JNK1 downregulation confers fibroblasts with a mammary epithelial cell fate

Abstract

The fate of cells is determined by their specific transcription patterns. Previously, we demonstrated that chemical cocktails, including the single small molecule TGFβR1 inhibitor RepSox, can induce changes in transcription patterns and drive somatic cells to reprogram into chemically induced mammary epithelial cells (CiMECs) by downregulating TGFβR1 expression. However, the underlying mechanism of chemical induction for reprogramming remains unclear. Here, we employed single-cell sequencing (scRNA-seq and scATAC-seq) to uncover RepSox-induced reprogramming events and molecular trajectories and clarify the similarities and differences to the iMECs generated by chemical cocktails induction. Importantly, we found that JNK1 expression, a downstream gene of TGFβR1 signaling pathway, plays a critical role in iMEC conversion as its downregulation induces iMEC generation. Thus, the TGFβR1-JNK1 signaling may regulate fibroblast-to-mammary epithelial cell cell fate decision. These findings provide valuable insights into the mechanisms governing mammary epithelial cell fate decisions and may pave the way for developing novel strategies to generate a large number of milk-secreting mammary cells in vitro and facilitate mammary gland regeneration in vivo.