Drug Discovery via Human-Derived Stem Cell Organoids

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.

The pathogenesis of mucositis: updated perspectives and emerging targets

“…Human cell, three-dimensional, tissue models of oral mucosa [83][84][85][86], and the role of co-culturing with microbial biofilm [7] provide a more comprehensive interaction of factors related to radiation-induced oral mucositis pathogenesis. Finally, intestinal organoids; crypt structures formed by stem cells from either human or mice, can be genetically manipulated for expression of factors important in mucositis pathogenesis [87][88][89]. It is expected that these approaches will overcome the reliance on monoculture models and rodents which been used in the past and provide an incomplete view of dynamic interactions between tissues during mucositis development, or lack translatability between animal and human settings, respectively.…”

Organoid-derived Duodenum Intestine-Chip for preclinical drug assessment in a human relevant system

“…A promising alternative to conventional cell monolayer systems emerged with the establishment of the protocols for generation of three-dimensional intestinal organoids (or enteroids) from human biopsy specimens [19][20][21][22] . Using these methods, organoids derived from all regions of the intestinal tract can be established 21,23 and applied into different areas of research including organ development, disease modeling, and regenerative medicine 24 .…”

Enteroids for Nutritional Studies

“…Nevertheless, primary cells and ex vivo xenografts often have quite a short lifespan, leading to practical difficulties in nutritional research. Animal models are considered to be the gold standard for in vivo studies, however, they do not reflect the genetic and clinical features of the human tissues . Therefore, there is an urgent need for a proper model to represent the human intestinal epithelial cells for nutritional studies.…”