The in vitro generation of clinically relevant cells, such as neurons, cardiomyocytes, and hepatocytes, offers potential for regenerative therapy and permits disease modeling, toxicology testing and drug discovery. Current strategies aim to engineer cell fate by means of directed differentiation from a pluripotent state or by transcription factor-driven conversion between differentiated states. Directed differentiation protocols typically involve multiple steps, can be laborious, and commonly yield immature cells corresponding to embryonic stages of development rather than fully mature adult cells. In contrast, direct conversion is relatively straightforward and rapid but there is evidence for incomplete conversion, especially between divergent cell types.

Using a network biology approach, we recently found that cells generated by direct conversion do not faithfully recapitulate the target cell type. Original cell identity was not extinguished and the converted cells did not resemble fully mature cell types. Employing induced hepatocytes (iHeps) generated from fibroblasts as a prototypical conversion, our computational and functional analyses showed that iHeps behave as embryonic progenitors with the potential to functionally engraft both the liver and colon. We found that these engineered cells resembled mature colonic epithelium only after transplantation into the colon niche.

Our research focuses on the study of gene regulatory networks to dissect and engineer cell fate of clinically relevant tissues such as the liver. First, we aim to understand how transcription factor overexpression drives changes in the transcriptional program to remodel cell identity, and how we can exploit this to derive desired cell types. Second, we transplant engineered cells into the in vivo niche, tracking their maturation in order to understand the steps required to fully differentiate cells in vitro. Finally, we employ single cell transcriptomics to understand how cell fate is specified in the developing embryo, formulating a blueprint of cell identity to help engineer fate in vitro. Ultimately, we wish to translate new insights in cell fate specification into better human models of liver disease and eventually into the development of novel therapeutic strategies.

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