Mechanisms driving in vivo transdifferentiation The extent to which differentiated cells, while remaining in their native microenvironment, can be reprogrammed to assume a different identity will reveal fundamental insight into cellular plasticity and impact regenerative medicine. To investigate in vivo cell lineage potential, we leveraged the zebrafish as a practical vertebrate platform to determine factors and mechanisms necessary to induce differentiated cells of one germ layer to adopt the lineage of another. We found that ectopic co-expression of Sox32 and Oct4 in several non-endoderm lineages, including skeletal muscle cells, can specifically trigger an early endoderm genetic program. Endoderm-induced muscle cells rapidly lose muscle gene expression and morphology, while specifically gaining endoderm organ lineage markers via a mechanism resembling normal development. Further, muscle lineage conversion is independent of a dedifferentiation or a pluripotency mechanism, suggesting that reprogramming occurs via direct transdifferentiation. However, inhibition of the skeletal muscle master regulator Myod and activation of the cell recycling process autophagy are necessary for, and can enhance, the earliest events in muscle cell reprogramming, revealing that active repression of muscle identity is critical for the initiation of lineage conversion. Importantly, examination of other models of direct lineage conversion, such as induced neurons, cardiomyocytes, and pancreatic endocrine cells, reveal that autophagy is fundamental for transdifferentiation. Our work demonstrates that within a vertebrate animal, differentiated cells can be induced to directly adopt the identity of a completely unrelated cell lineage, while remaining in a distinct microenvironment, suggesting that differentiated cells in vivo may be more amenable to lineage conversion than previously appreciated. Furthermore, our mechanistic studies suggest stimulating the loss of a cell’s identity, both its transcriptome and proteome, to be a novel strategy for increasing the efficiency and efficacy of induced transdifferentiation.
Sanford Burnham Prebys Medical Discovery Institute
You must be logged in and own this session in order to