Lateral confined growth of cells activates Lef1 dependent pathways to regulate cell-state transitions.

Abstract

Cells naturally undergo differentiation, trans-differentiation and dedifferentiation within in vivo systems during embryonic development, tissue repair, and cancer progression. In recent work, we showed that laterally confined growth of fibroblasts induces dedifferentiation programs. However, the underlying molecular mechanisms are poorly understood. In this study, we identify Lef1 as a critical somatic transcription factor for this lateral confinement induced de-differentiation pathway. Network optimization methods applied to time-lapse RNA-seq data identify Lef1 dependent signalling as potential regulators of such cell-state transitions. We show that Lef1 knockdown results in the down-regulation of fibroblast de-differentiation and that Lef1 directly interacts with the promoter regions of downstream reprogramming factors. We also evaluate the potential upstream activation pathways of Lef1, thereby identifying that Smad4 and Atf2 may be critical for Lef1 activation. In addition, we found that actomyosin pathways regulate the dedifferentiation progression. Collectively, we describe an important mechanotransduction pathway, including Lef1, which upon activation, through progressive lateral cell confinement, results in fibroblast de-differentiation.