Specialized cells in our body make biological tradeoffs to do certain jobs. To support large and hardworking hearts that power our other organs, our heart cells evolved to be extremely efficient and resilient.
Because the adult human heart can no longer 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 being reprogrammed.
Scientists at Sanford Burnham Prebys Medical Discovery Institute and collaborators at The Johns Hopkins University School of Medicine published findings July 17, 2026, in Nature Communications uncovering a new mechanism used by cells to protect their cellular identities and ward off reprogramming attempts. Continued study of the obstacles to cellular reprogramming may lead to treatments that can help the heart fix itself after injury.
Prior research had pointed the scientists to a type of protein that is heavily decorated with sugar molecules, a process known as glycosylation. Tests of these sugar-bearing proteins found that a family of proteoglycan-modifying protein called carbohydrate sulfotransferases were 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, PhD , associate professor in the Center for Cardiovascular and Muscular Diseases at Sanford Burnham Prebys.
Additional investigation demonstrated that CHST7 rebuffed cellular reprogramming by increasing the volume of 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 messaging activity led to a change in behavior of a transcription factor protein called JUNB.
"These changes in the levels of JUNB along with how it binds to DNA-storing chromatin and controls the transcription of RNA all promote a more stable cellular identity," said Colas.
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 therein. The trio worked in concert to allow access to chromatin at points that favor cell fate stability while locking down regions that promote cellular identities to change, 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.
The scientists then looked for enzymes or other signaling molecules that are 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 to one that only initiated cellular reprogramming, the linked 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 versus 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."
Michaela R. Romero, PhD, a postdoctoral fellow at Ionis Pharmaceuticals and former member of the Colas lab, shares first authorship of the publication with Sean Murphy, PhD, a senior computational biologist at Immunai.
Additional authors include:
- Yu-Ling Chang, Aashna Lamba, Sara Ancel, Alicia Llorente, James Marchant, Chun-Teng Huang, Caroline Kumsta, Sanjeev Ranade, Ahmed I. Mahmoud, Hudson H. Freeze, Peter D. Adams, Alessandra Sacco, Brooke M. Emerling and Yu Xin Wang at Sanford Burnham Prebys
- Peter Andersen, Chulan Kwon and Mark J. Ranek at The Johns Hopkins University School of Medicine
The study was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, Sanford Burnham Prebys, Rocket Fund and American Heart Association.
The study's DOI is 10.1038/s41467-026-75583-8 .
