ReviewEngineering cell fate: Spotlight on cell-activation and signaling-directed lineage conversion

- Transient expression of pluripotency reprogramming factors induces a plastic state in somatic cells.
- Pluripotency factors can be used to convert one cell type into another.
- Environmental signals direct plastic or primed cells into the desired cell type.
- Specific small-molecules can induce a plastic state in somatic cells.
- Cell-activation and signaling-directed transdifferentiation can convert derivatives of one germ layer into another.

Direct reprogramming of specialized cells into other cell types has revolutionized the fields of stem cell, differentiation, and regenerative medicine. Direct reprogramming technology can convert various differentiated cell types to other fates by the forced expression of lineage-specific transcription factors. In addition to this approach, transdifferentiation can be induced in somatic cells by a method named cell-activation and signaling-directed (CASD) lineage conversion, which uses pluripotency reprogramming factors in combination with specific differentiation signals. This approach is capable of generating tissue-specific progenitors in addition to functional mature cells through a challenging transitory (pluripotent or non-pluripotent) state. Interestingly, the CASD lineage conversion has been accomplished by using small molecules and growth factors in a chemical-only paradigm. This approach will have a substantial positive impact on the field and bring reprogramming technology into the translational pipeline. From the regenerative medicine perspective, in future, new therapies might be designed based on the patient's own cells that are directly reprogrammed into the desired cell types in vitro and in situ. This review provides an overview of direct reprogramming to different lineages and describes what is known about the cell-activation and signaling-directed transdifferentiation.