Transdifferentiation

Transdifferentiation, also called direct lineage conversion, is the process by which a mature somatic cell switches from one differentiated identity to another without passing through a pluripotent state. This contrasts with reprogramming to induced pluripotent stem cells. Transdifferentiation can occur in culture or in living tissue and is usually achieved by forcing lineage-determining transcription factors, microRNAs, or epigenetic modifiers to rewire gene networks.

Classical examples include converting B cells to macrophages via C/EBPα; and direct reprogramming of fibroblasts to induced cardiomyocytes using GATA4, MEF2C, TBX5. Neuronal conversions have been achieved by delivering ASCL1, BRN2 and MYT1L to fibroblasts to produce induced neurons, with microRNAs such as miR-124 further enhancing efficiency and maturation. In vivo, astrocytes have been reprogrammed into neurons in mouse models using NeuroD1, among other factors, suggesting potential for tissue repair.

Mechanistically, transdifferentiation rewires a cell's regulatory network, often requiring chromatin remodeling and epigenetic changes to suppress the original program and activate a new lineage program. The resulting cells may be heterogeneous and only partially mature; efficiency is typically low and protocol-dependent.

Applications include regenerative medicine and disease modeling, with ongoing research to improve fidelity, safety, and scalability. Challenges include ensuring stable identity, preventing unintended cell fates, and avoiding genetic or epigenetic abnormalities.