Drug Discovery via Human-Derived Stem Cell Organoids - PubMed (original) (raw)

Review

Drug Discovery via Human-Derived Stem Cell Organoids

Fangkun Liu et al. Front Pharmacol. 2016.

Abstract

Patient-derived cell lines and animal models have proven invaluable for the understanding of human intestinal diseases and for drug development although both inherently comprise disadvantages and caveats. Many genetically determined intestinal diseases occur in specific tissue microenvironments that are not adequately modeled by monolayer cell culture. Likewise, animal models incompletely recapitulate the complex pathologies of intestinal diseases of humans and fall short in predicting the effects of candidate drugs. Patient-derived stem cell organoids are new and effective models for the development of novel targeted therapies. With the use of intestinal organoids from patients with inherited diseases, the potency and toxicity of drug candidates can be evaluated better. Moreover, owing to the novel clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 genome-editing technologies, researchers can use organoids to precisely modulate human genetic status and identify pathogenesis-related genes of intestinal diseases. Therefore, here we discuss how patient-derived organoids should be grown and how advanced genome-editing tools may be applied to research on modeling of cancer and infectious diseases. We also highlight practical applications of organoids ranging from basic studies to drug screening and precision medicine.

Keywords: inflammatory bowel disease; intestinal cancer; organoid; pluripotent stem cells.

PubMed Disclaimer

Figures

FIGURE 1

FIGURE 1

The epithelial innate immune response and its effect on epithelial homeostasis, regeneration, inflammation, and gastric carcinogenesis after activation of inflammation by a pathogen. Epithelial cells can express pathogen recognition receptors to pass microbial signals (Nigro et al., 2014; Amieva and Peek, 2016) and generate various peptides against infection and prevent a strong T-cell-mediated immune response (Farin et al., 2014; Leslie et al., 2015); IEC-produced cytokines and dendritic cells can promote T-cell maturation and differentiation (Liu Y. et al., 2015); innate lymphoid cells can produce IL-22 and then regulate ISC survival and proliferation (Bermudez-Brito et al., 2013; Lindemans et al., 2015).

FIGURE 2

FIGURE 2

Schematic diagram of mini-gut culture and application to stem cell transplantation. The image shows organoid development from isolated crypts to round spheres and budding organoids. After the cultured and dissociated organoids are transplanted into animal models or human bodies, they spontaneously move toward the damaged focus of the DSS-colitis ulcer and promote reconstruction of the epithelial structure.

Similar articles

Cited by

References

    1. Amieva M., Peek R. M., Jr. (2016). Pathobiology of Helicobacter pylori-induced gastric cancer. Gastroenterology 150 64–78. 10.1053/j.gastro.2015.09.004 - DOI - PMC - PubMed
    1. Andersson-Rolf A., Fink J., Mustata R. C., Koo B. K. (2014). A video protocol of retroviral infection in primary intestinal organoid culture. J. Vis. Exp. 90:e51765 10.3791/51765 - DOI - PMC - PubMed
    1. Ayabe T., Satchell D. P., Wilson C. L., Parks W. C., Selsted M. E., Ouellette A. J. (2000). Secretion of microbicidal alpha-defensins by intestinal Paneth cells in response to bacteria. Nat. Immunol. 1 113–118. 10.1038/77783 - DOI - PubMed
    1. Barker N., Huch M., Kujala P., Van De Wetering M., Snippert H. J., Van Es J. H., et al. (2010). Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro. Cell Stem Cell 6 25–36. 10.1016/j.stem.2009.11.013 - DOI - PubMed
    1. Bartfeld S., Bayram T., Van De Wetering M., Huch M., Begthel H., Kujala P., et al. (2015). In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology 148:e126 10.1053/j.gastro.2014.09.042 - DOI - PMC - PubMed

Publication types

LinkOut - more resources