New mechanism reveals how heart cells resist regenerative reprogramming

Specialized cells in the human body make biological trade-offs to perform certain jobs. To support the large, hardworking hearts that power other organs, heart cells have evolved to be extremely efficient and resilient. Because the adult human heart cannot repair itself the way skin does, scientists have studied ways to “reprogram” heart cells to regenerate after heart attacks. Heart cells have very stable identities, however, and are resistant to reprogramming.

Scientists at Sanford Burnham Prebys Medical Discovery Institute and collaborators at Johns Hopkins University School of Medicine published findings in Nature Communications that cover a new mechanism cells use to protect their identities and ward off reprogramming attempts. Continued study of the obstacles to cellular reprogramming may lead to treatments that can help the heart repair itself after injury.

Sugar-linked proteins emerge as barriers

Prior research had pointed the scientists to a type of protein heavily decorated with sugar molecules, a process known as glycosylation. Tests of these sugar-bearing proteins found that a family of proteoglycan-modifying proteins called carbohydrate sulfotransferases was a previously unrecognized class of reprogramming barriers.

“Carbohydrate sulfotransferase 7, or CHST7, emerged from our experiments as the most potent preventer of reprogramming in mouse and human cells,” said Alexandre Colas, associate professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys.

CD44 helps enforce cell identity

Additional investigation demonstrated that CHST7 rebuffed cellular reprogramming by increasing signaling governed by the cell membrane receptor CD44. In cells genetically edited to produce extra CHST7 and no CD44 receptors, the research team’s reprogramming treatment was 47% more efficient than it was in cells with extra CHST7 and normal CD44.

“These findings support a model in which CD44 is required for CHST7 to block cellular reprogramming,” said Colas, the senior and corresponding author of the manuscript.

The scientists found that CD44’s increased signaling activity led to a change in the behavior of a transcription factor protein called JUNB.

“These changes in the levels of JUNB, along with how it binds to DNA-containing chromatin and controls the transcription of RNA, all promote a more stable cellular identity,” said Colas.

Locking down access to DNA

By combining RNA and chromatin accessibility sequencing, the researchers determined that CHST7 acts through CD44 and JUNB to control access to chromatin and the DNA housed within it. The trio worked in concert to allow access to chromatin at points that favor cell fate stability while locking down regions that promote changing cellular identities, including those containing the reprogramming factor myocyte enhancer factor 2C (MEF2C).

“By changing where transcription factors and enzymes can interact with our DNA, CHST7 constrains cardiac reprogramming by sustaining cell-specific transcriptional programs and limiting reprogramming factor access to target DNA,” said Colas.

Blocking PIP4K2C boosts recovery

The scientists then looked for enzymes or other signaling molecules influenced by these three cell identity stabilizers. The results led to an enzyme called phosphatidylinositol-5-phosphate 4-kinase type 2 gamma (PIP4K2C).

When the research team compared a combined treatment that blocked PIP4K2C and prompted reprogramming in the hearts of mice with one that only initiated cellular reprogramming, the combined treatment was significantly more successful.

“One month after suffering a heart attack, the mice that received the combined treatment pumped a relatively normal 58.6% of blood, compared with only 24.9% for the other group,” said Colas.

“Our work to better understand how heart cells reinforce resistance to reprogramming allowed us to discover this new and promising target to enhance cardiac repair after injury.”

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Sadie Harley

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Robert Egan

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