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. 2022 Nov 21;16(3):3976–3990. doi: 10.1007/s12274-022-5150-4

Advancing intestinal organoid technology to decipher nano-intestine interactions and treat intestinal disease

Lin Bao 1,3, Xuejing Cui 1,2,✉, Ru Bai 1, Chunying Chen 1,2,3,✉
PMCID: PMC9685037  PMID: 36465523

Abstract

With research burgeoning in nanoscience and nanotechnology, there is an urgent need to develop new biological models that can simulate native structure, function, and genetic properties of tissues to evaluate the adverse or beneficial effects of nanomaterials on a host. Among the current biological models, three-dimensional (3D) organoids have developed as powerful tools in the study of nanomaterial-biology (nano-bio) interactions, since these models can overcome many of the limitations of cell and animal models. A deep understanding of organoid techniques will facilitate the development of more efficient nanomedicines and further the fields of tissue engineering and personalized medicine. Herein, we summarize the recent progress in intestinal organoids culture systems with a focus on our understanding of the nature and influencing factors of intestinal organoid growth. We also discuss biomimetic extracellular matrices (ECMs) coupled with nanotechnology. In particular, we analyze the application prospects for intestinal organoids in investigating nano-intestine interactions. By integrating nanotechnology and organoid technology, this recently developed model will fill the gaps left due to the deficiencies of traditional cell and animal models, thus accelerating both our understanding of intestine-related nanotoxicity and the development of nanomedicines. graphic file with name 12274_2022_5150_Fig1_HTML.jpg

Keywords: intestinal organoid, biomimetic extracellular matrices (ECMs), intestinal tissue engineering, nano-intestine interaction

Acknowledgments

This work was supported by the National Key Research and Development Program of China (No. 2021YFA1200900), the National Natural Science Foundation of China (NSFC, No. 32271460), the Major instrument project of NSFC (No. 22027810), NSFC Major Research Plan-Integrated Program (No. 92143301), the Innovative Research Group Project of NSFC (No. 11621505), the CAS international cooperative project (No. GJHZ201949), the CAS Interdisciplinary Innovation Team, the CAS Key Research Program for Frontier Sciences (No. QYZDJ-SS-SLH022), the Research and Development Project in Key Areas of Guangdong Province (No. 2019B090917011), CAMS Innovation Fund for Medical Sciences (No. CIFMS 2019-I2M-5-018), and the Strategic Priority Research Program of Chinese Academy of Sciences (No. XDB36000000). All figures in this review are created with Biorender.com (2022).

Contributor Information

Xuejing Cui, Email: cuixj@nanoctr.cn.

Chunying Chen, Email: chenchy@nanoctr.cn.

References

  • [1].Zhao H, Xu J B, Huang W J, Zhan G T, Zhao Y B, Chen H B, Yang X L. Spatiotemporally light-activatable platinum nanocomplexes for selective and cooperative cancer therapy. ACS Nano. 2019;13:6647–6661. doi: 10.1021/acsnano.9b00972. [DOI] [PubMed] [Google Scholar]
  • [2].Zhao H, Xu J B, Wang Y Q, Sun C Y, Bao L, Zhao Y B, Yang X L, Zhao Y L. A photosensitizer discretely loaded nanoaggregate with robust photodynamic effect for local treatment triggers systemic antitumor responses. ACS Nano. 2022;16:3070–3080. doi: 10.1021/acsnano.1c10590. [DOI] [PubMed] [Google Scholar]
  • [3].Wu J G, Cui X J, Ke P C, Mortimer M, Wang X Y, Bao L, Chen C Y. Nanomaterials as novel agents for amelioration of Parkinson’s disease. Nano Today. 2021;41:101328. doi: 10.1016/j.nantod.2021.101328. [DOI] [Google Scholar]
  • [4].Zhao H, Wang Y Q, Bao L, Chen C Y. Engineering nano-bio interfaces from nanomaterials to nanomedicines. Acc. Mater. Res. 2022;3:812–829. doi: 10.1021/accountsmr.2c00072. [DOI] [Google Scholar]
  • [5].Zhao H, Xu J B, Wan J S, Huang W J, Zhao Y B, Yang X L. A versatile strategy for improving phototherapeutic efficacy on deep-sited tumor by tissue optical clearing technique. Nano Today. 2021;36:101058. doi: 10.1016/j.nantod.2020.101058. [DOI] [Google Scholar]
  • [6].Chen H Q, Wang B, Gao D, Guan M, Zheng L N, Ouyang H, Chai Z F, Zhao Y L, Feng W Y. Broad-spectrum antibacterial activity of carbon nanotubes to human gut bacteria. Small. 2013;9:2735–2746. doi: 10.1002/smll.201202792. [DOI] [PubMed] [Google Scholar]
  • [7].Valsami-Jones E, Lynch I. How safe are nanomaterials? Science. 2015;350:388–389. doi: 10.1126/science.aad0768. [DOI] [PubMed] [Google Scholar]
  • [8].Wu Y, Sun M H, Wang D, Li G Y, Huang J G, Tan S W, Bao L, Li Q, Li G, Si L Q. A PepT1 mediated medicinal nano-system for targeted delivery of cyclosporine A to alleviate acute severe ulcerative colitis. Biomater. Sci. 2019;7:4299–4309. doi: 10.1039/C9BM00925F. [DOI] [PubMed] [Google Scholar]
  • [9].Cui X J, Bao L, Wang X Y, Chen C Y. The nano-intestine interaction: Understanding the location-oriented effects of engineered nanomaterials in the intestine. Small. 2020;16:1907665. doi: 10.1002/smll.201907665. [DOI] [PubMed] [Google Scholar]
  • [10].Bao L, Cui X J, Wang X Y, Wu J G, Guo M Y, Yan N, Chen C Y. Carbon nanotubes promote the development of intestinal organoids through regulating extracellular matrix viscoelasticity and intracellular energy metabolism. ACS Nano. 2021;15:15858–15873. doi: 10.1021/acsnano.1c03707. [DOI] [PubMed] [Google Scholar]
  • [11].Clevers H. Modeling development and disease with organoids. Cell. 2016;165:1586–1597. doi: 10.1016/j.cell.2016.05.082. [DOI] [PubMed] [Google Scholar]
  • [12].Drost J, Clevers H. Organoids in cancer research. Nat. Rev. Cancer. 2018;18:407–418. doi: 10.1038/s41568-018-0007-6. [DOI] [PubMed] [Google Scholar]
  • [13].Fatehullah A, Tan S H, Barker N. Organoids as an in vitro model of human development and disease. Nat. Cell Biol. 2016;18:246–254. doi: 10.1038/ncb3312. [DOI] [PubMed] [Google Scholar]
  • [14].Davoudi Z, Peroutka-Bigus N, Bellaire B, Wannemuehler M, Barrett T A, Narasimhan B, Wang Q. Intestinal organoids containing poly(lactic-co-glycolic acid) nanoparticles for the treatment of inflammatory bowel diseases. J. Biomed. Mater. Res., Part A. 2018;106:876–886. doi: 10.1002/jbm.a.36305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Capeling M M, Czerwinski M, Huang S, Tsai Y H, Wu A, Nagy M S, Juliar B, Sundaram N, Song Y, Han W M, et al. Nonadhesive alginate hydrogels support growth of pluripotent stem cell-derived intestinal organoids. Stem Cell Rep. 2019;12:381–394. doi: 10.1016/j.stemcr.2018.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Sato T, Vries R G, Snippert H J, van de Wetering M, Barker N, Stange D E, van Es J H, Abo A, Kujala P, Peters P J, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459:262–265. doi: 10.1038/nature07935. [DOI] [PubMed] [Google Scholar]
  • [17].Li M, Izpisua Belmonte J C. Organoids-preclinical models of human disease. N. Engl. J. Med. 2019;380:569–579. doi: 10.1056/NEJMra1806175. [DOI] [PubMed] [Google Scholar]
  • [18].Ballard D H, Boyer C J, Alexander J S. Organoids-preclinical models of human disease. N. Engl. J. Med. 2019;380:1981–1982. doi: 10.1056/NEJMc1903253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Sato T, Clevers H. Growing self-organizing mini-guts from a single intestinal stem cell: Mechanism and applications. Science. 2013;340:1190–1194. doi: 10.1126/science.1234852. [DOI] [PubMed] [Google Scholar]
  • [20].Sato T, Stange D E, Ferrante M, Vries R G J, van Es J H, van den Brink S, van Houdt W J, Pronk A, van Gorp J, Siersema P D, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762–1772. doi: 10.1053/j.gastro.2011.07.050. [DOI] [PubMed] [Google Scholar]
  • [21].Spence J R, Mayhew C N, Rankin S A, Kuhar M F, Vallance J E, Tolle K, Hoskins E E, Kalinichenko V V, Wells S I, Zorn A M, et al. Directed differentiation of human pluripotent stem cells into intestinal tissue in vitro. Nature. 2011;470:105–120. doi: 10.1038/nature09691. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Stelzner M, Helmrath M, Dunn J C Y, Henning S J, Houchen C W, Kuo C, Lynch J, Li L H, Magness S T, Martin M G, et al. A nomenclature for intestinal in vitro cultures. Am. J. Physiol. Gastrointest. Liver Physiol. 2012;302:G1359–G1363. doi: 10.1152/ajpgi.00493.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].van der Flier L G, Clevers H. Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 2009;71:241–260. doi: 10.1146/annurev.physiol.010908.163145. [DOI] [PubMed] [Google Scholar]
  • [24].Marchiando A M, Shen L, Graham W V, Edelblum K L, Duckworth C A, Guan Y F, Montrose M H, Turner J R, Watson A J M. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology. 2011;140:1208–1218.e2. doi: 10.1053/j.gastro.2011.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [25].Leushacke M, Barker N. Ex vivo culture of the intestinal epithelium: Strategies and applications. Gut. 2014;63:1345–1354. doi: 10.1136/gutjnl-2014-307204. [DOI] [PubMed] [Google Scholar]
  • [26].Clevers H. The intestinal crypt, a prototype stem cell compartment. Cell. 2013;154:274–284. doi: 10.1016/j.cell.2013.07.004. [DOI] [PubMed] [Google Scholar]
  • [27].Yan K S, Janda C Y, Chang J L, Zheng G X Y, Larkin K A, Luca V C, Chia L A, Mah A T, Han A, Terry J M, et al. Non-equivalence of Wnt and R-spondin ligands during Lgr5+ intestinal stem-cell self-renewal. Nature. 2017;545:238–242. doi: 10.1038/nature22313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Zhang Y C, Que J W. BMP signaling in development, stem cells, and diseases of the gastrointestinal tract. Annu. Rev. Physiol. 2020;82:251–273. doi: 10.1146/annurev-physiol-021119-034500. [DOI] [PubMed] [Google Scholar]
  • [29].Serra D, Mayr U, Boni A, Lukonin I, Rempfler M, Meylan L C, Stadler M B, Strnad P, Papasaikas P, Vischi D, et al. Self-organization and symmetry breaking in intestinal organoid development. Nature. 2019;569:66–72. doi: 10.1038/s41586-019-1146-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Middendorp S, Schneeberger K, Wiegerinck C L, Mokry M, Akkerman R D L, van Wijngaarden S, Clevers H, Nieuwenhuis E E S. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cells. 2014;32:1083–1091. doi: 10.1002/stem.1655. [DOI] [PubMed] [Google Scholar]
  • [31].Wang X, Yamamoto Y, Wilson L H, Zhang T, Howitt B E, Farrow M A, Kern F, Ning G, Hong Y, Khor C C, et al. Cloning and variation of ground state intestinal stem cells. Nature. 2015;522:173–178. doi: 10.1038/nature14484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [32].Finkbeiner S R, Hill D R, Altheim C H, Dedhia P H, Taylor M J, Tsai Y H, Chin A M, Mahe M M, Watson C L, Freeman J J, et al. Transcriptome-wide analysis reveals hallmarks of human intestine development and maturation in vitro and in vivo. Stem Cell Rep. 2015;4:1140–1155. doi: 10.1016/j.stemcr.2015.04.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Rossi G, Manfrin A, Lutolf M P. Progress and potential in organoid research. Nat. Rev. Genet. 2018;19:671–687. doi: 10.1038/s41576-018-0051-9. [DOI] [PubMed] [Google Scholar]
  • [34].Gjorevski N, Ranga A, Lutolf M P. Bioengineering approaches to guide stem cell-based organogenesis. Development. 2014;141:1794–1804. doi: 10.1242/dev.101048. [DOI] [PubMed] [Google Scholar]
  • [35].Hughes C S, Postovit L M, Lajoie G A. Matrigel: A complex protein mixture required for optimal growth of cell culture. Proteomics. 2010;10:1886–1890. doi: 10.1002/pmic.200900758. [DOI] [PubMed] [Google Scholar]
  • [36].Sachs N, Tsukamoto Y, Kujala P, Peters P J, Clevers H. Intestinal epithelial organoids fuse to form self-organizing tubes in floating collagen gels. Development. 2017;144:1107–1112. doi: 10.1242/dev.143933. [DOI] [PubMed] [Google Scholar]
  • [37].Broguiere N, Isenmann L, Hirt C, Ringel T, Placzek S, Cavalli E, Ringnalda F, Villiger L, Züllig R, Lehmann R, et al. Growth of epithelial organoids in a defined hydrogel. Adv. Mater. 2018;30:1801621. doi: 10.1002/adma.201801621. [DOI] [PubMed] [Google Scholar]
  • [38].Amukarimi S, Mozafari M. Biodegradable magnesium-based biomaterials: An overview of challenges and opportunities. MedComm. 2021;2:123–144. doi: 10.1002/mco2.59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [39].Ahmed J, Gultekinoglu M, Bayram C, Kart D, Ulubayram K, Edirisinghe M. Alleviating the toxicity concerns of antibacterial cinnamon-polycaprolactone biomaterials for healthcare-related biomedical applications. MedComm. 2021;2:236–246. doi: 10.1002/mco2.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [40].Gjorevski N, Sachs N, Manfrin A, Giger S, Bragina M E, Ordóñez-Morán P, Clevers H, Lutolf M P. Designer matrices for intestinal stem cell and organoid culture. Nature. 2016;539:560–564. doi: 10.1038/nature20168. [DOI] [PubMed] [Google Scholar]
  • [41].Ranga A, Girgin M, Meinhardt A, Eberle D, Caiazzo M, Tanaka E M, Lutolf M P. Neural tube morphogenesis in synthetic 3D microenvironments. Proc. Natl. Acad. Sci. USA. 2016;113:E6831–E6839. doi: 10.1073/pnas.1603529113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Cruz-Acuña R, Quirós M, Farkas A E, Dedhia P H, Huang S, Siuda D, García-Hernández V, Miller A J, Spence J R, Nusrat A, et al. Synthetic hydrogels for human intestinal organoid generation and colonic wound repair. Nat. Cell Biol. 2017;19:1326–1335. doi: 10.1038/ncb3632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Dosh R. Developing models of the small intestine. Sheffield, UK: Sheffield Hallam University; 2018. [Google Scholar]
  • [44].Rosales A M, Anseth K S. The design of reversible hydrogels to capture extracellular matrix dynamics. Nat. Rev. Mater. 2016;1:15012. doi: 10.1038/natrevmats.2015.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].DiMarco R L, Su J, Yan K S, Dewi R, Kuo C J, Heilshorn S C. Engineering of three-dimensional microenvironments to promote contractile behavior in primary intestinal organoids. Integr. Biol. 2014;6:127–142. doi: 10.1039/C3IB40188J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [46].Chrisnandy A, Blondel D, Rezakhani S, Broguiere N, Lutolf M P. Synthetic dynamic hydrogels promote degradation-independent in vitro organogenesis. Nat. Mater. 2022;21:479–487. doi: 10.1038/s41563-021-01136-7. [DOI] [PubMed] [Google Scholar]
  • [47].Hernandez-Gordillo V, Kassis T, Lampejo A, Choi G, Gamboa M E, Gnecco J S, Brown A, Breault D T, Carrier R, Griffith L G. Fully synthetic matrices for in vitro culture of primary human intestinal enteroids and endometrial organoids. Biomaterials. 2020;254:120125. doi: 10.1016/j.biomaterials.2020.120125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [48].Parisi-Amon A, Mulyasasmita W, Chung C, Heilshorn S C. Protein-engineered injectable hydrogel to improve retention of transplanted adipose-derived stem cells. Adv. Healthcare Mater. 2013;2:428–432. doi: 10.1002/adhm.201200293. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [49].Zhao H, Zhao Y B, Xu J B, Feng X, Liu G Y, Zhao Y B, Yang X L. Programmable co-assembly of various drugs with temperature sensitive nanogels for optimizing combination chemotherapy. Chem. Eng. J. 2020;398:125614. doi: 10.1016/j.cej.2020.125614. [DOI] [Google Scholar]
  • [50].Zhao H, Xu J B, Huang W J, Zhao Y B, Yang X L. Thermosensitive nanogels with cross-linked Pd(II) ions for improving therapeutic effects on platinum-resistant cancers via intratumoral formation of hydrogels. Chem. Mater. 2019;31:5089–5103. doi: 10.1021/acs.chemmater.9b00986. [DOI] [Google Scholar]
  • [51].Li X, Su X L. Multifunctional smart hydrogels: Potential in tissue engineering and cancer therapy. J. Mater. Chem. B. 2018;6:4714–4730. doi: 10.1039/C8TB01078A. [DOI] [PubMed] [Google Scholar]
  • [52].O’Donnell N, Okkelman I A, Timashev P, Gromovykh T I, Papkovsky D B, Dmitriev R I. Cellulose-based scaffolds for fluorescence lifetime imaging-assisted tissue engineering. Acta Biomater. 2018;80:85–96. doi: 10.1016/j.actbio.2018.09.034. [DOI] [PubMed] [Google Scholar]
  • [53].Schöneberg J, Dambournet D, Liu T L, Forster R, Hockemeyer D, Betzig E, Drubin D G. 4D cell biology: Big data image analytics and lattice light-sheet imaging reveal dynamics of clathrin-mediated endocytosis in stem cell-derived intestinal organoids. Mol. Biol. Cell. 2018;29:2959–2968. doi: 10.1091/mbc.E18-06-0375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [54].Klotz B J, Oosterhoff L A, Utomo L, Lim K S, Vallmajo-Martin Q, Clevers H, Woodfield T B F, Rosenberg A J W P, Malda J, Ehrbar M, et al. A versatile biosynthetic hydrogel platform for engineering of tissue analogues. Adv. Healthcare Mater. 2019;8:1900979. doi: 10.1002/adhm.201900979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Zhao H, Xu J B, Feng C, Ren J Y, Bao L, Zhao Y B, Tao W, Zhao Y L, Yang X L. Tailoring aggregation extent of photosensitizers to boost phototherapy potency for eliciting systemic antitumor immunity. Adv. Mater. 2022;34:2106390. doi: 10.1002/adma.202106390. [DOI] [PubMed] [Google Scholar]
  • [56].Zhang Z P, Zhang R J, Xiao H, Bhattacharya K, Bitounis D, Demokritou P, McClements D J. Development of a standardized food model for studying the impact of food matrix effects on the gastrointestinal fate and toxicity of ingested nanomaterials. NanoImpact. 2019;13:13–25. doi: 10.1016/j.impact.2018.11.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [57].Tripathi A, Debelius J, Brenner D A, Karin M, Loomba R, Schnabl B, Knight R. The gut-liver axis and the intersection with the microbiome. Nat. Rev. Gastroenterol. Hepatol. 2018;55:397–411. doi: 10.1038/s41575-018-0011-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Budden K F, Gellatly S L, Wood D L A, Cooper M A, Morrison M, Hugenholtz P, Hansbro P M. Emerging pathogenic links between microbiota and the gut-lung axis. Nat. Rev. Microbiol. 2017;15:55–63. doi: 10.1038/nrmicro.2016.142. [DOI] [PubMed] [Google Scholar]
  • [59].Hua S S, Marks E, Schneider J J, Keely S. Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: Selective targeting to diseased versus healthy tissue. Nanomedicine. 2015;11:1117–1132. doi: 10.1016/j.nano.2015.02.018. [DOI] [PubMed] [Google Scholar]
  • [60].Guo J F, Yu Z, Das M, Huang L. Nano codelivery of oxaliplatin and folinic acid achieves synergistic chemo-immunotherapy with 5-fluorouracil for colorectal cancer and liver metastasis. ACS Nano. 2020;14:5075–5089. doi: 10.1021/acsnano.0c01676. [DOI] [PubMed] [Google Scholar]
  • [61].Klotz B J, Gawlitta D, Rosenberg A J W P, Malda J, Melchels F P W. Gelatin-methacryloyl hydrogels: Towards biofabrication-based tissue repair. Trends Biotechnol. 2016;44:394–407. doi: 10.1016/j.tibtech.2016.01.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [62].Lin S S, Mukherjee S, Li J J, Hou W L, Pan C, Liu J Y. Mucosal immunity-mediated modulation of the gut microbiome by oral delivery of probiotics into Peyer’s patches. Sci. Adv. 2021;7:eabf0677. doi: 10.1126/sciadv.abf0677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [63].Miao Y B, Lin Y J, Chen K H, Luo P K, Chuang S H, Yu Y T, Tai H M, Chen C T, Lin K J, Sung H W. Engineering nano- and microparticles as oral delivery vehicles to promote intestinal lymphatic drug transport. Adv. Mater. 2021;33:2104139. doi: 10.1002/adma.202104139. [DOI] [PubMed] [Google Scholar]
  • [64].Kanaya T, Sakakibara S, Jinnohara T, Hachisuka M, Tachibana N, Hidano S, Kobayashi T, Kimura S, Iwanaga T, Nakagawa T, et al. Development of intestinal M cells and follicle-associated epithelium is regulated by TRAF6-mediated NF-κB signaling. J. Exp. Med. 2018;215:501–519. doi: 10.1084/jem.20160659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [65].Farin H F, Jordens I, Mosa M H, Basak O, Korving J, Tauriello D V F, de Punder K, Angers S, Peters P J, Maurice M M, et al. Visualization of a short-range Wnt gradient in the intestinal stem-cell niche. Nature. 2016;530:340–343. doi: 10.1038/nature16937. [DOI] [PubMed] [Google Scholar]
  • [66].Sato T, van Es J H, Snippert H J, Stange D E, Vries R G, van den Born M, Barker N, Shroyer N F, van de Wetering M, Clevers H. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature. 2011;469:415–418. doi: 10.1038/nature09637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [67].Rodríguez-Colman M J, Schewe M, Meerlo M, Stigter E, Gerrits J, Pras-Raves M, Sacchetti A, Hornsveld M, Oost K C, Snippert H J, et al. Interplay between metabolic identities in the intestinal crypt supports stem cell function. Nature. 2017;543:424–427. doi: 10.1038/nature21673. [DOI] [PubMed] [Google Scholar]
  • [68].Gao M, Wang Z Z, Zheng H Z, Wang L, Xu S J, Liu X, Li W, Pan Y X, Wang W L, Cai X M, et al. Two-dimensional tin selenide (SnSe) nanosheets capable of mimicking key dehydrogenases in cellular metabolism. Angew. Chem., Int. Ed. 2020;59:3618–3623. doi: 10.1002/anie.201913035. [DOI] [PubMed] [Google Scholar]
  • [69].Wu D, Li J K, Xu S J, Xie Q Q, Pan Y X, Liu X, Ma R L, Zheng H Z, Gao M, Wang W L, et al. Engineering Fe-N doped graphene to mimic biological functions of NADPH oxidase in cells. J. Am. Chem. Soc. 2020;142:19602–19610. doi: 10.1021/jacs.0c08360. [DOI] [PubMed] [Google Scholar]
  • [70].Akyildiz I F, Chen J D, Ghovanloo M, Guler U, Ozkaya-Ahmadov T, Pierobon M, Sarioglu A F, Unluturk B D. Microbiome-gut-brain axis as a biomolecular communication network for the internet of bio-nanothings. IEEE Access. 2019;7:136161–136175. doi: 10.1109/ACCESS.2019.2942312. [DOI] [Google Scholar]
  • [71].Kaelberer M M, Buchanan K L, Klein M E, Barth B B, Montoya M M, Shen X L, Bohórquez D V. A gut-brain neural circuit for nutrient sensory transduction. Science. 2018;361:eaat5236. doi: 10.1126/science.aat5236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [72].Grün D, Lyubimova A, Kester L, Wiebrands K, Basak O, Sasaki N, Clevers H, van Oudenaarden A. Single-cell messenger RNA sequencing reveals rare intestinal cell types. Nature. 2015;525:251–255. doi: 10.1038/nature14966. [DOI] [PubMed] [Google Scholar]
  • [73].Haber A L, Biton M, Rogel N, Herbst R H, Shekhar K, Smillie C, Burgin G, Delorey T M, Howitt M R, Katz Y, et al. A single-cell survey of the small intestinal epithelium. Nature. 2017;551:333–339. doi: 10.1038/nature24489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [74].Coward S, Clement F, Benchimol E I, Bernstein C N, Avina-Zubieta J A, Bitton A, Carroll M W, Hazlewood G, Jacobson K, Jelinski S, et al. Past and future burden of inflammatory bowel diseases based on modeling of population-based data. Gastroenterology. 2019;156:1345–1353.e4. doi: 10.1053/j.gastro.2019.01.002. [DOI] [PubMed] [Google Scholar]
  • [75].Ding N S, Hart A, De Cruz P. Systematic review: Predicting and optimising response to anti-TNF therapy in Crohn’s disease-algorithm for practical management. Aliment. Pharmacol. Ther. 2016;43:30–51. doi: 10.1111/apt.13445. [DOI] [PubMed] [Google Scholar]
  • [76].Cooney R, Baker J, Brain O, Danis B, Pichulik T, Allan P, Ferguson D J P, Campbell B J, Jewell D, Simmons A. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat. Med. 2010;16:90–97. doi: 10.1038/nm.2069. [DOI] [PubMed] [Google Scholar]
  • [77].Ho S M, Lewis J D, Mayer E A, Bernstein C N, Plevy S E, Chuang E, Rappaport S M, Croitoru K, Korzenik J R, Krischer J, et al. Challenges in IBD research: Environmental triggers. Inflamm. Bowel Dis. 2019;25:S13–S23. doi: 10.1093/ibd/izz076. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [78].Kotla N G, Burke O, Pandit A, Rochev Y. An orally administrated hyaluronan functionalized polymeric hybrid nanoparticle system for colon-specific drug delivery. Nanomaterials. 2019;9:1246. doi: 10.3390/nano9091246. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [79].Zhang S F, Langer R, Traverso G. Nanoparticulate drug delivery systems targeting inflammation for treatment of inflammatory bowel disease. Nano Today. 2017;16:82–96. doi: 10.1016/j.nantod.2017.08.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [80].Suzuki K, Murano T, Shimizu H, Ito G, Nakata T, Fujii S, Ishibashi F, Kawamoto A, Anzai S, Kuno R, et al. Single cell analysis of Crohn’s disease patient-derived small intestinal organoids reveals disease activity-dependent modification of stem cell properties. J. Gastroenterol. 2018;53:1035–1047. doi: 10.1007/s00535-018-1437-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [81].Rouch J D, Scott A, Lei N Y, Solorzano-Vargas R S, Wang J F, Hanson E M, Kobayashi M, Lewis M, Stelzner M G, Dunn J C Y, et al. Development of functional microfold (M) cells from intestinal stem cells in primary human enteroids. PLoS One. 2016;11:e0148216. doi: 10.1371/journal.pone.0148216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [82].Driehuis E, Clevers H. CRISPR/Cas 9 genome editing and its applications in organoids. Am. J. Physiol. Gastrointest. Liver Physiol. 2017;312:G257–G265. doi: 10.1152/ajpgi.00410.2016. [DOI] [PubMed] [Google Scholar]
  • [83].Gazouli M, Pachoula I, Panayotou I, Mantzaris G, Chrousos G, Anagnou N P, Roma-Giannikou E. NOD2/CARD15, ATG16L1 and IL23R gene polymorphisms and childhood-onset of Crohn’s disease. World J. Gastroenterol. 2010;16:1753–1758. doi: 10.3748/wjg.v16.i14.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [84].Borcherding D C, Ambrosini Y M, Atherly T, Rudolph T, Essner J, Wierson W, Jergens A, Allenspach K, Moch J P. Su1046-CRISPR/Cas9-mediated genome editing of multi-drug resistance proteins in a novel canine enteroid model. Gastroenterology. 2019;156:S–494. doi: 10.1016/S0016-5085(19)38100-4. [DOI] [Google Scholar]
  • [85].Lenti M V, Di Sabatino A. Intestinal fibrosis. Mol. Aspects Med. 2019;65:100–109. doi: 10.1016/j.mam.2018.10.003. [DOI] [PubMed] [Google Scholar]
  • [86].Rodansky E S, Johnson L A, Huang S, Spence J R, Higgins P D R. Intestinal organoids: A model of intestinal fibrosis for evaluating anti-fibrotic drugs. Exp. Mol. Pathol. 2015;98:346–351. doi: 10.1016/j.yexmp.2015.03.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [87].Luo M, Wang H, Wang Z H, Cai H C, Lu Z G, Li Y, Du M J, Huang G, Wang C S, Chen X, et al. A STING-activating nanovaccine for cancer immunotherapy. Nat. Nanotechnol. 2017;12:648–654. doi: 10.1038/nnano.2017.52. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [88].AbouAitah K, Hassan H A, Swiderska-Sroda A, Gohar L, Shaker O G, Wojnarowicz J, Opalinska A, Smalc-Koziorowska J, Gierlotka S, Lojkowski W. Targeted nano-drug delivery of colchicine against colon cancer cells by means of mesoporous silica nanoparticles. Cancers. 2020;12:144. doi: 10.3390/cancers12010144. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [89].Anirudhan T S, Chithra S V, Shainy F, Thomas J P. Effect of dual stimuli responsive dextran/nanocellulose polyelectrolyte complexes for chemophotothermal synergistic cancer therapy. Int. J. Biol. Macromol. 2019;135:776–789. doi: 10.1016/j.ijbiomac.2019.05.218. [DOI] [PubMed] [Google Scholar]
  • [90].Gkika D A, Magafas L, Cool P, Braet J. Balancing nanotoxicity and returns in health applications: The prisoner’s dilemma. Toxicology. 2018;393:83–89. doi: 10.1016/j.tox.2017.11.008. [DOI] [PubMed] [Google Scholar]
  • [91].Hansen S F, Lennquist A. Carbon nanotubes added to the SIN List as a nanomaterial of Very High Concern. Nat. Nanotechnol. 2020;15:3–4. doi: 10.1038/s41565-019-0613-9. [DOI] [PubMed] [Google Scholar]
  • [92].Tentler J J, Tan A C, Weekes C D, Jimeno A, Leong S, Pitts T M, Arcaroli J J, Messersmith W A, Eckhardt S G. Patient-derived tumour xenografts as models for oncology drug development. Nat. Rev. Clin. Oncol. 2012;9:338–350. doi: 10.1038/nrclinonc.2012.61. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [93].Bleijs M, van de Wetering M, Clevers H, Drost J. Xenograft and organoid model systems in cancer research. EMBO J. 2019;38:e101654. doi: 10.15252/embj.2019101654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [94].Weeber F, Ooft S N, Dijkstra K K, Voest E E. Tumor organoids as a pre-clinical cancer model for drug discovery. Cell Chem. Biol. 2017;24:1092–1100. doi: 10.1016/j.chembiol.2017.06.012. [DOI] [PubMed] [Google Scholar]
  • [95].Matano M, Date S, Shimokawa M, Takano A, Fujii M, Ohta Y, Watanabe T, Kanai T, Sato T. Modeling colorectal cancer using CRISPR-Cas9-mediated engineering of human intestinal organoids. Nat. Med. 2015;21:256–262. doi: 10.1038/nm.3802. [DOI] [PubMed] [Google Scholar]
  • [96].Fumagalli A, Drost J, Suijkerbuijk S J E, Van Boxtel R, De Ligt J, Offerhaus G J, Begthel H, Beerling E, Tan E H, Sansom O J, et al. Genetic dissection of colorectal cancer progression by orthotopic transplantation of engineered cancer organoids. Proc. Natl. Acad. Sci. USA. 2017;114:E2357–E2364. doi: 10.1073/pnas.1701219114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [97].Lukonin I, Serra D, Challet Meylan L, Volkmann K, Baaten J, Zhao R, Meeusen S, Colman K, Maurer F, Stadler M B, et al. Phenotypic landscape of intestinal organoid regeneration. Nature. 2020;586:275–280. doi: 10.1038/s41586-020-2776-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [98].Winkler D A. Role of artificial intelligence and machine learning in nanosafety. Small. 2020;16:2001883. doi: 10.1002/smll.202001883. [DOI] [PubMed] [Google Scholar]
  • [99].Monteil V, Kwon H, Prado P, Hagelkrüys A, Wimmer R A, Stahl M, Leopoldi A, Garreta E, Hurtado Del Pozo C, Prosper F, et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell. 2020;181:905–913.e7. doi: 10.1016/j.cell.2020.04.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [100].Hills R D, Pontefract B A, Mishcon H R, Black C A, Sutton S C, Theberge C R. Gut microbiome: Profound implications for diet and disease. Nutrients. 2019;11:1613. doi: 10.3390/nu11071613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [101].Ren L L, Ye J, Zhao B, Sun J B, Cao P, Yang Y. The role of intestinal microbiota in colorectal cancer. Front. Pharmacol. 2021;12:674807. doi: 10.3389/fphar.2021.674807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [102].Zheng H Z, Gu Z L, Pan Y X, Chen J, Xie Q Q, Xu S J, Gao M, Cai X M, Liu S T, Wang W L, et al. Biotransformation of rare earth oxide nanoparticles eliciting microbiota imbalance. Part. Fibre Toxicol. 2021;18:17. doi: 10.1186/s12989-021-00410-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [103].Daoud A, Múnera J O. Insights into human development and disease from human pluripotent stem cell derived intestinal organoids. Front. Med. 2019;6:297. doi: 10.3389/fmed.2019.00297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [104].Verma S, Senger S, Cherayil B J, Faherty C S. Spheres of influence: Insights into salmonella pathogenesis from intestinal organoids. Microorganisms. 2020;8:504. doi: 10.3390/microorganisms8040504. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [105].Zhang Y G, Wu S P, Xia Y L, Sun J. Salmonella-infected crypt-derived intestinal organoid culture system for host-bacterial interactions. Physiol. Rep. 2014;2:e12147. doi: 10.14814/phy2.12147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [106].Wilson S S, Tocchi A, Holly M K, Parks W C, Smith J G. A small intestinal organoid model of non-invasive enteric pathogen-epithelial cell interactions. Mucosal Immunol. 2015;8:352–361. doi: 10.1038/mi.2014.72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [107].Forbester J L, Goulding D, Vallier L, Hannan N, Hale C, Pickard D, Mukhopadhyay S, Dougan G. Interaction of Salmonella enterica serovar typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infect. Immun. 2015;83:2926–2934. doi: 10.1128/IAI.00161-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [108].Tse C M, In J G, Yin J Y, Donowitz M, Doucet M, Foulke-Abel J, Ruiz-Perez F, Nataro J P, Zachos N C, Kaper J B, et al. Enterohemorrhagic E. coli (EHEC)-secreted serine protease EspP stimulates electrogenic ion transport in human colonoid monolayers. Toxins. 2018;10:351. doi: 10.3390/toxins10090351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [109].Rajan A, Vela L, Zeng X L, Yu X M, Shroyer N, Blutt S E, Poole N M, Carlin L G, Nataro J P, Estes M K, et al. Novel segment- and host-specific patterns of enteroaggregative Escherichia coli adherence to human intestinal enteroids. mBio. 2018;9:e02419–17. doi: 10.1128/mBio.02419-17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [110].Engevik M A, Yacyshyn M B, Engevik K A, Wang J, Darien B, Hassett D J, Yacyshyn B R, Worrell R T. Human clostridium difficile infection: Altered mucus production and composition. Am. J. Physiol. Gastrointest. Liver Physiol. 2015;308:G510–G524. doi: 10.1152/ajpgi.00091.2014. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [111].Finkbeiner S R, Zeng X L, Utama B, Atmar R L, Shroyer N F, Estes M K. Stem cell-derived human intestinal organoids as an infection model for rotaviruses. mBio. 2012;3:e00159–12. doi: 10.1128/mBio.00159-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [112].Saxena K, Blutt S E, Ettayebi K, Zeng X L, Broughman J R, Crawford S E, Karandikar U C, Sastri N P, Conner M E, Opekun A R, et al. Human intestinal enteroids: A new model to study human rotavirus infection, host restriction, and pathophysiology. J. Virol. 2016;90:43–56. doi: 10.1128/JVI.01930-15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [113].Yin Y B, Bijvelds M, Dang W, Xu L, van der Eijk A A, Knipping K, Tuysuz N, Dekkers J F, Wang Y J, de Jonge J, et al. Modeling rotavirus infection and antiviral therapy using primary intestinal organoids. Antiviral Res. 2015;123:120–131. doi: 10.1016/j.antiviral.2015.09.010. [DOI] [PubMed] [Google Scholar]
  • [114].Hakim M S, Chen S R, Ding S H, Yin Y B, Ikram A, Ma X X, Wang W S, Peppelenbosch M P, Pan Q W. Basal interferon signaling and therapeutic use of interferons in controlling rotavirus infection in human intestinal cells and organoids. Sci. Rep. 2018;8:8341. doi: 10.1038/s41598-018-26784-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [115].Blutt S E, Crawford S E, Ramani S, Zou W Y, Estes M K. Engineered human gastrointestinal cultures to study the microbiome and infectious diseases. Cell. Mol. Gastroenterol. Hepatol. 2018;5:241–251. doi: 10.1016/j.jcmgh.2017.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [116].Ettayebi K, Crawford S E, Murakami K, Broughman J R, Karandikar U, Tenge V R, Neill F H, Blutt S E, Zeng X L, Qu L, et al. Replication of human noroviruses in stem cell-derived human enteroids. Science. 2016;353:1387–1393. doi: 10.1126/science.aaf5211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [117].Zhang D S, Tan M, Zhong W M, Xia M, Huang P W, Jiang X. Human intestinal organoids express histo-blood group antigens, bind norovirus VLPs, and support limited norovirus replication. Sci. Rep. 2017;7:12621. doi: 10.1038/s41598-017-12736-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [118].Heo I, Dutta D, Schaefer D A, Iakobachvili N, Artegiani B, Sachs N, Boonekamp K E, Bowden G, Hendrickx A P A, Willems R J L, et al. Modelling Cryptosporidium infection in human small intestinal and lung organoids. Nat. Microbiol. 2018;3:814–823. doi: 10.1038/s41564-018-0177-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [119].Lamers M M, Beumer J, van der Vaart J, Knoops K, Puschhof J, Breugem T I, Ravelli R B G, van Schayck J P, Mykytyn A Z, Duimel H Q, et al. SARS-CoV-2 productively infects human gut enterocytes. Science. 2020;369:50–54. doi: 10.1126/science.abc1669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [120].Zhou J, Li C, Liu X J, Chiu M C, Zhao X Y, Wang D, Wei Y X, Lee A, Zhang A J, Chu H, et al. Infection of bat and human intestinal organoids by SARS-CoV-2. Nat. Med. 2020;26:1077–1083. doi: 10.1038/s41591-020-0912-6. [DOI] [PubMed] [Google Scholar]
  • [121].Yui S, Nakamura T, Sato T, Nemoto Y, Mizutani T, Zheng X, Ichinose S, Nagaishi T, Okamoto R, Tsuchiya K, et al. Functional engraftment of colon epithelium expanded in vitro from a single adult Lgr5+ stem cell. Nat. Med. 2012;18:618–623. doi: 10.1038/nm.2695. [DOI] [PubMed] [Google Scholar]
  • [122].Fordham R P, Yui S, Hannan N R F, Soendergaard C, Madgwick A, Schweiger P J, Nielsen O H, Vallier L, Pedersen R A, Nakamura T, et al. Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell. 2013;13:734–744. doi: 10.1016/j.stem.2013.09.015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [123].Fukuda M, Mizutani T, Mochizuki W, Matsumoto T, Nozaki K, Sakamaki Y, Ichinose S, Okada Y, Tanaka T, Watanabe M, et al. Small intestinal stem cell identity is maintained with functional Paneth cells in heterotopically grafted epithelium onto the colon. Genes Dev. 2014;28:1752–1757. doi: 10.1101/gad.245233.114. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [124].Sugimoto S, Ohta Y, Fujii M, Matano M, Shimokawa M, Nanki K, Date S, Nishikori S, Nakazato Y, Nakamura T, et al. Reconstruction of the human colon epithelium in vivo. Cell Stem Cell. 2018;22:171–176. doi: 10.1016/j.stem.2017.11.012. [DOI] [PubMed] [Google Scholar]
  • [125].Jeppesen P B, Pertkiewicz M, Messing B, Iyer K, Seidner D L, O’Keefe S J D, Forbes A, Heinze H, Joelsson B. Teduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology. 2012;143:1473–1481.e3. doi: 10.1053/j.gastro.2012.09.007. [DOI] [PubMed] [Google Scholar]
  • [126].Sung J H, Yu J J, Luo D, Shuler M L, March J C. Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model. Lab Chip. 2011;11:389–392. doi: 10.1039/C0LC00273A. [DOI] [PubMed] [Google Scholar]
  • [127].Costello C M, Jia H P, Shaffiey S, Yu J J, Jain N K, Hackam D, March J C. Synthetic small intestinal scaffolds for improved studies of intestinal differentiation. Biotechnol. Bioeng. 2014;111:1222–1232. doi: 10.1002/bit.25180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [128].Finkbeiner S R, Freeman J J, Wieck M M, El-Nachef W, Altheim C H, Tsai Y H, Huang S, Dyal R, White E S, Grikscheit T C, et al. Generation of tissue-engineered small intestine using embryonic stem cell-derived human intestinal organoids. Biol. Open. 2015;4:1462–1472. doi: 10.1242/bio.013235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [129].Yan N, Hu B, Xu J C, Cai R, Liu Z H, Fu D P, Huo B B, Liu Z H, Zhao Y L, Chen C Y, et al. Stem cell Janus patch for periodontal regeneration. Nano Today. 2022;42:101336. doi: 10.1016/j.nantod.2021.101336. [DOI] [Google Scholar]
  • [130].Gjorevski N, Nikolaev M, Brown T E, Mitrofanova O, Brandenberg N, DelRio F W, Yavitt F M, Liberali P, Anseth K S, Lutolf M P. Tissue geometry drives deterministic organoid patterning. Science. 2022;375:eaaw9021. doi: 10.1126/science.aaw9021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [131].Nikolaev M, Mitrofanova O, Broguiere N, Geraldo S, Dutta D, Tabata Y, Elci B, Brandenberg N, Kolotuev I, Gjorevski N, et al. Homeostatic mini-intestines through scaffold-guided organoid morphogenesis. Nature. 2020;585:574–578. doi: 10.1038/s41586-020-2724-8. [DOI] [PubMed] [Google Scholar]
  • [132].Shaffiey S A, Jia H P, Keane T, Costello C, Wasserman D, Quidgley M, Dziki J, Badylak S, Sodhi C P, March J C, et al. Intestinal stem cell growth and differentiation on a tubular scaffold with evaluation in small and large animals. Regen. Med. 2016;11:45–61. doi: 10.2217/rme.15.70. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [133].Lindemans C A, Calafiore M, Mertelsmann A M, O’Connor M H, Dudakov J A, Jenq R R, Velardi E, Young L F, Smith O M, Lawrence G, et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature. 2015;528:560–564. doi: 10.1038/nature16460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [134].Workman M J, Mahe M M, Trisno S, Poling H M, Watson C L, Sundaram N, Chang C F, Schiesser J, Aubert P, Stanley E G, et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Nat. Med. 2017;23:49–59. doi: 10.1038/nm.4233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [135].Yu L, Tian X, Gao D X, Lang Y, Zhang X X, Yang C, Gu M M, Shi J M, Zhou P K, Shang Z F. Oral administration of hydroxylated-graphene quantum dots induces intestinal injury accompanying the loss of intestinal stem cells and proliferative progenitor cells. Nanotoxicology. 2019;13:1409–1421. doi: 10.1080/17435390.2019.1668068. [DOI] [PubMed] [Google Scholar]

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