Inhibiting the Ability of Cells to Resist Reprogramming Improves Transdifferentiation Therapy
Researchers here discuss an interesting approach to transdifferentiation as a basis for therapy. In transdifferention, a cell of one type is reprogrammed to become another type directly, without passing through an intermediary stage of dedifferentiation to pluripotency. There has long been interest in directly converting scar tissue cells into heart muscle cells following a heart attack or similar injury, as animal studies have been promising. How do cells hold on to their state and resist a change of cell identity, however? If the mechanisms holding cell state firm can be identified and inhibited, then cells can be more readily changed into other cell types. That is demonstrated here in heart tissue, a novel approach to the challenge of enhancing regeneration in this normally poorly regenerative organ.
Defining the mechanisms safeguarding cell fate identity in differentiated cells is crucial to improve 1) our understanding of how differentiation is maintained in healthy tissues or altered in a disease state, and 2) our ability to use cell fate reprogramming for regenerative purposes. Here, using a genome-wide transcription factor screen followed by validation steps in a variety of reprogramming assays (cardiac, neural and iPSC in fibroblasts and endothelial cells), we identified a set of four transcription factors (ATF7IP, JUNB, SP7, and ZNF207, collective AJSZ) that robustly opposes cell fate reprogramming in both lineage and cell type independent manners.
Mechanistically, our approach revealed that AJSZ oppose cell fate reprogramming by 1) maintaining chromatin enriched for reprogramming transcription factor motifs in a closed state and 2) downregulating genes required for reprogramming. Finally, knockdown of AJSZ in combination with overexpression of cardiac reprogramming factors Mef2c, Gata4, and Tbx5, collectively MGT, significantly reduced scar size and improved heart function by 50%, by reprogramming fibroblasts into cardiomyocytes, as compared to MGT alone post-myocardial infarction.
Collectively, our study suggests that inhibition of barrier to reprogramming mechanisms represents a promising therapeutic avenue to improve adult organ function post-injury.