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Pig islets

Yunxia O'Malley, Pavana G Rotti, Ian M Thornell, Oriana G Vanegas Calderón, Christopher Febres-Aldana, Katelin Durham, Jianrong Yao, Xiaopeng Li, Zheng Zhu, Andrew W Norris, Joseph Zabner, John F Engelhardt, Aliye Uc
Pancreatic ductular epithelial cells comprise the majority of duct cells in pancreas, control cystic fibrosis transmembrane conductance regulator (CFTR)-dependent bicarbonate [HCO3 - ] secretion, but are difficult to grow as a polarized monolayer. Using NIH-3T3-J2 fibroblast feeder cells and a Rho-associated kinase inhibitor, we produced well-differentiated and polarized porcine pancreatic ductular epithelial cells. Cells grown on semipermeable filters at air-liquid interface (ALI) developed typical epithelial cell morphology and stable transepithelial resistance (TER), expressed epithelial cell markers (zona occludens-1 and beta catenin), duct cell markers (SOX-9 and CFTR), but no acinar (amylase) or islet cell (chromogranin) markers...
March 8, 2018: Journal of Applied Physiology
Jung-Sik Kim, Hyunwoo Chung, Nari Byun, Seong-Jun Kang, Sunho Lee, Jun-Seop Shin, Chung-Gyu Park
Pancreatic islet transplantation is an ultimate solution for treating patients with type 1 diabetes (T1D). The pig is an ideal donor of islets for replacing scarce human islets. Besides immunological hurdles, non-immunological hurdles including fragmentation and delayed engraftment of porcine islets need solutions to succeed in porcine islet xenotransplantation. In this study, we suggest a simple but effective modality, a cell/islet co-localizing composite, to overcome these challenges. Endothelial-like mesenchymal stem cells (EMSCs), differentiated from bone-marrow derived mouse mesenchymal stem cells (MSCs), and MSCs evenly coated the surface of porcine islets (>85%) through optimized culture conditions...
February 7, 2018: Biochemical and Biophysical Research Communications
Florentina Tofoleanu, Ye Yuan, Frank C Pickard, Bartlomiej Tywoniuk, Bernard R Brooks, Nicolae-Viorel Buchete
Human Islet Amyloid Polypeptide (hIAPP), also known as Amylin, is a 37-aminoacid peptide, co-secreted with insulin and widely found in fibril form in type-2 diabetes patients. By using all-atom molecular dynamics simulations, we study hIAPP fibril segments (i.e., protofilaments) formed with sequences of naturally-occurring variants from cat, rat and pig, presenting different aggregation propensities. We characterize the effect of mutations on the structural dynamics of solution-formed hIAPP protofilament models built from solid-state NMR data...
February 6, 2018: Journal of Physical Chemistry. B
Hee Jung Kang, Haneulnari Lee, Eun Mi Park, Jong-Min Kim, Jun-Seop Shin, Chung-Gyu Park
BACKGROUND: The development of a precise and easy-to-use tool for monitoring islet graft function is important in clarifying the causes of graft loss, identifying appropriate therapy, and ensuring graft survival in the nonhuman primate (NHP) model of porcine islet transplantation (PITx). Glycated albumin (GA) is an indicator of intermediate-term changes in blood glucose control and is useful in clinical diabetes management. The validity of GA for monitoring graft function in NHP recipients of PITx was evaluated using a retrospective analysis of cohort samples...
January 23, 2018: Xenotransplantation
Timothy K Cooper, Louis Huzella, Joshua C Johnson, Oscar Rojas, Sri Yellayi, Mei G Sun, Sina Bavari, Amanda Bonilla, Randy Hart, Peter B Jahrling, Jens H Kuhn, Xiankun Zeng
Survivors of Ebola virus infection may become subclinically infected, but whether animal models recapitulate this complication is unclear. Using histology in combination with immunohistochemistry and in situ hybridization in a retrospective review of a guinea pig confirmation-of-virulence study, we demonstrate for the first time Ebola virus infection in hepatic oval cells, the endocardium and stroma of the atrioventricular valves and chordae tendinae, satellite cells of peripheral ganglia, neurofibroblasts and Schwann cells of peripheral nerves and ganglia, smooth muscle cells of the uterine myometrium and vaginal wall, acini of the parotid salivary glands, thyroid follicular cells, adrenal medullary cells, pancreatic islet cells, endometrial glandular and surface epithelium, and the epithelium of the vagina, penis and, prepuce...
January 19, 2018: Scientific Reports
D K C Cooper, R Gaston, D Eckhoff, J Ladowski, T Yamamoto, L Wang, H Iwase, H Hara, M Tector, A J Tector
Introduction: There is a continuing worldwide shortage of organs from deceased human donors for transplantation into patients with end-stage organ failure. Genetically engineered pigs could resolve this problem, and could also provide tissues and cells for the treatment of conditions such as diabetes, Parkinson's disease and corneal blindness. Sources of data: The current literature has been reviewed. Areas of agreement: The pathobiologic barriers are now largely defined...
December 8, 2017: British Medical Bulletin
Byoung-Hoon Min, Jun-Seop Shin, Jong-Min Kim, Seong-Jun Kang, Hyun-Je Kim, Il-Hee Yoon, Su-Kyoung Park, Ji-Won Choi, Min-Suk Lee, Chung-Gyu Park
BACKGROUND: Pancreatic islet transplantation is currently proven as a promising treatment for type 1 diabetes patients with labile glycemic control and severe hypoglycemia unawareness. Upon islet transplantation, revascularization is essential for proper functioning of the transplanted islets. As IL-6 is important for endothelial cell survival and systemic inflammation related to xenograft, the effect of IL-6 receptor antagonist, tocilizumab, on revascularization of the transplanted islets was examined in pig to non-human primate islet xenotransplantation model...
January 2018: Xenotransplantation
Olof Eriksson, Peter Johnström, Zsolt Cselenyi, Mahabuba Jahan, Ram K Selvaraju, Marianne Jensen-Waern, Akihiro Takano, Maria Sörhede Winzell, Christer Halldin, Stanko Skrtic, Olle Korsgren
GPR44 expression has recently been described as highly β-cell selective in the human pancreas and constitutes a tentative surrogate imaging biomarker in diabetes. A radiolabeled small-molecule GPR44 antagonist, [11 C]AZ12204657, was evaluated for visualization of β-cells in pigs and nonhuman primates by positron emission tomography as well as in immunodeficient mice transplanted with human islets under the kidney capsule. In vitro autoradiography of human and animal pancreatic sections from subjects without and with diabetes, in combination with insulin staining, was performed to assess β-cell selectivity of the radiotracer...
February 2018: Diabetes
Kannan P Samy, James R Butler, Ping Li, David K C Cooper, Burcin Ekser
Pig-to-human xenotransplantation offers a potential bridge to the growing disparity between patients with end-stage organ failure and graft availability. Early studies attempting to overcome cross-species barriers demonstrated robust humoral immune responses to discordant xenoantigens. Recent advances have led to highly efficient and targeted genomic editing, drastically altering the playing field towards rapid production of less immunogenic porcine tissues and even the discussion of human xenotransplantation trials...
2017: Journal of Immunology Research
Xiaoqian Ma, Cejun Yang, Juan Zhang, Jia Wang, Wei Li, Chang Xu, Pengfei Rong, Bin Ye, Minghua Wu, Jianhui Jiang, Shounan Yi, Wei Wang
BACKGROUND: Neonatal pig islet-like cell clusters (NICC) are an attractive source of insulin-producing tissue for potential transplantation treatment of type 1 diabetic patients. However, a considerable loss of NICC after their transplantation due to apoptosis resulted from islet isolation and instant blood-mediated inflammatory reaction remains to be overcome. METHODS: EGM2 medium depleted with hydrocortisone and supplemented with 50 mmol/L isobutylmethylxanthine, 10 mmol/L nicotinamide, and 10 mmol/L glucose was used to culture NICC at day 1, the day after isolation and changed every other day...
November 12, 2017: Xenotransplantation
Jae-Il Lee, Jiyeon Kim, Yun-Jung Choi, Hi-Jung Park, Hye-Jin Park, Hae Joo Wi, Sunok Yoon, Jun-Seop Shin, Jin Kyun Park, Kyeong Cheon Jung, Eun Bong Lee, Hee Jung Kang, Eung Soo Hwang, Sang-Joon Kim, Chung-Gyu Park, Seong Hoe Park
BACKGROUND: Pig islet xenotransplantation is a promising alternative to allogeneic transplantation. However, the wide immunologic barrier between pigs and primates limits the long-term survival of the graft. MD-3, a novel monoclonal antibody (mAb) that recognizes a particular epitope of human ICAM-1, can render T cells tolerant to a xenograft by arresting dendritic cell maturation. We report the long-term survival of adult wild-type pig islets and successful retransplantation in nonhuman primates using a protocol comprising induction with MD-3 mAb and maintenance with anti-CD154 mAb and sirolimus...
November 12, 2017: Xenotransplantation
Yoshiki Nakashima, Chika Miyagi-Shiohira, Naoya Kobayashi, Issei Saitoh, Masami Watanabe, Hirofumi Noguchi
Liquid chromatography with tandem mass spectrometry (LC-MS/MS) is a proteome analysis method, and the shotgun analysis by LC-MS/MS comprehensively identifies proteins from tissues and cells with high resolving power. In this study, we analyzed the protein expression in pancreatic tissue by LC-MS/MS. Islets isolated from porcine pancreata (purity ≥95%) and exocrine tissue (purity ≥99%) were used in this study. LC-MS/MS showed that 13 proteins were expressed in pancreatic islets only (Group I), 43 proteins were expressed in both islets and exocrine tissue (Group I&E), and 102 proteins were expressed in exocrine tissue only (Group E)...
November 2, 2017: Islets
Jun-Seop Shin, Jong-Min Kim, Byoung-Hoon Min, Il Hee Yoon, Hyun Je Kim, Jung-Sik Kim, Yong-Hee Kim, Seong-Jun Kang, Jiyeon Kim, Hee-Jung Kang, Dong-Gyun Lim, Eung-Soo Hwang, Jongwon Ha, Sang-Joon Kim, Wan Beom Park, Chung-Gyu Park
BACKGROUND: Islet transplantation is an effective therapy for selected patients with type 1 diabetes with labile glycemic control and hypoglycemic unawareness, but donor organs are limited. Islet xenotransplantation using porcine islets will potentially solve this problem. Although successful proof of concept studies using clinically inapplicable anti-CD154 monoclonal antibody (mAb) in pig-to-non-human primate (NHP) islet xenotransplantation has been demonstrated by several groups worldwide, potentially clinically applicable anti-CD40 (2C10R4) mAb-based studies have not been reported...
October 22, 2017: Xenotransplantation
Timothy J Kieffer, Knut Woltjen, Kenji Osafune, Daisuke Yabe, Nobuya Inagaki
Diabetes is characterized by elevated levels of blood glucose as a result of insufficient production of insulin from loss or dysfunction of pancreatic islet β-cells. Here, we review several approaches to replacing β-cells that were recently discussed at a symposium held in Kyoto, Japan. Transplant of donor human islets can effectively treat diabetes and eliminate the need for insulin injections, supporting research aimed at identifying abundant supplies of cells. Studies showing the feasibility of producing mouse islets in rats support the concept of generating pigs with human pancreas that can serve as donors of human islets, although scientific and ethical challenges remain...
October 6, 2017: Journal of Diabetes Investigation
Dandan Huang, Ya Wang, Wayne J Hawthorne, Min Hu, Joanne Hawkes, Heather Burns, Sussan Davies, Feng Gao, Yi Vee Chew, Shounan Yi, Philip J O'Connell
BACKGROUND: A high immunosuppressive burden is required for long-term islet xenograft survival in non-human primates even using genetically modified donor pigs. AIMS: We aimed to investigate the capacity of baboon regulatory T cells (Treg) to suppress islet xenograft rejection, thereby developing a potential immunoregulatory or tolerance therapy that could be evaluated in NHP models of xenotransplantation. MATERIALS & METHODS: Baboon Treg expanded with stimulation by porcine peripheral blood mononuclear cells (PBMC) were characterized by cell phenotyping and suppressive activity assays in vitro...
November 2017: Xenotransplantation
Kazuhiko Yamada, Megan Sykes, David H Sachs
PURPOSE OF REVIEW: This review describes recent progress in tolerance-inducing strategies across xenogeneic immunological barriers as well as the potential benefit of a tolerance strategy for islets and kidney xenotransplantation. RECENT FINDINGS: Using advanced gene editing technologies, xenotransplantation from multitransgenic alpha-1,3-galactosyltransferase knockout pigs has demonstrated marked prolongation of renal xenograft survival, ranging from days to greater than several months for life-supporting kidneys, and more than 2 years in a heterotopic nonlife-supporting cardiac xenograft model...
December 2017: Current Opinion in Organ Transplantation
Nizar I Mourad, Pierre Gianello
PURPOSE OF REVIEW: Cell xenotransplantation has the potential to provide a safe, ethically acceptable, unlimited source for cell replacement therapies. This review focuses on genetic modification strategies aimed to overcome remaining hurdles standing in the way of clinical porcine islet transplantation and to develop neural cell xenotransplantation. RECENT FINDINGS: In addition to previously described genetic modifications aimed to mitigate hyperacute rejection, instant blood-mediated inflammatory reaction, and cell-mediated rejection, new data showing the possibility of increasing porcine islet insulin secretion by transgenesis is an interesting addition to the array of genetically modified pigs available for xenotransplantation...
2017: Current Transplantation Reports
Nizar I Mourad, Pierre Rene Gianello
PURPOSE OF REVIEW: Porcine islets are being extensively investigated as alternative sources of insulin-secreting cells for transplantation in insulin-dependent diabetic patients. The present review focuses on recent advances in porcine islet transplantation with particular emphasis on new transgenic pig models, islet encapsulation, and biosafety considerations. RECENT FINDINGS: Genetic modifications aimed to reduce islet cell immunogenicity, to prolong their survival, and to improve their secretory function have been reported...
December 2017: Current Opinion in Organ Transplantation
Burcin Ekser, Ping Li, David K C Cooper
PURPOSE OF REVIEW: To review the progress in the field of xenotransplantation with special attention to most recent encouraging findings which will eventually bring xenotransplantation to the clinic in the near future. RECENT FINDINGS: Starting from early 2000, with the introduction of galactose-α1,3-galactose (Gal)-knockout pigs, prolonged survival especially in heart and kidney xenotransplantation was recorded. However, remaining antibody barriers to non-Gal antigens continue to be the hurdle to overcome...
December 2017: Current Opinion in Organ Transplantation
Olof Eriksson, Ulrika Rosenström, Ram K Selvaraju, Barbro Eriksson, Irina Velikyan
AIMS: Radiolabeled Exendin-4 has been proposed as suitable imaging marker for pancreatic beta cell mass quantification mediated by Glucagon-like peptide-1 receptor (GLP-1R). However, noticeable species variations in basal pancreatic uptake as well as uptake reduction degree due to selective beta cell ablation were observed. METHODS: In vitro and ex vivo autoradiography studies of pancreas were performed using [(177)Lu]Lu-DO3A-VS-Cys(40)-Exendin4, in order to investigate the mechanism of uptake as well as the islet uptake contrast in mouse, rat, pig, and non-human primate...
November 2017: Acta Diabetologica
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