Keidai Yamato, Fujikura Junji, Yabe Daisuke
Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Diabetes and Endocrinology, Medical Research Institute Kitano Hospital, PIIF Tazuke-Kofukai, Osaka, Japan.
Cell Transplant. 2025 Jan-Dec;34:9636897251346599. doi: 10.1177/09636897251346599. Epub 2025 Jun 19.
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.
脂肪细胞功能障碍在包括2型糖尿病（T2D）在内的代谢性疾病发病机制中起关键作用。人诱导多能干细胞（hiPSC）为生成白色、米色和棕色脂肪细胞提供了一个强大平台，有助于疾病建模和治疗研究。本综述全面总结了目前从多能干细胞（PSC）产生三种功能成熟脂肪细胞类型的分化方法，包括强制基因表达技术、受发育生物学启发的方法以及增强细胞成熟度和功能相关性的先进三维（3D）培养系统。PSC来源的白色脂肪细胞不仅有助于在胰岛素抵抗、脂肪营养不良和早衰等情况下模拟脂肪细胞功能障碍，还能在包括T2D在内的更复杂代谢疾病中发挥作用，促进疾病机制研究和新型治疗靶点的识别。此外，基于iPSC的模型为通过群体遗传学探索全基因组关联研究（GWAS）确定的变异的遗传调控提供了一个强大平台。本综述还评估了iPSC来源的白色、米色和棕色脂肪细胞在代谢性疾病细胞移植治疗中的治疗潜力，重点关注植入潜力和代谢改善。提高PSC来源脂肪细胞的成熟度和亚型特异性有望加速代谢性疾病个性化医学和创新治疗策略的发展。
