Application of human iPSC-derived white, beige, and brown adipocytes for metabolic disease modeling and transplantation therapy

Abstract

Adipocyte dysfunction plays a critical role in the pathogenesis of metabolic diseases, including type 2 diabetes (T2D). Human induced pluripotent stem cells (hiPSCs) offer a powerful platform for generating white, beige, and brown adipocytes, supporting both disease modeling and therapeutic research. This review provides a comprehensive summary of current differentiation methods to produce three functionally mature adipocyte types from pluripotent stem cells (PSCs), including forced gene expression techniques, developmental biology-inspired approaches, and advanced three-dimensional (3D) culture systems that enhance cellular maturity and functional relevance. PSC-derived white adipocytes contribute to modeling adipocyte dysfunction not only in conditions such as insulin resistance, lipodystrophy, and premature aging but also in more complex metabolic diseases, including T2D, facilitating the investigation of disease mechanisms and the identification of novel therapeutic targets. In addition, iPSC-based models provide a robust platform for exploring genetic regulation by genome-wide association studies (GWAS)-identified variants through population genetics. This review also evaluates the therapeutic potential of iPSC-derived white, beige, and brown adipocytes in cell transplantation therapy for metabolic diseases, with a focus on engraftment potential and metabolic improvement. Enhancing the maturity and subtype specificity of PSC-derived adipocytes is expected to accelerate the development of personalized medicine and innovative therapeutic strategies for metabolic diseases.

Keywords: beige adipocytes; brown adipocytes; pluripotent stem cells; transplantation; white adipocytes.

Graphical Abstract

Figure 1.

Differentiation methods of PSC-derived adipocytes: white, beige, and brown lineages. This figure illustrates the various methodologies for differentiating pluripotent stem cells (PSCs) into white, beige, and brown adipocytes via distinct intermediate stages and culture conditions. Dashed arrows denote suspension culture, while solid arrows indicate adherent culture methods. Adipocyte types are color-coded: yellow for white adipocytes, light brown for beige adipocytes, and dark brown for brown adipocytes. ESC: embryonic stem cells; iPSC: induced pluripotent stem cells; MPC: mesenchymal progenitor cells; WAP: white adipocyte progenitor; BAP: brown adipocyte progenitor; RA: retinoic acid; MSC: mesenchymal stem cells. Created with BioRender.com.