Dedifferentiation of Mature Adipocytes and Their Future Potential for Regenerative Medicine Applications

Background/Objectives: Mature adipocytes were previously regarded as terminally differentiated cells that are restricted to lipid storage. Recent studies have shown that they can dedifferentiate into fibroblast-like progenitor cells, termed dedifferentiated fat (DFAT) cells. These cells exhibit stem cell-like properties and multilineage potential, highlighting their promising role in regenerative medicine and disease pathology. This systematic review aims to explore and consolidate the evidence regarding mechanisms, culture methods, pathophysiological roles, and therapeutic potential of adipocyte dedifferentiation. Methods: A systematic review was conducted in PubMed using the terms "dedifferentiation", "de-differentiation", "transdifferentiation", and related variants in combination with "adipocyte". Studies were screened and selected according to the PRISMA 2020 guidelines. Non-English articles, non-full texts, and non-review papers were excluded. After duplicate removal and eligibility assessment, 53 studies were included. Further, these were classified into categories according to their abstracts. Results: The evidence from the included articles indicates that mature adipocytes can dedifferentiate both in vitro, via ceiling culture, and in vivo, yielding DFAT cells with proliferative and multilineage differentiation capacity. Dedifferentiation involves lipid droplet secretion (liposecretion) and is characterized by downregulation of adipogenic genes such as PPARG and C/EBP alpha, alongside upregulation of proliferation, stemness, and lineage-associated markers. Functionally, DFAT cells contribute positively to tissue regeneration and wound repair, but they can drive adverse outcomes such as fibrosis, insulin resistance, and tumor progression through signaling pathways, including Wnt/beta-catenin and TGF-beta. Conclusions: Mature adipocyte dedifferentiation marks a dynamic reprogramming mechanism with dual roles-beneficial in regenerative medicine and wound healing, yet detrimental in cancer and metabolic disease. Further research is required to identify in vivo regulators, establish definitive markers, and translate adipocyte plasticity into regenerative medicine applications.