Genome engineering of stem cell organoids for disease modeling

Abstract

Precision medicine emerges as a new approach that takes into account individual variability. Successful realization of precision medicine requires disease models that are able to incorporate personalized disease information and recapitulate disease development processes at the molecular, cellular and organ levels. With recent development in stem cell field, a variety of tissue organoids can be derived from patient specific pluripotent stem cells and adult stem cells. In combination with the state-of-the-art genome editing tools, organoids can be further engineered to mimic disease-relevant genetic and epigenetic status of a patient. This has therefore enabled a rapid expansion of sophisticated in vitro disease models, offering a unique system for fundamental and biomedical research as well as the development of personalized medicine. Here we summarize some of the latest advances and future perspectives in engineering stem cell organoids for human disease modeling.

Keywords: genome editing; pluripotent/adult stem cell; precision medicine; tissue organoid.

Figure 1

Applications of genome engineering in disease modeling. With genome editing tools, stem cell lines from patients can be efficiently “cured” to correct the disease relevant genetic variants; or wild-type stem cells can also be introduced with genetic variants to create “patient” cell lines for disease modeling (A). Catalytically dead nucleases, such as deactivated Cas9 (dCas9), can be fused to different functional effectors and carry out molecular functions other than genome editing (B). High-throughput genetic screenings can be developed using genome editing tools to illuminate genes or signaling pathways involved in disease development (C)

Figure 2

Applications of organoid technology in basic and translational research. Tissue organoids can be derived from patient iPSCs or ASCs. The in vitro development of organoids offers a cellular system for studying the contribution of various signaling pathways in human tissue development and homeostasis. Established organoids can be used as a model system to study infectious diseases or tissue specific responses to toxins. Organoids with patient-specific disease information can also be generated for pathophysiology study, and can be expanded in a large scale for discovery of personalized treatment through high-throughput screenings (A). Biobanks with organoids generated from human populations are being established, which will provide high valuable resources that can be used to carry out preclinical efficacy and toxicity test of candidate drugs, screen for diagnostic and prognostic factors, and delineate genotype-phenotype causality in conjunction with current genetic studies (e.g. GWAS) (B). Complemented with advances in bioengineering approaches, “organs-on-a-chip” can be built up containing multiple tissues that can offer an efficient system for drug discovery and study of more complex physiological processes, such as human nutriology (C)