Patient-derived small intestinal myofibroblasts direct perfused, physiologically responsive capillary development in a microfluidic Gut-on-a-Chip Model.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
02 03 2020
02 03 2020
Historique:
received:
24
06
2019
accepted:
13
02
2020
entrez:
4
3
2020
pubmed:
4
3
2020
medline:
25
11
2020
Statut:
epublish
Résumé
The development and physiologic role of small intestine (SI) vasculature is poorly studied. This is partly due to a lack of targetable, organ-specific markers for in vivo studies of two critical tissue components: endothelium and stroma. This challenge is exacerbated by limitations of traditional cell culture techniques, which fail to recapitulate mechanobiologic stimuli known to affect vessel development. Here, we construct and characterize a 3D in vitro microfluidic model that supports the growth of patient-derived intestinal subepithelial myofibroblasts (ISEMFs) and endothelial cells (ECs) into perfused capillary networks. We report how ISEMF and EC-derived vasculature responds to physiologic parameters such as oxygen tension, cell density, growth factors, and pharmacotherapy with an antineoplastic agent (Erlotinib). Finally, we demonstrate effects of ISEMF and EC co-culture on patient-derived human intestinal epithelial cells (HIECs), and incorporate perfused vasculature into a gut-on-a-chip (GOC) model that includes HIECs. Overall, we demonstrate that ISEMFs possess angiogenic properties as evidenced by their ability to reliably, reproducibly, and quantifiably facilitate development of perfused vasculature in a microfluidic system. We furthermore demonstrate the feasibility of including perfused vasculature, including ISEMFs, as critical components of a novel, patient-derived, GOC system with translational relevance as a platform for precision and personalized medicine research.
Identifiants
pubmed: 32123209
doi: 10.1038/s41598-020-60672-5
pii: 10.1038/s41598-020-60672-5
pmc: PMC7051952
doi:
Substances chimiques
Oxygen
S88TT14065
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3842Subventions
Organisme : NIDDK NIH HHS
ID : T32 DK007130
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK114047
Pays : United States
Organisme : NIDDK NIH HHS
ID : R03 DK111473
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK118568
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK052574
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK112378
Pays : United States
Organisme : NIDDK NIH HHS
ID : K01 DK109081
Pays : United States
Références
McMellen, M. E., Wakeman, D., Erwin, C. R., Guo, J. & Warner, B. W. Epidermal growth factor receptor signaling modulates chemokine (CXC) ligand 5 expression and is associated with villus angiogenesis after small bowel resection. Surg. 148, 364–370 (2010).
doi: 10.1016/j.surg.2010.03.020
Binion, D. G. et al. Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease. Gastroenterology 112, 1895–1907 (1997).
doi: 10.1053/gast.1997.v112.pm9178682
pubmed: 9178682
pmcid: 9178682
Schirbel, A. et al. Pro-angiogenic activity of TLRs and NLRs: a novel link between gut microbiota and intestinal angiogenesis. Gastroenterology 144, 613–623 e619 (2013).
doi: 10.1053/j.gastro.2012.11.005
pubmed: 23149220
pmcid: 23149220
Nandikolla, A. G. & Rajdev, L. Targeting angiogenesis in gastrointestinal tumors: current challenges. Transl. Gastroenterol. Hepatol. 1, 67 (2016).
doi: 10.21037/tgh.2016.08.04
pubmed: 28138633
pmcid: 28138633
Schlieve, C. R. et al. Vascular Endothelial Growth Factor (VEGF) Bioavailability Regulates Angiogenesis and Intestinal Stem and Progenitor Cell Proliferation during Postnatal Small Intestinal Development. PLoS One 11, e0151396 (2016).
doi: 10.1371/journal.pone.0151396
pubmed: 26978773
pmcid: 26978773
Amin, D. N., Hida, K., Bielenberg, D. R. & Klagsbrun, M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173–2180 (2006).
doi: 10.1158/0008-5472.CAN-05-3387
pubmed: 16489018
pmcid: 16489018
Moya, M. L., Hsu, Y. H., Lee, A. P., Hughes, C. C. & George, S. C. In vitro perfused human capillary networks. Tissue Eng. Part. C. Methods 19, 730–737 (2013).
doi: 10.1089/ten.tec.2012.0430
pubmed: 23320912
pmcid: 23320912
Shin, W. & Kim, H. J. Intestinal barrier dysfunction orchestrates the onset of inflammatory host-microbiome cross-talk in a human gut inflammation-on-a-chip. Proc. Natl Acad. Sci. USA 115, E10539–E10547 (2018).
doi: 10.1073/pnas.1810819115
pubmed: 30348765
pmcid: 30348765
Newman, A. C., Nakatsu, M. N., Chou, W., Gershon, P. D. & Hughes, C. C. The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Mol. Biol. Cell 22, 3791–3800 (2011).
doi: 10.1091/mbc.e11-05-0393
pubmed: 21865599
pmcid: 21865599
Ghajar, C. M., Blevins, K. S., Hughes, C. C., George, S. C. & Putnam, A. J. Mesenchymal stem cells enhance angiogenesis in mechanically viable prevascularized tissues via early matrix metalloproteinase upregulation. Tissue Eng. 12, 2875–2888 (2006).
doi: 10.1089/ten.2006.12.2875
pubmed: 17518656
pmcid: 17518656
Sewell-Loftin, M. K. et al. Cancer-associated fibroblasts support vascular growth through mechanical force. Sci. Rep. 7(2017).
Vishy, C. E. et al. Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G185–G194 (2018).
doi: 10.1152/ajpgi.00224.2017
pubmed: 29631377
pmcid: 29631377
Lahar, N. et al. Intestinal subepithelial myofibroblasts support in vitro and in vivo growth of human small intestinal epithelium. PLoS One 6, e26898 (2011).
doi: 10.1371/journal.pone.0026898
pubmed: 22125602
pmcid: 22125602
Lei, N. Y. et al. Intestinal subepithelial myofibroblasts support the growth of intestinal epithelial stem cells. PLoS One 9, e84651 (2014).
doi: 10.1371/journal.pone.0084651
pubmed: 24400106
pmcid: 24400106
Otte, J. M., Rosenberg, I. M. & Podolsky, D. K. Intestinal myofibroblasts in innate immune responses of the intestine. Gastroenterology 124, 1866–1878 (2003).
doi: 10.1016/S0016-5085(03)00403-7
pubmed: 12806620
pmcid: 12806620
Andoh, A., Fujino, S., Okuno, T., Fujiyama, Y. & Bamba, T. Intestinal subepithelial myofibroblasts in inflammatory bowel diseases. J. Gastroenterol. 37(Suppl 14), 33–37 (2002).
doi: 10.1007/BF03326410
pubmed: 12572863
pmcid: 12572863
Morin, K. T. & Tranquillo, R. T. In vitro models of angiogenesis and vasculogenesis in fibrin gel. Exp. Cell Res. 319, 2409–2417 (2013).
doi: 10.1016/j.yexcr.2013.06.006
pubmed: 23800466
pmcid: 23800466
Shirure, V. S. et al. Tumor-on-a-chip platform to investigate progression and drug sensitivity in cell lines and patient-derived organoids. Lab. Chip 18, 3687–3702 (2018).
doi: 10.1039/C8LC00596F
pubmed: 30393802
pmcid: 30393802
Griffith, C. K. et al. Diffusion limits of an in vitro thick prevascularized tissue. Tissue Eng. 11, 257–266 (2005).
doi: 10.1089/ten.2005.11.257
pubmed: 15738680
pmcid: 15738680
Hughes, C. C. Endothelial-stromal interactions in angiogenesis. Curr. Opin. Hematol. 15, 204–209 (2008).
doi: 10.1097/MOH.0b013e3282f97dbc
pubmed: 18391786
pmcid: 18391786
Ausprunk, D. H. & Folkman, J. Migration and proliferation of endothelial cells in preformed and newly formed blood vessels during tumor angiogenesis. Microvasc. Res. 14, 53–65 (1977).
doi: 10.1016/0026-2862(77)90141-8
pubmed: 895546
pmcid: 895546
Phng, L. K. & Gerhardt, H. Angiogenesis: a team effort coordinated by notch. Dev. Cell 16, 196–208 (2009).
doi: 10.1016/j.devcel.2009.01.015
pubmed: 19217422
pmcid: 19217422
Geudens, I. & Gerhardt, H. Coordinating cell behaviour during blood vessel formation. Dev. 138, 4569–4583 (2011).
doi: 10.1242/dev.062323
Zudaire, E., Gambardella, L., Kurcz, C. & Vermeren, S. A computational tool for quantitative analysis of vascular networks. PLoS One 6, e27385 (2011).
doi: 10.1371/journal.pone.0027385
pubmed: 22110636
pmcid: 22110636
Mifflin, R. C., Pinchuk, I. V., Saada, J. I. & Powell, D. W. Intestinal myofibroblasts: targets for stem cell therapy. Am. J. Physiol. Gastrointest. Liver Physiol 300, G684–696 (2011).
doi: 10.1152/ajpgi.00474.2010
pubmed: 21252048
pmcid: 21252048
Sheridan, W. G., Lowndes, R. H. & Young, H. L. Intraoperative tissue oximetry in the human gastrointestinal tract. Am. J. Surg. 159, 314–319 (1990).
doi: 10.1016/S0002-9610(05)81226-7
pubmed: 2305939
pmcid: 2305939
Zheng, L., Kelly, C. J. & Colgan, S. P. Physiologic hypoxia and oxygen homeostasis in the healthy intestine. A Review in the Theme: Cellular Responses to Hypoxia. Am. J. Physiol. Cell Physiol 309, C350–360 (2015).
doi: 10.1152/ajpcell.00191.2015
pubmed: 26179603
pmcid: 26179603
Sukho, P. et al. Effect of Cell Seeding Density and Inflammatory Cytokines on Adipose Tissue-Derived Stem Cells: an in Vitro Study. Stem Cell Rev. 13, 267–277 (2017).
doi: 10.1007/s12015-017-9719-3
Sato, T. et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 141, 1762–1772 (2011).
doi: 10.1053/j.gastro.2011.07.050
Seiler, K. M. et al. Tissue underlying the intestinal epithelium elicits proliferation of intestinal stem cells following cytotoxic damage. Cell Tissue Res. 361, 427–438 (2015).
doi: 10.1007/s00441-015-2111-1
pubmed: 25693894
pmcid: 25693894
Sato, T. & Clevers, H. Primary mouse small intestinal epithelial cell cultures. Methods Mol. Biol. 945, 319–328 (2013).
doi: 10.1007/978-1-62703-125-7_19
pubmed: 23097115
pmcid: 23097115
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nat. 459, 262–265 (2009).
doi: 10.1038/nature07935
Walsh, D. A. Pathophysiological mechanisms of angiogenesis. Adv. Clin. Chem. 44, 187–221 (2007).
doi: 10.1016/S0065-2423(07)44006-9
pubmed: 17682343
pmcid: 17682343
Carmeliet, P. Angiogenesis in life, disease and medicine. Nat. 438, 932–936 (2005).
doi: 10.1038/nature04478
Chaet, M. S., Arya, G., Ziegler, M. M. & Warner, B. W. Epidermal growth factor enhances intestinal adaptation after massive small bowel resection. J. Pediatr. Surg. 29, 1035–1038; discussion 1038-1039 (1994).
Erwin, C. R. et al. Intestinal overexpression of EGF in transgenic mice enhances adaptation after small bowel resection. Am. J. Physiol. 277, G533–540 (1999).
pubmed: 10484377
pmcid: 10484377
Stern, L. E., Erwin, C. R., O’Brien, D. P., Huang, F. & Warner, B. W. Epidermal growth factor is critical for intestinal adaptation following small bowel resection. Microsc. Res. Tech. 51, 138–148 (2000).
doi: 10.1002/1097-0029(20001015)51:2<138::AID-JEMT5>3.0.CO;2-T
pubmed: 11054864
pmcid: 11054864
Martin, C. A. et al. Intestinal resection induces angiogenesis within adapting intestinal villi. J. Pediatr. Surg. 44, 1077–1082; discussion 1083 (2009).
Lee, J. G. & Wu, R. Erlotinib-cisplatin combination inhibits growth and angiogenesis through c-MYC and HIF-1alpha in EGFR-mutated lung cancer in vitro and in vivo. Neoplasia 17, 190–200 (2015).
doi: 10.1016/j.neo.2014.12.008
pubmed: 4351293
pmcid: 4351293
Li, Y. X. et al. Celecoxib-erlotinib combination delays growth and inhibits angiogenesis in EGFR-mutated lung cancer. Am. J. Cancer Res. 6, 1494–1510 (2016).
pubmed: 27508092
pmcid: 27508092
Ito, K. et al. Enhanced anti-angiogenic effect of E7820 in combination with erlotinib in epidermal growth factor receptor-tyrosine kinase inhibitor-resistant non-small-cell lung cancer xenograft models. Cancer Sci. 105, 1023–1031 (2014).
doi: 10.1111/cas.12450
pubmed: 24841832
pmcid: 24841832
Moyer, J. D. et al. Induction of apoptosis and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth factor receptor tyrosine kinase. Cancer Res. 57, 4838–4848 (1997).
pubmed: 9354447
pmcid: 9354447
Berndsen, R. H. et al. Combination of ruthenium(II)-arene complex [Ru(eta(6)-p-cymene)Cl2(pta)] (RAPTA-C) and the epidermal growth factor receptor inhibitor erlotinib results in efficient angiostatic and antitumor activity. Sci. Rep. 7, 43005 (2017).
doi: 10.1038/srep43005
pubmed: 28223694
pmcid: 28223694
Gruber, A. et al. Monitoring of erlotinib in pancreatic cancer patients during long-time administration and comparison to a physiologically based pharmacokinetic model. Cancer Chemother. Pharmacol. 81, 763–771 (2018).
doi: 10.1007/s00280-018-3545-4
pubmed: 29453635
pmcid: 29453635
Zhang, Y. et al. Optimized selection of three major EGFR-TKIs in advanced EGFR-positive non-small cell lung cancer: a network meta-analysis. Oncotarget 7, 20093–20108 (2016).
pubmed: 26933807
pmcid: 26933807
Kasendra, M. et al. Development of a primary human Small Intestine-on-a-Chip using biopsy-derived organoids. Sci. Rep. 8, 2871 (2018).
doi: 10.1038/s41598-018-21201-7
pubmed: 29440725
pmcid: 29440725
De Gregorio, V. et al. Intestine-on-chip device increases ECM remodeling inducing faster epithelial cell differentiation. Biotechnol Bioeng (2019).
Kim, H. J. & Ingber, D. E. Gut-on-a-Chip microenvironment induces human intestinal cells to undergo villus differentiation. Integr. Biol. 5, 1130–1140 (2013).
doi: 10.1039/c3ib40126j
Workman, M. J. et al. Enhanced Utilization of Induced Pluripotent Stem Cell-Derived Human Intestinal Organoids Using Microengineered Chips. Cell Mol. Gastroenterol. Hepatol. 5, 669–677 e662 (2018).
doi: 10.1016/j.jcmgh.2017.12.008
pubmed: 29930984
pmcid: 29930984
De Gregorio, V., Imparato, G., Urciuolo, F. & Netti, P. A. 3D stromal tissue equivalent affects intestinal epithelium morphogenesis in vitro. Biotechnol. Bioeng. 115, 1062–1075 (2018).
doi: 10.1002/bit.26522
pubmed: 29251351
pmcid: 29251351
Kim, H. J., Huh, D., Hamilton, G. & Ingber, D. E. Human gut-on-a-chip inhabited by microbial flora that experiences intestinal peristalsis-like motions and flow. Lab. Chip 12, 2165–2174 (2012).
doi: 10.1039/c2lc40074j
pubmed: 22434367
pmcid: 22434367
Robinson, P. S., Johnson, S. L., Evans, M. C., Barocas, V. H. & Tranquillo, R. T. Functional tissue-engineered valves from cell-remodeled fibrin with commissural alignment of cell-produced collagen. Tissue Eng. Part. A 14, 83–95 (2008).
doi: 10.1089/ten.a.2007.0148
pubmed: 18333807
pmcid: 18333807
Nolan, D. J. et al. Molecular signatures of tissue-specific microvascular endothelial cell heterogeneity in organ maintenance and regeneration. Dev. Cell 26, 204–219 (2013).
doi: 10.1016/j.devcel.2013.06.017
pubmed: 23871589
pmcid: 23871589
Shao, J., Sheng, G. G., Mifflin, R. C., Powell, D. W. & Sheng, H. Roles of myofibroblasts in prostaglandin E2-stimulated intestinal epithelial proliferation and angiogenesis. Cancer Res. 66, 846–855 (2006).
doi: 10.1158/0008-5472.CAN-05-2606
pubmed: 16424017
pmcid: 16424017
Vong, S. & Kalluri, R. The role of stromal myofibroblast and extracellular matrix in tumor angiogenesis. Genes. Cancer 2, 1139–1145 (2011).
doi: 10.1177/1947601911423940
pubmed: 22866205
pmcid: 22866205
DiMarco, R. L. et al. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr. Biol. 6, 127–142 (2014).
doi: 10.1039/C3IB40188J
Roulis, M. & Flavell, R. A. Fibroblasts and myofibroblasts of the intestinal lamina propria in physiology and disease. Differentiation (2016).
Aran, K., Sasso, L. A., Kamdar, N. & Zahn, J. D. Irreversible, direct bonding of nanoporous polymer membranes to PDMS or glass microdevices. Lab. Chip 10, 548–552 (2010).
doi: 10.1039/b924816a
pubmed: 20162227
pmcid: 20162227
Chen, X. et al. Rapid anastomosis of endothelial progenitor cell-derived vessels with host vasculature is promoted by a high density of cotransplanted fibroblasts. Tissue Eng. Part. A 16, 585–594 (2010).
doi: 10.1089/ten.tea.2009.0491
pubmed: 19737050
pmcid: 19737050
VanDussen, K. L. et al. Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut. 64, 911–920 (2015).
doi: 10.1136/gutjnl-2013-306651
pubmed: 25007816
pmcid: 25007816
Miyoshi, H. & Stappenbeck, T. S. In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nat. Protoc. 8, 2471–2482 (2013).
doi: 10.1038/nprot.2013.153
pubmed: 24232249
pmcid: 24232249
Moon, C., VanDussen, K. L., Miyoshi, H. & Stappenbeck, T. S. Development of a primary mouse intestinal epithelial cell monolayer culture system to evaluate factors that modulate IgA transcytosis. Mucosal Immunol. 7, 818–828 (2014).
doi: 10.1038/mi.2013.98
pubmed: 24220295
pmcid: 24220295