Mesenchymal tissue, including bone, fat, cartilage, muscle, and nerve, plays a critical role in the body's structural and functional integrity. However, these tissues often face significant challenges in terms of repair and regeneration following injury or disease. While surgical treatments are common, postoperative recovery often falls short of expectations. The use of mesenchymal stem cells (MSCs) as an approach to cell therapy has its own downsides, with cells sometimes failing to differentiate into the desired cell type, leading to a dysfunctional tissue construct. Increasing evidence highlights that epithelial-to-mesenchymal transition transcription factors (EMT-TFs)—ZEB, SNAI, and TWIST—play crucial roles not only in embryonic development and cancer progression but also in wound healing [1].

There is growing evidence indicating the regulatory roles of ZEB, SNAI, and TWIST in mesenchymal tissue regeneration, such as osteogenesis [2], [3], [4], adipogenesis [5], [6], [7], chondrogenesis [8], [9], [10], myogenesis [11], [12], [13], and neurogenesis [14]. Despite many reviews summarizing the role of EMT-TFs in tumor development [15], tissue repair, and fibrosis [16], there is a lack of comprehensive and systematic reviews focusing on the effects of EMT-TFs on mesenchymal tissue regeneration and elucidation of underlying molecular mechanisms.

This review aims to address this gap by summarizing the roles of the ZEB, SNAI, and TWIST families in mesenchymal tissue regeneration, including but not limited to bone, adipose tissue, cartilage, muscle, and nerve regeneration. This review presents an overview of the differential expression of EMT-TFs under normal and pathological conditions in humans, with a particular emphasis on their precise regulatory roles in cell survival. Moreover, this paper provides a comprehensive analysis of how EMT-TFs influence the multi-differentiation potential of various cell types involved in mesenchymal tissue regeneration. Furthermore, the molecular mechanisms underlying tissue regeneration are summarized to enhance understanding of how EMT-TFs regulate cellular functions. Finally, potential links between these factors and future perspectives are discussed. The goal of this review is to highlight the role of EMT-TFs in mesenchymal tissue regeneration, potentially paving the way for cell therapy strategies in tissue engineering and regenerative medicine.