-associated stressors (hypoxia, nutrient deprivation, reactive oxygen species, proinflammation cytokines, etc.) are induced during harvesting, isolation, and implantation of the islet cell mass. Although the quality of life are significantly improved in our TP-IAT patients, ony 25% of them become insulin independent (compared to >85% pre-operatively), 19% require minimal insulin (<10u/day) replacement and the rest develop pancreatogenic diabetes after surgery. Strategies that produce islets more """"""""robust"""""""" to resist stressors that induce ? cell apoptosis are extremely appealing to prevent onset of surgical diabetes and to improve the efficiency of human islet auto-transplantation. We have been focused on exploring strategies that can prevent islet ? cell death after allogeneic transplantation to treat patient with type 1 diabetes over the past 10 years. Our data indicate that induction of a protective gene, heme oxygenase-1 (HO-1), or exposing the product of HO-1 enzymatic activity, carbon monoxide (CO), protects islet allografts from immune rejection after transplantation. HO-1 gene expression was dramatically reduced in islets from chronic pancreatitis patient compared to those from healthy individual and HO-1 induction protects islets from hypoxia-induced cell death. Moreover, encapsulating islets with biodegradable poly-lactic-co-glycolic acid (PLGA) nanoparticles also protect islets from apoptosis in a murine islet transplantation model. We hypothesize that induction of HO-1/CO exposure, in combination with islet encapsulation, can make human islets more resistant to injuries and lead to better survival after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. In this proposal, we aim to develop a novel HO-1/CO-based islet encapsulation protocol that can make islets more resistant to injuries encountered during isolation and after transplantation so that more patients with chronic pancreatitis can be diabetes free after TP-IAT. Our strong research team that includes islet transplantation biologists, islet transplantation surgeons, endocrinologists and bioengineering experts, and our state-of-the-art cGMP facility at MUSC offers a convenient and powerful platform that can facilitate the translation of our research findings from bench to bedside.
In this proposal, we would like to test the hypothesis that HO-1 induction/CO exposure, in combination with islet encapsulation can enhance the survival and function of human islets after transplantation. Our long- term goal is to translate what we learn i animal studies into therapies to increase insulin independence in patients with chronic pancreatitis who undergo total pancreatectomy with islet auto-transplantation.
|Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) GRP94 Is an Essential Regulator of Pancreatic ?-Cell Development, Mass, and Function in Male Mice. Endocrinology 159:1062-1073|
|Wang, Hongjun; Strange, Charlie; Nietert, Paul J et al. (2018) Autologous Mesenchymal Stem Cell and Islet Cotransplantation: Safety and Efficacy. Stem Cells Transl Med 7:11-19|
|Kim, Do-Sung; Song, Lili; Wang, Jingjing et al. (2018) Carbon Monoxide Inhibits Islet Apoptosis via Induction of Autophagy. Antioxid Redox Signal 28:1309-1322|
|Dong, H; Zhang, Y; Wang, J et al. (2017) Regulator of G protein signaling 2 is a key regulator of pancreatic ?-cell mass and function. Cell Death Dis 8:e2821|
|Sun, Zhen; Gou, Wenyu; Kim, Do-Sung et al. (2017) Adipose Stem Cell Therapy Mitigates Chronic Pancreatitis via Differentiation into Acinar-like Cells in Mice. Mol Ther 25:2490-2501|
|Dong, Huansheng; Zhang, Yong; Song, Lili et al. (2016) Cell-Permeable Peptide Blocks TLR4 Signaling and Improves Islet Allograft Survival. Cell Transplant 25:1319-29|
|Zhang, Yanqing; Fava, Genevieve E; Wang, Hongjun et al. (2016) PAX4 Gene Transfer Induces ?-to-? Cell Phenotypic Conversion and Confers Therapeutic Benefits for Diabetes Treatment. Mol Ther 24:251-260|
|Cao, Mingjun; Pan, Qingjie; Dong, Huansheng et al. (2015) Adipose-derived mesenchymal stem cells improve glucose homeostasis in high-fat diet-induced obese mice. Stem Cell Res Ther 6:208|
|Liu, Jinfeng; Dong, Huansheng; Zhang, Yong et al. (2015) Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPAR? Levels. Sci Rep 5:9886|
|Dong, Huansheng; Huang, Hu; Yun, Xinxu et al. (2014) Bilirubin increases insulin sensitivity in leptin-receptor deficient and diet-induced obese mice through suppression of ER stress and chronic inflammation. Endocrinology 155:818-28|