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Integrated gut/liver microphysiological systems elucidates inflammatory inter‐tissue crosstalk

Chen, Wen L.K., Edington, Collin, Suter, Emily, Yu, Jiajie, Velazquez, Jeremy J., Velazquez, Jason G., Shockley, Michael, Large, Emma M. +8 more·2017·Biotechnology and Bioengineering
DOI 10.1002/bit.26370PMC PMC5614865
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Abstract

A capability for analyzing complex cellular communication among tissues is important in drug discovery and development, and in vitro technologies for doing so are required for human applications. A prominent instance is communication between the gut and the liver, whereby perturbations of one tissue can influence behavior of the other. Here, we present a study on human gut‐liver tissue interactions under normal and inflammatory contexts, via an integrative multi‐organ platform comprising human liver (hepatocytes and Kupffer cells), and intestinal (enterocytes, goblet cells, and dendritic cells) models. Our results demonstrated long‐term (>2 weeks) maintenance of intestinal (e.g., barrier integrity) and hepatic (e.g., albumin) functions in baseline interaction. Gene expression data comparing liver in interaction with gut, versus isolation, revealed modulation of bile acid metabolism. Intestinal FGF19 secretion and associated inhibition of hepatic CYP7A1 expression provided evidence of physiologically relevant gut‐liver crosstalk. Moreover, significant non‐linear modulation of cytokine responses was observed under inflammatory gut‐liver interaction; for example, production of CXCR3 ligands (CXCL9,10,11) was synergistically enhanced. RNA‐seq analysis revealed significant upregulation of IFNα/β/γ signaling during inflammatory gut‐liver crosstalk, with these pathways implicated in the synergistic CXCR3 chemokine production. Exacerbated inflammatory response in gut‐liver interaction also negatively affected tissue‐specific functions (e.g., liver metabolism). These findings illustrate how an integrated multi‐tissue platform can generate insights useful for understanding complex pathophysiological processes such as inflammatory organ crosstalk. Biotechnol. Bioeng. 2017;114: 2648–2659. © 2017 Wiley Periodicals, Inc.

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  • Reported GLA-MPSs showed better predictive capabilities of organ-to-organ interaction compared to normal static cell-culture models.

    “They showed better predictive capabilities of organ to organ interaction, compared to normal static cell-culture models.”

    From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [8]

    The Results section on bile-acid synthesis reports gut–liver crosstalk in the integrated system, including higher FGF19 in interacting than isolated tissue controls. But those controls were single-tissue MPSs on the same platform, not conventional static cell cultures. The paper does not establish that the system has better predictive capability than static models. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • A number of MPSs as an in vitro GLA model (GLA-MPS) have been reported, such as GLA for metabolism and inflammation axes.

    “Thus far, a number of MPSs as an in vitro GLA model (GLA-MPS) have been reported, such as GLA for metabolism and inflammation axess.3,7- 11”

    From Gut-liver-axis microphysiological system for studying cellular fluidic shear stress and inter-tissue interaction (2022) · cites this paper as [8]

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Research works printed but not linked: 68

  1. Abaci HE, Shuler ML. 2015 Human‐on‐a‐chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling. Integrative Biology 7(4): 383– 391. 25739725 PMC4407827
  2. Brown RP, Delp MD, Lindstedt SL, Rhomberg LR, Beliles RP. 1997 Physiological parameter values for physiologically based pharmacokinetic models. Toxicol Ind Health 13(4): 407– 484. 9249929
  3. Clark AM, Wheeler SE, Young CL, Stockdale L, Shepard Neiman J, Zhao W, Stolz DB, Venkataramanan R, Lauffenburger D, Griffith L, Wells A. 2016 A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties. Lab Chip 17(1): 156– 168. 27910972 PMC5242229
  4. Denayer T, Stöhr T, Van Roy M. 2014 Animal models in translational medicine: Validation and prediction. New Horizons Transl Med 2(1): 5– 11.
  5. Deng X, Luyendyk JP, Ganey PE, Roth RA. 2009 Inflammatory stress and idiosyncratic hepatotoxicity: Hints from animal models. Pharmacol Rev 61(3): 262– 282. 19805476 PMC2763781
  6. Domansky K, Inman W, Serdy J, Dash A, Lim MH, Griffith LG. 2010 Perfused multiwell plate for 3D liver tissue engineering. Lab Chip 10(1): 51– 58. 20024050 PMC3972823
  7. Dwinell MB, Lugering N, Eckmann L, Kagnoff MF. 2001 Regulated production of interferon‐inducible T‐cell chemoattractants by human intestinal epithelial cells. Gastroenterology 120(1): 49– 59. 11208713
  8. Ebrahimkhani MR, Neiman JA, Raredon MS, Hughes DJ, Griffith LG. 2014 Bioreactor technologies to support liver function in vitro. Adv Drug Deliv Rev 69‐70: 132– 157. PMC4144187 24607703
  9. Edington CD, Cirit M, Chen WLK, Clark AM, Wells A, Trumper DL, Griffith LG. 2017. Integration of systems biology with organs‐on‐chips to humanize therapeutic development. In SPIE BiOS, pp. 1006113–1006113. International Society for Optics and Photonics.
  10. Esch MB, Prot JM, Wang YI, Miller P, Llamas‐Vidales JR, Naughton BA, Applegate DR, Shuler ML. 2015 Multi‐cellular 3D human primary liver cell culture elevates metabolic activity under fluidic flow. Lab Chip 15(10): 2269– 2277. 25857666 PMC4422761
  11. Esch MB, Ueno H, Applegate DR, Shuler ML. 2016 Modular, pumpless body‐on‐a‐chip platform for the co‐culture of GI tract epithelium and 3D primary liver tissue. Lab Chip 16(14): 2719– 2729. 27332143
  12. Feaver RE, Cole BK, Lawson MJ, Hoang SA, Marukian S, Blackman BR, Figler RA, Sanyal AJ, Wamhoff BR, Dash A. 2016 Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight 1(20): e90954. 27942596 PMC5135271
  13. Frey O, Misun PM, Fluri DA, Hengstler JG, Hierlemann A. 2014 Reconfigurable microfluidic hanging drop network for multi‐tissue interaction and analysis. Nat Commun 5: 4250. 24977495
  14. Gardiner KR, Halliday MI, Barclay GR, Milne L, Brown D, Stephens S, Maxwell RJ, Rowlands BJ. 1995 Significance of systemic endotoxaemia in inflammatory bowel disease. Gut 36(6): 897– 901. 7615280 PMC1382629
  15. Giese C, Marx U. 2014 Human immunity in vitro—Solving immunogenicity and more. Adv Drug Deliv Rev 69: 103– 122. 24447895
  16. Groom JR, Luster AD. 2011 CXCR3 ligands: Redundant, collaborative and antagonistic functions. Immunol Cell Biol 89(2): 207– 215. 21221121 PMC3863330
  17. Guo S, Al‐Sadi R, Said HM, Ma TY. 2013 Lipopolysaccharide causes an increase in intestinal tight junction permeability in vitro and in vivo by inducing enterocyte membrane expression and localization of TLR‐4 and CD14. Am J Pathol 182(2): 375– 387. 23201091 PMC3562736
  18. Helander HF, Fandriks L. 2014 Surface area of the digestive tract—Revisited. Scand J Gastroenterol 49(6): 681– 689. 24694282
  19. Huang SM, Zhao H, Lee JI, Reynolds K, Zhang L, Temple R, Lesko LJ. 2010 Therapeutic protein‐drug interactions and implications for drug development. Clin Pharmacol Ther 87(4): 497– 503. 20200513
  20. Huebsch N, Loskill P, Deveshwar N, Spencer CI, Judge LM, Mandegar MA, Fox BC, Mohamed TMA, Ma Z, Mathur A, Sheehan AM, Truong A, Saxton M, Yoo J, Srivastava D, Desai TA, So P‐L, Healy KE, Conklin BR. 2016 Miniaturized iPS‐cell‐derived cardiac muscles for physiologically relevant drug response analyses. Scientific Rep 6: 24726. PMC4837370 27095412
  21. Huh D, Torisawa YS, Hamilton GA, Kim HJ, Ingber DE. 2012 Microengineered physiological biomimicry: Organs‐on‐chips. Lab Chip 12(12): 2156– 2164. 22555377
  22. Inman W, Domansky K, Serdy J, Owens B, Trumper D, Griffith LG. 2007 Design, modeling and fabrication of a constant flow pneumatic micropump. J Micromech Microeng 17(5): 891.
  23. Iori E, Vinci B, Murphy E, Marescotti MC, Avogaro A, Ahluwalia A. 2012 Glucose and fatty acid metabolism in a 3 tissue in‐vitro model challenged with normo‐ and hyperglycaemia. PLoS ONE 7(4)): e34704. 22509346 PMC3324505
  24. Jacob A, Zhou M, Wu R, Wang P. 2009 The role of hepatic cytochrome P‐450 in sepsis. Int J Clin Exp Med 2(3): 203– 211. 19918313 PMC2770183
  25. Kim TH, Lee SH, Lee SM. 2011 Role of Kupffer cells in pathogenesis of sepsis‐induced drug metabolizing dysfunction. FEBS J 278(13): 2307– 2317. 21535472
  26. Kitamura T, Pollard JW. 2015 Therapeutic potential of chemokine signal inhibition for metastatic breast cancer. Pharmacol Res 100: 266– 270. 26275794 PMC4617477
  27. Leblond F, Seidah NG, Precourt LP, Delvin E, Dominguez M, Levy E. 2009 Regulation of the proprotein convertase subtilisin/kexin type 9 in intestinal epithelial cells. Am J Physiol Gastrointest Liver Physiol 296(4): G805– G815. 19179626
  28. Lee H, Kim DS, Ha SK, Choi I, Lee JM, Sung JH. 2017 A pumpless multi‐organ‐on‐a‐chip (MOC) combined with a pharmacokinetic‐pharmacodynamic (PK‐PD) model. Biotechnol Bioeng 114(2): 432– 443. 27570096
  29. Liaskou E, Wilson DV, Oo YH. 2012 Innate immune cells in liver inflammation. Mediators Inflamm 2012: 949157. 22933833 PMC3425885
  30. Long TJ, Cosgrove PA, Dunn RT, Stolz DB, Hamadeh H, Afshari C, McBride H, Griffith LG. 2016 Modeling therapeutic antibody‐small molecule drug‐drug interactions using a three‐dimensional perfusable human liver coculture platform. Drug Metab Dispos 44(12): 1940– 1948. 27621203 PMC5118635
  31. Loskill P, Marcus SG, Mathur A, Reese WM, Healy KE. 2015 µOrgano: A Lego®‐like plug & play system for modular multi‐organ‐chips. PLoS ONE 10(10): e0139587. 26440672 PMC4595286
  32. Maass C, Stokes CL, Griffith LG, Cirit M. 2017 Multi‐functional scaling methodology for translational pharmacokinetic and pharmacodynamic applications using integrated microphysiological systems (MPS). Integrative Biol 9(4): 290– 302. PMC5729907 28267162
  33. Mahler GJ, Esch MB, Tako E, Southard TL, Archer SD, Glahn RP, Shuler ML. 2012 Oral exposure to polystyrene nanoparticles affects iron absorption. Nat Nanotechnol 7(4): 264– 271. 22327877
  34. Marshall JC. 1993 Immunologic dyshomeostasis in multiple organ failure: The gut‐Liver axis In: Faist E, Meakins JL, Schildberg FW, editors. Host defense dysfunction in trauma, shock and sepsis: Mechanisms and therapeutic approaches. Berlin, Heidelberg: Springer Berlin Heidelberg p 243– 252.
  35. Maschmeyer I, Hasenberg T, Jaenicke A, Lindner M, Lorenz AK, Zech J, Garbe LA, Sonntag F, Hayden P, Ayehunie S, Lauster R, Marx U, Materne EM. 2015a Chip‐based human liver‐intestine and liver‐skin co‐cultures–A first step toward systemic repeated dose substance testing in vitro. Eur J Pharm Biopharm 95(Pt A): 77– 87. 25857839 PMC6574126
  36. Materne EM, Ramme AP, Terrasso AP, Serra M, Alves PM, Brito C, Sakharov DA, Tonevitsky AG, Lauster R, Marx U. 2015 A multi‐organ chip co‐culture of neurospheres and liver equivalents for long‐term substance testing. J Biotechnol 205: 36– 46. 25678136
  37. Mathur A, Loskill P, Shao K, Huebsch N, Hong S, Marcus SG, Marks N, Mandegar M, Conklin BR, Lee LP, Healy KE. 2015 Human iPSC‐based cardiac microphysiological system for drug screening applications. Sci Rep 5: 8883. 25748532 PMC4352848
  38. Mestas J, Hughes CCW. 2004 Of mice and not men: Differences between mouse and human immunology. J Immunol 172(5): 2731– 2738. 14978070
  39. Miller PG, Shuler ML. 2016 Design and demonstration of a pumpless 14 compartment microphysiological system. Biotechnol Bioeng 113(10): 2213– 2227. 27070809
  40. Morgan ET. 2001 Regulation of cytochrome p450 by inflammatory mediators: Why and how? Drug Metab Dispos 29(3): 207– 212. 11181485
  41. Nguyen TV, Ukairo O, Khetani SR, McVay M, Kanchagar C, Seghezzi W, Ayanoglu G, Irrechukwu O, Evers R. 2015 Establishment of a hepatocyte‐kupffer cell coculture model for assessment of proinflammatory cytokine effects on metabolizing enzymes and drug transporters. Drug Metab Dispos 43(5): 774– 785. 25739975
  42. Noah TK, Donahue B, Shroyer NF. 2011 Intestinal development and differentiation. Exp Cell Res 317(19): 2702– 2710. 21978911 PMC3210330
  43. Nollevaux G, Deville C, El Moualij B, Zorzi W, Deloyer P, Schneider YJ, Peulen O, Dandrifosse G. 2006 Development of a serum‐free co‐culture of human intestinal epithelium cell‐lines (Caco‐2/HT29‐5M21). BMC Cell Biol 7: 20. 16670004 PMC1617214
  44. Oleaga C, Bernabini C, Smith AS, Srinivasan B, Jackson M, McLamb W, Platt V, Bridges R, Cai Y, Santhanam N, Berry B, Najjar S, Akanda N, Guo X, Martin C, Ekman G, Esch MB, Langer J, Ouedraogo G, Cotovio J, Breton L, Shuler ML, Hickman JJ. 2016 Multi‐organ toxicity demonstration in a functional human in vitro system composed of four organs. Sci Rep 6: 20030. 26837601 PMC4738272
  45. Powers MJ, Domansky K, Kaazempur‐Mofrad MR, Kalezi A, Capitano A, Upadhyaya A, Kurzawski P, Wack KE, Stolz DB, Kamm R, Griffith LG. 2002a A microfabricated array bioreactor for perfused 3D liver culture. Biotechnol Bioeng 78(3): 257– 269. 11920442
  46. Prothero JW. 1982 Organ scaling in mammals: The liver. Comp Biochem Physiol A Comp Physiol 71(4): 567– 577. 6124345
  47. Rebelo SP, Dehne EM, Brito C, Horland R, Alves PM, Marx U. 2016 Validation of bioreactor and human‐on‐a‐chip devices for chemical safety assessment. Adv Exp Med Biol 856: 299– 316. 27671728
  48. Roth A, Singer T. 2014 The application of 3D cell models to support drug safety assessment: Opportunities & challenges. Advanced Drug Deliv Rev 69–70: 179– 189. 24378580
  49. Sarkar CA, Lauffenburger DA. 2003 Cell‐level pharmacokinetic model of granulocyte colony‐stimulating factor: Implications for ligand lifetime and potency in vivo. Mol Pharmacol 63(1): 147– 158. 12488547
  50. Sarkar U, Ravindra KC, Large E, Young CL, Rivera‐Burgos D, Yu J, Cirit M, Hughes DJ, Wishnok JS, Lauffenburger DA, Griffith LG, Tannenbaum SR. 2017 Integrated assessment of diclofenac biotransformation, pharmacokinetics, and omics ‐based toxicity in a 3D human liver ‐immunocompetent co ‐culture system. Drug Metab Dispos 45(7): 855– 866. 28450578 PMC5469400
  51. Sarkar U, Rivera‐Burgos D, Large EM, Hughes DJ, Ravindra KC, Dyer RL, Ebrahimkhani MR, Wishnok JS, Griffith LG, Tannenbaum SR. 2015 Metabolite profiling and pharmacokinetic evaluation of hydrocortisone in a perfused three‐dimensional human liver bioreactor. Drug Metab Dispos 43(7): 1091– 1099. 25926431 PMC4468434
  52. Sin A, Chin KC, Jamil MF, Kostov Y, Rao G, Shuler ML. 2004 The design and fabrication of three‐chamber microscale cell culture analog devices with integrated dissolved oxygen sensors. Biotechnol Prog 20(1): 338– 345. 14763861
  53. Singh UP, Venkataraman C, Singh R, Lillard JW, Jr. 2007 CXCR3 axis: Role in inflammatory bowel disease and its therapeutic implication. Endocr Metab Immune Disord Drug Targets 7(2): 111– 123. 17584151
  54. Stokes CL, Cirit M, Lauffenburger DA. 2015 Physiome‐on‐a‐chip: The challenge of “scaling” in design, operation, and translation of microphysiological systems. CPT Pharmacometrics Syst Pharmacol 4(10): 559– 562. 26535154 PMC4625858
  55. Sung JH, Esch MB, Prot JM, Long CJ, Smith A, Hickman JJ, Shuler ML. 2013 Microfabricated mammalian organ systems and their integration into models of whole animals and humans. Lab Chip 13(7): 1201– 1212. 23388858 PMC3593746
  56. Sung JH, Kam C, Shuler ML. 2010 A microfluidic device for a pharmacokinetic‐pharmacodynamic (PK‐PD) model on a chip. Lab Chip 10(4): 446– 455. 20126684
  57. Sung JH, Shuler ML. 2009 A micro cell culture analog (microCCA) with 3‐D hydrogel culture of multiple cell lines to assess metabolism‐dependent cytotoxicity of anti‐cancer drugs. Lab Chip 9(10): 1385– 1394. 19417905
  58. Toepke MW, Beebe DJ. 2006 PDMS absorption of small molecules and consequences in microfluidic applications. Lab Chip 6(12): 1484– 1486. 17203151
  59. Tsamandouras N, Kostrzewski T, Stokes CL, Griffith LG, Hughes DJ, Cirit M. 2017 Quantitative assessment of population variability in hepatic drug metabolism using a perfused three‐dimensional human liver microphysiological system. J Pharmacol Exp Therap 360(1): 95– 105. 27760784 PMC5193075
  60. Ucciferri N, Sbrana T, Ahluwalia A. 2014 Allometric scaling and cell ratios in multi‐organ in vitro models of human metabolism. Front Bioeng Biotechnol 2: 74. 25566537 PMC4269269
  61. VanDussen KL, Marinshaw JM, Shaikh N, Miyoshi H, Moon C, Tarr PI, Ciorba MA, Stappenbeck TS. 2015 Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient‐based assays. Gut 64(6): 911– 920. 25007816 PMC4305344
  62. Viravaidya K, Sin A, Shuler ML. 2004 Development of a microscale cell culture analog to probe naphthalene toxicity. Biotechnol Prog 20(1): 316– 323. 14763858
  63. Vivares A, Salle‐Lefort S, Arabeyre‐Fabre C, Ngo R, Penarier G, Bremond M, Moliner P, Gallas JF, Fabre G, Klieber S. 2015 Morphological behaviour and metabolic capacity of cryopreserved human primary hepatocytes cultivated in a perfused multiwell device. Xenobiotica 45(1): 29– 44. 25068923
  64. Wheeler SE, Clark AM, Taylor DP, Young CL, Pillai VC, Stolz DB, Venkataramanan R, Lauffenburger D, Griffith L, Wells A. 2014 Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system. Br J Cancer 111(12): 2342– 2350. 25314052 PMC4264444
  65. Wikswo JP. 2014 The relevance and potential roles of microphysiological systems in biology and medicine. Exp Biol Med (Maywood) 239(9): 1061– 1072. 25187571 PMC4330974
  66. Wikswo JP, Curtis EL, Eagleton ZE, Evans BC, Kole A, Hofmeister LH, Matloff WJ. 2013 Scaling and systems biology for integrating multiple organs‐on‐a‐chip. Lab Chip 13(18): 3496– 3511. 23828456 PMC3818688
  67. Yeruva S, Ramadori G, Raddatz D. 2008 NF‐kappaB‐dependent synergistic regulation of CXCL10 gene expression by IL‐1beta and IFN‐gamma in human intestinal epithelial cell lines. Int J Colorectal Dis 23(3): 305– 317. 18046562 PMC2225996
  68. Zhu L, Xia H, Wang Z, Fong ELS, Fan J, Tong WH, Seah YPD, Zhang W, Li Q, Yu H. 2016 A vertical‐flow bioreactor array compacts hepatocytes for enhanced polarity and functions. Lab on a Chip 16(20): 3898– 3908. 27722715

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Authors
Chen, W. L. K., Edington, C., Suter, E., Yu, J., Velazquez, J. J., Velazquez, J. G., Shockley, M., Large, E. M., Venkataramanan, R., Hughes, D. J., Stokes, C. L., Trumper, D. L., Carrier, R. L., Cirit, M., Griffith, L. G., & Lauffenburger, D. A.
Affiliations
  • Department of Biological Engineering Massachusetts Institute of Technology 77 Massachusetts Avenue, Cambridge Massachusetts, 02139
  • CN Bio Innovations Welwyn Garden City Hertfordshire UK
  • Department of Pharmaceutical Sciences School of Pharmacy University of Pittsburgh Pittsburgh Pennsylvania
  • Stokes Consulting Redwood City California
  • Department of Mechanical Engineering Massachusetts Institute of Technology Cambridge Massachusetts
  • Department of Chemical Engineering Northeastern University Boston Massachusetts
ORCID
Lauffenburger, Douglas A.
Venue
Biotechnology and Bioengineering
Publisher
Wiley
Published
2017-07-27
Volume
114
Issue
11
Pages
2648-2659
ISSN
  • 0006-3592
  • 1097-0290
DOI
10.1002/bit.26370
PMC
PMC5614865
Cited by
171
References
10
Language
en
Licence
Funders
  • National Institutes of Health (UH3TR000696)
  • Defense Advanced Research Projects Agency (Microphysiological Systems Program (W911NF‐12‐2‐00))

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