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Multiscale and Tissue Realistic Translational Modeling of Gut Inflammation

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Complex Systems and Computational Biology Approaches to Acute Inflammation

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Abstract

Gut inflammation plays a crucial role in a host of disease processes, most notably in inflammatory bowel disease (IBD) and gut derived sepsis. The gut is also the primary interface between an individual’s microbiome and the host, where appropriate equipoise of mucosal inflammatory potential is a critical goal. The architecture and histological structure of the gut mucosa remains a primary means of diagnosing different gastrointestinal diseases, and as such, computational representations with a translational goal should be able to replicate, at least to some degree, the alterations of gut mucosal architecture resulting from different pathophysiological processes. Given that gut inflammation forms the common pathway by which a host of different disease processes can manifest, we propose that a translationally useful computational representation of gut inflammation should be able to generate these different disease processes through different perturbations on a common, underlying model (as is the case in the real world). To that end we have developed the Spatially Explicit General-purpose Model of Enteric Tissue (SEGMEnT) as a common, unifying platform with which to examine how different perturbations and disorders can lead to a range of recognized pathophysiologic phenotypes. We have additionally expanded SEGMEnT to a high-performance computing (HPC) version that gives the capability to simulate billions of cells and achieve anatomic-scale representation.

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Abbreviations

ABM:

Agent-based model

Akt:

Protein kinase B

BMP:

Bone morphogenetic protein

GEC:

Gut epithelial cell

Hh:

Sonic hedgehog homolog

HPC:

High-performance computing

IBD:

Inflammatory bowel disease

I-FABP:

Intestinal fatty acid binding protein

PTEN/PI3K:

Phosphatase and tensin homolog/Phosphoinositide 3-kinase

RIP:

Receptor interacting protein kinase

SEGMEnT:

Spatially explicit general-purpose model of enteric tissue

TLR:

Toll-like receptor

Wnt:

Wingless-related integration site

References

  1. Latella G, Papi C (2012) Crucial steps in the natural history of inflammatory bowel disease. World J Gastroenterol 18(29):3790–3799

    Article  Google Scholar 

  2. Seal JB, Morowitz M, Zaborina O, An G, Alverdy JC (2010) The molecular Koch’s postulates and surgical infection: a view forward. Surgery 147(6):757–765

    Article  Google Scholar 

  3. Korpe PS, Petri WA Jr (2012) Environmental enteropathy: critical implications of a poorly understood condition. Trends Mol Med 18(6):328–336

    Article  Google Scholar 

  4. De Plaen IG (2013) Inflammatory signaling in necrotizing enterocolitis. Clin Perinatol 40(1):109–124

    Article  Google Scholar 

  5. Rizzo A, Pallone F, Monteleone G, Fantini MC (2011) Intestinal inflammation and colorectal cancer: a double-edged sword? World J Gastroenterol 17(26):3092–3100

    Google Scholar 

  6. Turner JR (2004) The gastrointestinal tract. In: Vinay Kumar AKA, Aster JC, Fausto N (eds) Robbins and Cotran: pathological basis of disease, 8th edn. Saunders-Elsevier, Philadelphia

    Google Scholar 

  7. Dunn S-J, Appleton PL, Nelson SA, Näthke IS, Gavaghan DJ, Osborne JM (2012) A two-dimensional model of the colonic crypt accounting for the role of the basement membrane and pericryptal fibroblast sheath. PLoS Comput Biol 8(5):e1002515

    Article  CAS  Google Scholar 

  8. Edwards CM, Chapman SJ (2007) Biomechanical modelling of colorectal crypt budding and fission. Bull Math Biol 69(6):1927–1942

    Article  Google Scholar 

  9. Zhang L, Lander AD, Nie Q (2012) A reaction-diffusion mechanism influences cell lineage progression as a basis for formation, regeneration, and stability of intestinal crypts. BMC Syst Biol 6:93

    Article  CAS  Google Scholar 

  10. Hannezo E, Prost J, Joanny JF (2011) Instabilities of monolayered epithelia: shape and structure of villi and crypts. Phys Rev Lett 107(7):078104

    Article  CAS  Google Scholar 

  11. Murray PJ, Kang J-W, Mirams GR, Shin S-Y, Byrne HM, Maini PK et al (2010) Modelling spatially regulated beta-catenin dynamics and invasion in intestinal crypts. Biophys J 99(3):716–725

    Article  CAS  Google Scholar 

  12. van Leeuwen IM, Mirams GR, Walter A, Fletcher A, Murray P, Osborne J et al (2009) An integrative computational model for intestinal tissue renewal. Cell Prolif 42(5):617–636

    Article  Google Scholar 

  13. Meineke FA, Potten CS, Loeffler M (2001) Cell migration and organization in the intestinal crypt using a lattice-free model. Cell Prolif 34(4):253–266

    Article  CAS  Google Scholar 

  14. Buske P, Galle J, Barker N, Aust G, Clevers H, Loeffler M (2011) A comprehensive model of the spatio-temporal stem cell and tissue organisation in the intestinal crypt. PLoS Comput Biol 7(1):e1001045

    Article  CAS  Google Scholar 

  15. Wong SY, Chiam K-H, Lim CT, Matsudaira P (2010) Computational model of cell positioning: directed and collective migration in the intestinal crypt epithelium. J R Soc Interface 7(Suppl 3):S351–S363

    Google Scholar 

  16. Cockrell C, Christley S, An G (2014) Investigation of inflammation and tissue patterning in the gut using a spatially explicit general-purpose model of enteric tissue (SEGMEnT). PLoS Comput Biol 10(3):e1003507

    Article  CAS  Google Scholar 

  17. Bonabeau E (2002) Agent-based modeling: methods and techniques for simulating human systems. Proc Natl Acad Sci U S A 99(Suppl 3):7280–7287

    Article  CAS  Google Scholar 

  18. An G, Mi Q, Dutta-Moscato J, Vodovotz Y (2009) Agent-based models in translational systems biology. Wiley Interdiscip Rev Syst Biol Med 1(2):159–171

    Article  CAS  Google Scholar 

  19. Grimm V, Revilla E, Berger U, Jeltsch F, Mooij WM, Railsback SF et al (2005) Pattern-oriented modeling of agent-based complex systems: lessons from ecology. Science 310(5750):987–991

    Article  CAS  Google Scholar 

  20. Hunt CA, Kennedy RC, Kim SH, Ropella GE (2013) Agent-based modeling: a systematic assessment of use cases and requirements for enhancing pharmaceutical research and development productivity. Wiley Interdiscip Rev Syst Biol Med 5(4):461–480

    Article  Google Scholar 

  21. Thorne BC, Bailey AM, Peirce SM (2007) Combining experiments with multi-cell agent-based modeling to study biological tissue patterning. Brief Bioinform 8(4):245–257

    Article  CAS  Google Scholar 

  22. Zhang L, Wang Z, Sagotsky JA, Deisboeck TS (2009) Multiscale agent-based cancer modeling. J Math Biol 58(4–5):545–559

    Article  Google Scholar 

  23. Garcia-Armengol J, Hinojosa J, Lledo S, Roig JV, Garcia-Granero E, Martinez B (1998) Prospective study of morphologic and functional changes with time in the mucosa of the ileoanal pouch: functional appraisal using transmucosal potential differences. Dis Colon Rectum 41(7):846–853

    Article  CAS  Google Scholar 

  24. Willis S, Kisielinski K, Klosterhalfen B, Schumpelick V (2002) Morphological and functional adaptation of the small intestine after colectomy and ileal pouch-anal anastomosis in rats. Int J Color Dis 17(2):85–91

    Article  Google Scholar 

  25. Fruin AB, El-Zammer O, Stucchi AF, O'Brien M, Becker JM (2003) Colonic metaplasia in the ileal pouch is associated with inflammation and is not the result of long-term adaptation. J Gastrointest Surg 7(2):246–253; discussion 53–4

    Article  Google Scholar 

  26. Kim NH, Jeon S, Lee HJ, Lee AY (2007) Impaired PI3K/Akt activation-mediated NF-kappaB inactivation under elevated TNF-alpha is more vulnerable to apoptosis in vitiliginous keratinocytes. J Invest Dermatol 127(11):2612–2617

    Article  CAS  Google Scholar 

  27. Hunt CA, Glen EP (2011) Ropella. Moving beyond in silico tools to in silico science in support of drug development research. Drug Dev Res 72(2):153–161

    Article  CAS  Google Scholar 

  28. Kim SH, Park S, Ropella GEP, Hunt CA (2010) Agent-directed tracing of multi-scale drug disposition events within normal and diseased in silico livers. Int J Agent Technol Syst 2(3):1–19

    Article  CAS  Google Scholar 

  29. Feldman M, Friedman L, Brandt L (2010) Sleisenger and Fordtran’s gastrointestinal and liver disease. 9th edn. Saunders, Philadelphia, 2480 p

    Google Scholar 

  30. Scoville DH, Sato T, He XC, Li L (2008) Current view: intestinal stem cells and signaling. Gastroenterology 134(3):849–864

    Article  CAS  Google Scholar 

  31. Pinto D, Gregorieff A, Begthel H, Clevers H (2003) Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. Genes Dev 17(14):1709–1713

    Article  CAS  Google Scholar 

  32. Kuhnert F, Davis CR, Wang HT, Chu P, Lee M, Yuan J et al (2004) Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1. Proc Natl Acad Sci U S A 101(1):266–271

    Article  CAS  Google Scholar 

  33. Gregorieff A, Clevers H (2005) Wnt signaling in the intestinal epithelium: from endoderm to cancer. Genes Dev 19(8):877–890

    Article  CAS  Google Scholar 

  34. Fevr T, Robine S, Louvard D, Huelsken J (2007) Wnt/beta-catenin is essential for intestinal homeostasis and maintenance of intestinal stem cells. Mol Cell Biol 27(21):7551–7559

    Article  CAS  Google Scholar 

  35. Kawano Y, Kypta R (2003) Secreted antagonists of the Wnt signalling pathway. J Cell Sci 116(Pt 13):2627–2634

    Article  CAS  Google Scholar 

  36. He XC, Zhang J, Tong WG, Tawfik O, Ross J, Scoville DH et al (2004) BMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signaling. Nat Genet 36(10):1117–1121

    Article  CAS  Google Scholar 

  37. Haramis AP, Begthel H, van den Born M, van Es J, Jonkheer S, Offerhaus GJ et al (2004) De novo crypt formation and juvenile polyposis on BMP inhibition in mouse intestine. Science 303(5664):1684–1686

    Article  CAS  Google Scholar 

  38. Batts LE, Polk DB, Dubois RN, Kulessa H (2006) Bmp signaling is required for intestinal growth and morphogenesis. Dev Dyn 235(6):1563–1570

    Article  CAS  Google Scholar 

  39. Hall B, Limaye A, Kulkarni AB (2009) Overview: generation of gene knockout mice. Curr Protoc Cell Biol. 12–19

    Google Scholar 

  40. Marsh V, Winton DJ, Williams GT, Dubois N, Trumpp A, Sansom OJ et al (2008) Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nat Genet 40(12):1436–1444

    Article  CAS  Google Scholar 

  41. Schoenberg MH, Beger HG (1993) Reperfusion injury after intestinal ischemia. Crit Care Med 21(9):1376–1386

    Article  CAS  Google Scholar 

  42. Haglund U (1994) Gut ischaemia. Gut 35(1 Suppl):S73–S76

    Article  CAS  Google Scholar 

  43. Derikx JP, Matthijsen RA, de Bruine AP, van Bijnen AA, Heineman E, van Dam RM et al (2008) Rapid reversal of human intestinal ischemia-reperfusion induced damage by shedding of injured enterocytes and reepithelialisation. PLoS One 3(10):e3428

    Article  CAS  Google Scholar 

  44. Matthijsen RA, Derikx JP, Kuipers D, van Dam RM, Dejong CH, Buurman WA (2009) Enterocyte shedding and epithelial lining repair following ischemia of the human small intestine attenuate inflammation. PLoS One 4(9):e7045

    Article  CAS  Google Scholar 

  45. Li X, Jiang S, Tapping RI (2010) Toll-like receptor signaling in cell proliferation and survival. Cytokine 49(1):1–9

    Article  CAS  Google Scholar 

  46. Papadakis KA, Targan SR (2000) Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 119(4):1148–1157

    Article  CAS  Google Scholar 

  47. Vanden Berghe T, Vanlangenakker N, Parthoens E, Deckers W, Devos M, Festjens N et al (2010) Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features. Cell Death Differ 17(6):922–930

    Article  CAS  Google Scholar 

  48. Pinzone JJ, Hall BM, Thudi NK, Vonau M, Qiang YW, Rosol TJ et al (2009) The role of Dickkopf-1 in bone development, homeostasis, and disease. Blood 113(3):517–525

    Article  CAS  Google Scholar 

  49. Abell K, Bilancio A, Clarkson RW, Tiffen PG, Altaparmakov AI, Burdon TG et al (2005) Stat3-induced apoptosis requires a molecular switch in PI(3)K subunit composition. Nat Cell Biol 7(4):392–398

    Article  CAS  Google Scholar 

  50. Koch S, Nusrat A (2012) The life and death of epithelia during inflammation: lessons learned from the gut. Annu Rev Pathol 7:35–60

    Article  CAS  Google Scholar 

  51. Cockrell RC, Christley S, Chang E, An G (2015) Towards anatomic scale agent-based modeling with a massively parallel spatially explicit general-purpose model of enteric tissue (SEGMEnT_HPC). PLoS One 10(3):e0122192

    Article  CAS  Google Scholar 

  52. Becker JM, Raymond JL (1986) Ileal pouch-anal anastomosis. A single surgeon’s experience with 100 consecutive cases. Ann Surg 204(4):375

    Article  CAS  Google Scholar 

  53. Hager G, Wellein G (2010) Introduction to high performance computing for scientists and engineers. CRC Press, Boca Raton

    Book  Google Scholar 

  54. Kim M, Christley S, Alverdy JC, Liu D, An G (2012) Immature oxidative stress management as a unifying principle in the pathogenesis of necrotizing enterocolitis: insights from an agent-based model. Surg Infect 13(1):18–32

    Article  Google Scholar 

  55. Seal JB, Alverdy JC, Zaborina O, An G (2011) Agent-based dynamic knowledge representation of Pseudomonas aeruginosa virulence activation in the stressed gut: towards characterizing host-pathogen interactions in gut-derived sepsis. Theor Biol Med Model 8(1):33

    Article  Google Scholar 

  56. An G, Kulkarni S (2015) An agent-based modeling framework linking inflammation and cancer using evolutionary principles: description of a generative hierarchy for the hallmarks of cancer and developing a bridge between mechanism and epidemiological data. Math Biosci 260:16–24

    Article  Google Scholar 

  57. Cockrell C, Axelrod DE (2019) Optimization of dose schedules for chemotherapy of early colon cancer determined by high-performance computer simulations. Cancer Informat 18:1176935118822804

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, University of Vermont, Burlington, VT, USA

    Chase Cockrell & Gary An

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  1. Chase Cockrell
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  1. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, USA

    Yoram Vodovotz

  2. Department of Surgery, University of Vermont, Burlington, VT, USA

    Gary An

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Cockrell, C., An, G. (2021). Multiscale and Tissue Realistic Translational Modeling of Gut Inflammation. In: Vodovotz, Y., An, G. (eds) Complex Systems and Computational Biology Approaches to Acute Inflammation. Springer, Cham. https://doi.org/10.1007/978-3-030-56510-7_13

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