AbstractLiver is one of the few organs with immense regenerative potential even at adulthood in mammals. It is composed of primarily two cell types: hepatocytes and cholangiocytes, that can trans-differentiate to one another either directly or through intermediate progenitor states, contributing to remarkable regenerative potential of the liver. However, the dynamical features of decision-making between these cell-fates during liver development and regeneration remains elusive. Here, we identify a core gene regulatory network comprising c/EBPα, TGFBR2 and SOX9 that underlies liver development and injury-induced reprogramming. Dynamic simulations for this network reveal its multistable nature, enabling three distinct cell states – hepatocytes, cholangiocytes and liver progenitor cells (hepatoblasts/oval cells) – and stochastic switching among them. Predicted expression signature for these three states are validated through multiple bulk and single-cell transcriptomic datasets collected across developmental stages and injury-induced liver repair. This network can also explain the experimentally observed spatial organisation of phenotypes in liver parenchyma and predict strategies for efficient cellular reprogramming among these cell-fates. Our analysis elucidates how the emergent multistable dynamics of underlying gene regulatory networks drive diverse cell-state decisions in liver development and regeneration.
High-Dimensional ODEs Coupled With Mixed-Effects Modeling Techniques for Dynamic Gene Regulatory Network Identification