A circuit of mechanically regulated transcription factors balances regenerative and fibrotic memory of mesenchymal stromal cells [ATAC-Seq]

The promoters of genes that were highly accessible and upregulated upon soft priming and memorized after switch to stiff substrates were significantly enriched for motifs predicted to bind the transcription factor HOXA11. Knockdown of HOXA11 resulted in enhanced expression of fibrogenic and osteogenic genes in soft-primed MSCs and reduced expression of anti-fibrotic factors, including the transcription factor SALLl1. SALL1 is a potent suppressor of pro-fibrotic genes such as Postn, Col8a1, Grem2, Thps1 and Thps2, and the transcription factor Gata6.

GATA6, in turn, emerges as a keeper of stiff-induced myofibroblast memory by maintaining the accessibility of pro-fibrotic genes even after switch to soft substrates. By manipulating the SALL1-GATA6 transcriptional circuit in culture, we produced therapeutic MSCs that suppress fibrosis in an animal model of hypertrophic skin scarring. We propose that similar control over myofibroblast memory will enhance the success of therapeutic MSC applications in organ repair.