Scientists at Sanford Burnham Prebys Medical Discovery Institute and The Johns Hopkins University School of Medicine announced on July 28 that they have identified a new mechanism used by heart cells to protect their identities and resist reprogramming, according to findings published July 17 in Nature Communications.
The study addresses why adult human hearts cannot repair themselves after injury in the same way as skin. Researchers have long sought ways to reprogram heart cells for regeneration following heart attacks, but these cells maintain very stable identities that make them resistant to such interventions.
Prior research pointed scientists toward proteins heavily decorated with sugar molecules, a process called glycosylation. The team found that carbohydrate sulfotransferases—a family of proteoglycan-modifying proteins—act as previously unrecognized barriers to cellular reprogramming. Further investigation revealed that one member, CHST7, impedes reprogramming by increasing signaling through the cell membrane receptor CD44. In experiments where cells were genetically edited to produce extra CHST7 but lacked CD44 receptors, the researchers’ reprogramming treatment was 47% more efficient than in cells with normal CD44 levels.
"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 increased activity of CD44 led to changes in the 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, researchers determined that CHST7 acts through both CD44 and JUNB to control access to chromatin—the structure housing DNA—thereby stabilizing cell fate while restricting regions associated with identity change. "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 team also identified an enzyme influenced by these stabilizers: phosphatidylinositol-5-phosphate 4-kinase type 2 gamma (PIP4K2C). In mice treated after heart attack with both PIP4K2C inhibition and induced cellular reprogramming, cardiac function improved significantly compared with those receiving only standard treatment. "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."
