Animal Reproduction (AR)
https://animal-reproduction.org/article/doi/10.1590/1984-3143-AR2020-0064
Animal Reproduction (AR)
Thematic Section: 34th Annual Meeting of the Brazilian Embryo Technology Society (SBTE)

A decade of experience with genetically tailored pig models for diabetes and metabolic research

Silja Zettler; Simone Renner; Elisabeth Kemter; Arne Hinrichs; Nikolai Klymiuk; Mattias Backman; Evamaria Olga Riedel; Christiane Mueller; Elisabeth Streckel; Christina Braun-Reichhart; Ana Sofia Martins; Mayuko Kurome; Barbara Keßler; Valeri Zakhartchenko; Florian Flenkenthaler; Georg Josef Arnold; Thomas Fröhlich; Helmut Blum; Andreas Blutke; Rüdiger Wanke; Eckhard Wolf

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Abstract

Abstract: The global prevalence of diabetes mellitus and other metabolic diseases is rapidly increasing. Animal models play pivotal roles in unravelling disease mechanisms and developing and testing therapeutic strategies. Rodents are the most widely used animal models but may have limitations in their resemblance to human disease mechanisms and phenotypes. Findings in rodent models are consequently often difficult to extrapolate to human clinical trials. To overcome this ‘translational gap’, we and other groups are developing porcine disease models. Pigs share many anatomical and physiological traits with humans and thus hold great promise as translational animal models. Importantly, the toolbox for genetic engineering of pigs is rapidly expanding. Human disease mechanisms and targets can therefore be reproduced in pigs on a molecular level, resulting in precise and predictive porcine (PPP) models. In this short review, we summarize our work on the development of genetically (pre)diabetic pig models and how they have been used to study disease mechanisms and test therapeutic strategies. This includes the generation of reporter pigs for studying beta-cell maturation and physiology. Furthermore, genetically engineered pigs are promising donors of pancreatic islets for xenotransplantation. In summary, genetically tailored pig models have become an important link in the chain of translational diabetes and metabolic research.

Keywords

pig model, diabetes, biobank, xenotransplantation

References

Aigner B, Renner S, Kessler B, Klymiuk N, Kurome M, Wunsch A, Wolf E. Transgenic pigs as models for translational biomedical research. J Mol Med. 2010;88(7):653-64. http://dx.doi.org/10.1007/s00109-010-0610-9. PMid:20339830.

Albl B, Haesner S, Braun-Reichhart C, Streckel E, Renner S, Seeliger F, Wolf E, Wanke R, Blutke A. Tissue sampling guides for porcine biomedical models. Toxicol Pathol. 2016;44(3):414-20. http://dx.doi.org/10.1177/0192623316631023. PMid:26883152.

Backman M, Flenkenthaler F, Blutke A, Dahlhoff M, Ländström E, Renner S, Philippou-Massier J, Krebs S, Rathkolb B, Prehn C, Grzybek M, Coskun Ü, Rothe M, Adamski J, Hrabe de Angelis M, Wanke R, Fröhlich T, Arnold GJ, Blum H, Wolf E. Multi-omics insights into functional alterations of the liver in insulin-deficient diabetes mellitus. Mol Metab. 2019;26:30-44. http://dx.doi.org/10.1016/j.molmet.2019.05.011. PMid:31221621.

Bakhti M, Böttcher A, Lickert H. Modelling the endocrine pancreas in health and disease. Nat Rev Endocrinol. 2019;15(3):155-71. http://dx.doi.org/10.1038/s41574-018-0132-z. PMid:30504925.

Blutke A, Renner S, Flenkenthaler F, Backman M, Haesner S, Kemter E, Ländström E, Braun-Reichhart C, Albl B, Streckel E, Rathkolb B, Prehn C, Palladini A, Grzybek M, Krebs S, Bauersachs S, Bähr A, Brühschwein A, Deeg CA, De Monte E, Dmochewitz M, Eberle C, Emrich D, Fux R, Groth F, Gumbert S, Heitmann A, Hinrichs A, Keßler B, Kurome M, Leipig-Rudolph M, Matiasek K, Öztürk H, Otzdorff C, Reichenbach M, Reichenbach HD, Rieger A, Rieseberg B, Rosati M, Saucedo MN, Schleicher A, Schneider MR, Simmet K, Steinmetz J, Übel N, Zehetmaier P, Jung A, Adamski J, Coskun Ü, Hrabe de Angelis M, Simmet C, Ritzmann M, Meyer-Lindenberg A, Blum H, Arnold GJ, Fröhlich T, Wanke R, Wolf E. The Munich MIDY Pig Biobank: a unique resource for studying organ crosstalk in diabetes. Mol Metab. 2017;6(8):931-40. http://dx.doi.org/10.1016/j.molmet.2017.06.004. PMid:28752056.

Blutke A, Wanke R. Sampling strategies and processing of biobank tissue samples from porcine biomedical models. J Vis Exp. 2018;6(133):57276. http://dx.doi.org/10.3791/57276. PMid:29578524.

Clauss S, Bleyer C, Schuttler D, Tomsits P, Renner S, Klymiuk N, Wakili R, Massberg S, Wolf E, Kaab S. Animal models of arrhythmia: classic electrophysiology to genetically modified large animals. Nat Rev Cardiol. 2019;16(8):457-75. http://dx.doi.org/10.1038/s41569-019-0179-0. PMid:30894679.

Cohrs CM, Chen C, Jahn SR, Stertmann J, Chmelova H, Weitz J, Bahr A, Klymiuk N, Steffen A, Ludwig B, Kamvissi V, Wolf E, Bornstein SR, Solimena M, Speier S. Vessel network architecture of adult human islets promotes distinct cell-cell interactions in situ and is altered after transplantation. Endocrinology. 2017;158(5):1373-85. http://dx.doi.org/10.1210/en.2016-1184. PMid:28324008.

Cooper DK, Matsumoto S, Abalovich A, Itoh T, Mourad NI, Gianello PR, Wolf E, Cozzi E. Progress in clinical encapsulated islet xenotransplantation. Transplantation. 2016;100(11):2301-8. http://dx.doi.org/10.1097/TP.0000000000001371. PMid:27482959.

Cowan PJ, Ayares D, Wolf E, Cooper DK. First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 2b: genetically modified source pigs. Xenotransplantation. 2016;23(1):32-7. http://dx.doi.org/10.1111/xen.12224. PMid:26926888.

Dinnyes A, Schnur A, Muenthaisong S, Bartenstein P, Burcez CT, Burton N, Cyran C, Gianello P, Kemter E, Nemeth G, Nicotra F, Prepost E, Qiu Y, Russo L, Wirth A, Wolf E, Ziegler S, Kobolak J. Integration of nano- and biotechnology for beta-cell and islet transplantation in type-1 diabetes treatment. Cell Prolif. 2020;53(5):e12785. http://dx.doi.org/10.1111/cpr.12785. PMid:32339373.

Dmochewitz M, Wolf E. Genetic engineering of pigs for the creation of translational models of human pathologies. Anim Front. 2015;5(1):50-6. http://dx.doi.org/10.2527/af.2015-0008.

Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13. http://dx.doi.org/10.1126/scitranslmed.3001845. PMid:21325617.

Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, Kaczmarek V, Moretti A, Laugwitz KL, Skroblin P, Mayr M, Milting H, Dendorfer A, Reichart B, Wolf E, Kupatt C. Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol. 2017;69(2):131-43. http://dx.doi.org/10.1016/j.jacc.2016.10.058. PMid:28081822.

Hinrichs A, Kessler B, Kurome M, Blutke A, Kemter E, Bernau M, Scholz AM, Rathkolb B, Renner S, Bultmann S, Leonhardt H, Hrabe de Angelis M, Nagashima H, Hoeflich A, Blum WF, Bidlingmaier M, Wanke R, Dahlhoff M, Wolf E. Growth hormone receptor-deficient pigs resemble the pathophysiology of human Laron syndrome and reveal altered activation of signaling cascades in the liver. Mol Metab. 2018;11:113-28. http://dx.doi.org/10.1016/j.molmet.2018.03.006. PMid:29678421.

Hoang DT, Matsunari H, Nagaya M, Nagashima H, Millis JM, Witkowski P, Periwal V, Hara M, Jo J. A conserved rule for pancreatic islet organization. PLoS One. 2014;9(10):e110384. http://dx.doi.org/10.1371/journal.pone.0110384. PMid:25350558.

Hofmann A, Kessler B, Ewerling S, Weppert M, Vogg B, Ludwig H, Stojkovic M, Boelhauve M, Brem G, Wolf E, Pfeifer A. Efficient transgenesis in farm animals by lentiviral vectors. EMBO Rep. 2003;4(11):1054-60. http://dx.doi.org/10.1038/sj.embor.7400007. PMid:14566324.

International Diabetes Federation – IDF. IDF diabetes atlas [Internet]. 2019 [cited 2020 July 27]. Available from: https://www.diabetesatlas.org/en/

Kemter E, Cohrs CM, Schafer M, Schuster M, Steinmeyer K, Wolf-van Buerck L, Wolf A, Wuensch A, Kurome M, Kessler B, Zakhartchenko V, Loehn M, Ivashchenko Y, Seissler J, Schulte AM, Speier S, Wolf E. INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. Diabetologia. 2017;60(6):1152-6. http://dx.doi.org/10.1007/s00125-017-4250-2. PMid:28315950.

Kemter E, Denner J, Wolf E. Will genetic engineering carry xenotransplantation of pig islets to the clinic? Curr Diab Rep. 2018;18(11):103. http://dx.doi.org/10.1007/s11892-018-1074-5. PMid:30229378.

Kemter E, Schnieke A, Fischer K, Cowan PJ, Wolf E. Xeno-organ donor pigs with multiple genetic modifications - the more the better? Curr Opin Genet Dev. 2020;64:60-5. http://dx.doi.org/10.1016/j.gde.2020.05.034. PMid:32619817.

Kemter E, Wolf E. Recent progress in porcine islet isolation, culture and engraftment strategies for xenotransplantation. Curr Opin Organ Transplant. 2018;23(6):633-41. http://dx.doi.org/10.1097/MOT.0000000000000579. PMid:30247169.

Kim S, Whitener RL, Peiris H, Gu X, Chang CA, Lam JY, Camunas-Soler J, Park I, Bevacqua RJ, Tellez K, Quake SR, Lakey JRT, Bottino R, Ross PJ, Kim SK. Molecular and genetic regulation of pig pancreatic islet cell development. Development. 2020;147(6):dev186213. http://dx.doi.org/10.1242/dev.186213. PMid:32108026.

Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, Huypens P, Beckers J, Hrabe de Angelis M, Schurmann A, Bakhti M, Klingenspor M, Heiman M, Cherrington AD, Ristow M, Lickert H, Wolf E, Havel PJ, Muller TD, Tschop MH. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol. 2018;14(3):140-62. http://dx.doi.org/10.1038/nrendo.2017.161. PMid:29348476.

Kleinwort KJH, Amann B, Hauck SM, Hirmer S, Blutke A, Renner S, Uhl PB, Lutterberg K, Sekundo W, Wolf E, Deeg CA. Retinopathy with central oedema in an INS (C94Y) transgenic pig model of long-term diabetes. Diabetologia. 2017;60(8):1541-9. http://dx.doi.org/10.1007/s00125-017-4290-7. PMid:28480495.

Klymiuk N, Ludwig B, Seissler J, Reichart B, Wolf E. Current concepts of using pigs as a source for beta-cell replacement therapy of type 1 diabetes. Curr Mol Biol Rep. 2016;2(2):73-82. http://dx.doi.org/10.1007/s40610-016-0039-1.

Klymiuk N, van Buerck L, Bahr A, Offers M, Kessler B, Wuensch A, Kurome M, Thormann M, Lochner K, Nagashima H, Herbach N, Wanke R, Seissler J, Wolf E. Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes. 2012;61(6):1527-32. http://dx.doi.org/10.2337/db11-1325. PMid:22522620.

Längin M, Mayr T, Reichart B, Michel S, Buchholz S, Guethoff S, Dashkevich A, Baehr A, Egerer S, Bauer A, Mihalj M, Panelli A, Issl L, Ying J, Fresch AK, Buttgereit I, Mokelke M, Radan J, Werner F, Lutzmann I, Steen S, Sjoberg T, Paskevicius A, Qiuming L, Sfriso R, Rieben R, Dahlhoff M, Kessler B, Kemter E, Kurome M, Zakhartchenko V, Klett K, Hinkel R, Kupatt C, Falkenau A, Reu S, Ellgass R, Herzog R, Binder U, Wich G, Skerra A, Ayares D, Kind A, Schonmann U, Kaup FJ, Hagl C, Wolf E, Klymiuk N, Brenner P, Abicht JM. Consistent success in life-supporting porcine cardiac xenotransplantation. Nature. 2018;564(7736):430-3. http://dx.doi.org/10.1038/s41586-018-0765-z. PMid:30518863.

Ludwig B, Wolf E, Schonmann U, Ludwig S. Large animal models of diabetes. Methods Mol Biol. 2020;2128:115-34. http://dx.doi.org/10.1007/978-1-0716-0385-7_9. PMid:32180190.

Reichart B, Niemann H, Chavakis T, Denner J, Jaeckel E, Ludwig B, Marckmann G, Schnieke A, Schwinzer R, Seissler J, Tonjes RR, Klymiuk N, Wolf E, Bornstein SR. Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future. Horm Metab Res. 2015;47(1):31-5. PMid:25506683.

Renner S, Blutke A, Clauss S, Deeg CA, Kemter E, Merkus D, Wanke R, Wolf E. Porcine models for studying complications and organ crosstalk in diabetes mellitus. Cell Tissue Res. 2020;380(2):341-78. http://dx.doi.org/10.1007/s00441-019-03158-9. PMid:31932949.

Renner S, Blutke A, Dobenecker B, Dhom G, Muller TD, Finan B, Clemmensen C, Bernau M, Novak I, Rathkolb B, Senf S, Zols S, Roth M, Gotz A, Hofmann SM, Hrabe de Angelis M, Wanke R, Kienzle E, Scholz AM, DiMarchi R, Ritzmann M, Tschop MH, Wolf E. Metabolic syndrome and extensive adipose tissue inflammation in morbidly obese Gottingen minipigs. Mol Metab. 2018;16:180-90. http://dx.doi.org/10.1016/j.molmet.2018.06.015. PMid:30017782.

Renner S, Blutke A, Streckel E, Wanke R, Wolf E. Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models. J Pathol. 2016a;238(2):345-58. http://dx.doi.org/10.1002/path.4655. PMid:26455904.

Renner S, Braun-Reichhart C, Blutke A, Herbach N, Emrich D, Streckel E, Wunsch A, Kessler B, Kurome M, Bahr A, Klymiuk N, Krebs S, Puk O, Nagashima H, Graw J, Blum H, Wanke R, Wolf E. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes. 2013;62(5):1505-11. http://dx.doi.org/10.2337/db12-1065. PMid:23274907.

Renner S, Dobenecker B, Blutke A, Zols S, Wanke R, Ritzmann M, Wolf E. Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research. Theriogenology. 2016b;86(1):406-21. http://dx.doi.org/10.1016/j.theriogenology.2016.04.055. PMid:27180329.

Renner S, Fehlings C, Herbach N, Hofmann A, von Waldthausen DC, Kessler B, Ulrichs K, Chodnevskaja I, Moskalenko V, Amselgruber W, Goke B, Pfeifer A, Wanke R, Wolf E. Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes. 2010;59(5):1228-38. http://dx.doi.org/10.2337/db09-0519. PMid:20185813.

Renner S, Martins AS, Streckel E, Braun-Reichhart C, Backman M, Prehn C, Klymiuk N, Bahr A, Blutke A, Landbrecht-Schessl C, Wunsch A, Kessler B, Kurome M, Hinrichs A, Koopmans SJ, Krebs S, Kemter E, Rathkolb B, Nagashima H, Blum H, Ritzmann M, Wanke R, Aigner B, Adamski J, Wanke R, Aigner B, Adamski Angelis M, Wolf E. Mild maternal hyperglycemia in INS (C93S) transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring. Dis Model Mech. 2019;12(8):dmm039156. http://dx.doi.org/10.1242/dmm.039156. PMid:31308048.

Renner S, Römisch-Margl W, Prehn C, Krebs S, Adamski J, Göke B, Blum H, Suhre K, Roscher AA, Wolf E. Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced β-cell mass. Diabetes. 2012;61(8):2166-75. http://dx.doi.org/10.2337/db11-1133. PMid:22492530.

Riedel EO, Hinrichs A, Kemter E, Dahlhoff M, Backman M, Rathkolb B, Prehn C, Adamski J, Renner S, Blutke A, Hrabe de Angelis M, Bidlingmaier M, Schopohl J, Arnold GJ, Frohlich T, Wolf E. Functional changes of the liver in the absence of growth hormone (GH) action - proteomic and metabolomic insights from a GH receptor deficient pig model. Mol Metab. 2020;36:100978. http://dx.doi.org/10.1016/j.molmet.2020.100978. PMid:32277923.

Schneider MR, Wolf E. Genetically engineered pigs as investigative and translational models in dermatology. Br J Dermatol. 2016;174(1):237-9. http://dx.doi.org/10.1111/bjd.14092. PMid:26287372.

Streckel E, Braun-Reichhart C, Herbach N, Dahlhoff M, Kessler B, Blutke A, Bahr A, Ubel N, Eddicks M, Ritzmann M, Krebs S, Goke B, Blum H, Wanke R, Wolf E, Renner S. Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition. J Transl Med. 2015;13(1):73. http://dx.doi.org/10.1186/s12967-015-0431-2. PMid:25890210.

Suchy F, Nakauchi H. Interspecies chimeras. Curr Opin Genet Dev. 2018;52:36-41. http://dx.doi.org/10.1016/j.gde.2018.05.007. PMid:29859382.

Suchy F, Yamaguchi T, Nakauchi H. iPSC-derived organs in vivo: challenges and promise. Cell Stem Cell. 2018;22(1):21-4. http://dx.doi.org/10.1016/j.stem.2017.12.003. PMid:29304339.

Vogel H, Kamitz A, Hallahan N, Lebek S, Schallschmidt T, Jonas W, Jahnert M, Gottmann P, Zellner L, Kanzleiter T, Damen M, Altenhofen D, Burkhardt R, Renner S, Dahlhoff M, Wolf E, Muller TD, Bluher M, Joost HG, Chadt A, Al-Hasani H, Schurmann A. A collective diabetes cross in combination with a computational framework to dissect the genetics of human obesity and Type 2 diabetes. Hum Mol Genet. 2018;27(17):3099-112. http://dx.doi.org/10.1093/hmg/ddy217. PMid:29893858.

Walters EM, Wolf E, Whyte JJ, Mao J, Renner S, Nagashima H, Kobayashi E, Zhao J, Wells KD, Critser JK, Riley LK, Prather RS. Completion of the swine genome will simplify the production of swine as a large animal biomedical model. BMC Med Genomics. 2012;5(1):55. http://dx.doi.org/10.1186/1755-8794-5-55. PMid:23151353.

Weigand M, Degroote RL, Amann B, Renner S, Wolf E, Hauck SM, Deeg CA. Proteome profile of neutrophils from a transgenic diabetic pig model shows distinct changes. J Proteomics. 2020;224:103843. http://dx.doi.org/10.1016/j.jprot.2020.103843. PMid:32470542.

Whitelaw CB, Sheets TP, Lillico SG, Telugu BP. Engineering large animal models of human disease. J Pathol. 2016;238(2):247-56. http://dx.doi.org/10.1002/path.4648. PMid:26414877.

Wolf E, Braun-Reichhart C, Streckel E, Renner S. Genetically engineered pig models for diabetes research. Transgenic Res. 2014;23(1):27-38. http://dx.doi.org/10.1007/s11248-013-9755-y. PMid:24065178.

Wolf E, Kemter E, Klymiuk N, Reichart B. Genetically modified pigs as donors of cells, tissues, and organs for xenotransplantation. Anim Front. 2019;9(3):13-20. http://dx.doi.org/10.1093/af/vfz014. PMid:32002258.

Wolf-van Buerck L, Schuster M, Oduncu FS, Baehr A, Mayr T, Guethoff S, Abicht J, Reichart B, Klymiuk N, Wolf E, Seissler J. LEA29Y expression in transgenic neonatal porcine islet-like cluster promotes long-lasting xenograft survival in humanized mice without immunosuppressive therapy. Sci Rep. 2017;7(1):3572. http://dx.doi.org/10.1038/s41598-017-03913-4. PMid:28620237.

Wu J, Greely HT, Jaenisch R, Nakauchi H, Rossant J, Belmonte JC. Stem cells and interspecies chimaeras. Nature. 2016a;540(7631):51-9. http://dx.doi.org/10.1038/nature20573. PMid:27905428.

Wu J, Platero Luengo A, Gil MA, Suzuki K, Cuello C, Morales Valencia M, Parrilla I, Martinez CA, Nohalez A, Roca J, Martinez EA, Izpisua Belmonte JC. Generation of human organs in pigs via interspecies blastocyst complementation. Reprod Domest Anim. 2016b;51(Suppl 2):18-24. http://dx.doi.org/10.1111/rda.12796. PMid:27762052.

Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Morales Valencia M, Okumura D, Luo J, Vilariño M, Parrilla I, Soto DA, Martinez CA, Hishida T, Sánchez-Bautista S, Martinez-Martinez ML, Wang H, Nohalez A, Aizawa E, Martinez-Redondo P, Ocampo A, Reddy P, Roca J, Maga EA, Esteban CR, Berggren WT, Nuñez Delicado E, Lajara J, Guillen I, Guillen P, Campistol JM, Martinez EA, Ross PJ, Izpisua Belmonte JC. Interspecies chimerism with mammalian pluripotent stem cells. Cell. 2017;168(3):473-486.e415. http://dx.doi.org/10.1016/j.cell.2016.12.036. PMid:28129541.

Zhao S, Todorov MI, Cai R, Maskari RA, Steinke H, Kemter E, Mai H, Rong Z, Warmer M, Stanic K, Schoppe O, Paetzold JC, Gesierich B, Wong MN, Huber TB, Duering M, Bruns OT, Menze B, Lipfert J, Puelles VG, Wolf E, Bechmann I, Erturk A. Cellular and molecular probing of intact human organs. Cell. 2020;180(4):796-812.e719. http://dx.doi.org/10.1016/j.cell.2020.01.030. PMid:32059778.

Zhou Q, Melton DA. Pancreas regeneration. Nature. 2018;557(7705):351-8. http://dx.doi.org/10.1038/s41586-018-0088-0. PMid:29769672.
 


Submitted date:
06/11/2020

Accepted date:
07/15/2020

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