Modelling metabolic diseases and drug response using stem cells and organoids

Abstract

Metabolic diseases, including obesity, diabetes mellitus and cardiovascular disease, are a major threat to health in the modern world, but efforts to understand the underlying mechanisms and develop rational treatments are limited by the lack of appropriate human model systems. Notably, advances in stem cell and organoid technology allow the generation of cellular models that replicate the histological, molecular and physiological properties of human organs. Combined with marked improvements in gene editing tools, human stem cells and organoids provide unprecedented systems for studying mechanisms of metabolic diseases. Here, we review progress made over the past decade in the generation and use of stem cell-derived metabolic cell types and organoids in metabolic disease research, especially obesity and liver diseases. In particular, we discuss the limitations of animal models and the advantages of stem cells and organoids, including their application to metabolic diseases. We also discuss mechanisms of drug action, understanding the efficacy and toxicity of existing therapies, screening for new treatments and pursuing personalized therapies. We highlight the potential of combining stem cell-derived organoids with gene editing and functional genomics to revolutionize the approach to finding treatments for metabolic diseases.

Fig. 1. Development of pluripotent stem cell-derived adipocyte models and generation of 3D adipose culture systems.

a | Different methodologies can be used to guide the differentiation of white or brown adipocytes from human pluripotent stem cells^,,. b | Adipose tissue stromal vascular fraction (SVF) can be cultured in hang drop or low-attachment plates to grow as spheroids. Moreover, when embedded in Matrigel, SVF cells can develop into vascularized adipose organoids or immune cell-contained adipose organoids under optimal culture conditions^,,. Furthermore, tissue engineering, bioprinting and organ-on-chip technology can help create more complex and mature adipose organoids that facilitate the study of adipose development, diseases and crosstalk with other organs^–. BAT, brown adipose tissue; hPSC, human pluripotent stem cell; MPC, mesenchymal progenitor cell.

Fig. 2. Generation of liver organoids from liver progenitor cells, primary hepatocytes, fibroblasts or human pluripotent stem cells.

a | Liver organoids established from LGR5⁺ or EpCAM⁺ bipotent liver progenitor cells^, or directly from primary hepatocytes^, or from fibroblasts. b | Various liver organoid models can be generated from pluripotent stem cells under different culture conditions. These models include liver buds^,, hepatic organoids, cholangiocyte organoids^–, hepatobiliary organoids^–, multicellular liver organoids^, and hepato–biliary–pancreatic organoids, in order of increasing structural and functional complexity. ESC, embryonic stem cell; iPSC, induced pluripotent stem cell.

Fig. 3. Applications of organoids in metabolic research.

a | Liver organoids can be used to model many liver diseases, such as inherited liver diseases and non-alcoholic fatty liver disease (NAFLD), as well as virus–host interactions. Adipose organoids provide a platform to study adipogenesis, lipogenesis, lipolysis and the adipose tissue response to insulin. b | The establishment of a large cohort of organoids can serve as a biobank for use in precision medicine. c | Reproducible and scalable organoids allow high-throughput drug screening. d | Organoids can be used to predict drug toxicity. e | Drug responses in human organoids can be measured based on the structure, gene profile and metabolic properties of organoids. f | Patient-derived organoids exhibit great power in predicting individual-specific drug responses.

Fig. 4. Regenerative medicine for metabolic disease.

a | Rescue of disease-relevant organoids using CRISPR–Cas9 or other gene-editing tools, and autologous transplantation of gene-edited organoids into individuals with metabolic diseases. b | The establishment of HLA-matched induced pluripotent stem cells (iPSCs) can be utilized to restrict immune rejection of transplanted allogeneic organoids. c | Transplantation of iPSC-derived brown adipocytes to treat individuals with obesity by enhancing energy expenditure.