Scientists Break Barriers to Regenerating Damaged Heart Tissue

Adult heart muscle cells have evolved an extraordinary stability: they are built for efficiency and endurance, not rapid rewiring. This is a major obstacle for regenerative strategies, because after myocardial injury the adult heart cannot heal itself as readily as skin. Even when researchers try to reprogram one cell state into another, mature cardiac cells resist the molecular transitions required to change identity.

A study from Sanford Burnham Prebys Medical Discovery Institute and collaborators at Johns Hopkins University identifies a previously unrecognized layer of protection. The work centers on glycosylation-related enzymes—specifically carbohydrate sulfotransferases—that modify proteins with sugar groups. Among them, CHST7 emerged as a particularly strong barrier to therapeutic reprogramming in both mouse and human cells.

Mechanistically, CHST7 prevents reprogramming by boosting signaling at the plasma membrane through the receptor CD44. In engineered cells with elevated CHST7 but lacking CD44, reprogramming became markedly more effective, indicating that CD44 is a necessary conduit for CHST7’s inhibitory effect rather than an unrelated marker.

The downstream consequences involve the transcription factor JUNB. Enhanced CD44-driven messaging shifts JUNB levels and alters how JUNB binds chromatin, thereby reinforcing native gene-expression programs that preserve cell fate. In this framework, CHST7 does not simply block a single switch—it reshapes the regulatory landscape that determines which genes can be activated.

Using combined RNA sequencing and chromatin accessibility profiling, the researchers showed that CHST7 acts through CD44 and JUNB to control where transcriptional regulators can access DNA. By tuning chromatin accessibility, the pathway supports identity-stabilizing regions while locking down loci that would otherwise permit lineage change.

Notably, regions associated with the cardiac reprogramming factor MEF2C were among those constrained, aligning the molecular findings with the functional reprogramming outcomes. “Where” the genome is permissive—and “where” it is closed—became the central theme of the study.

The team then searched for additional nodes that influence these identity-stabilizing circuits. Their target was PIP4K2C, an enzyme implicated in lipid signaling dynamics. When they combined PIP4K2C inhibition with reprogramming initiation in mouse hearts, outcomes substantially improved compared with reprogramming alone.

One month after heart attack, the combination therapy produced substantially higher cardiac pumping, highlighting that removing barriers can convert an otherwise partial response into a more durable therapeutic effect. The results suggest that durable cardiac repair may require both a reprogramming trigger and a strategy to neutralize identity-constraining signaling.