When the heart is damaged, such as in a myocardial infarction, the damaged heart muscle cannot regenerate and scar tissue forms instead. Cardiomyocytes, the heart muscle cells that produce contractile force, are permanently lost. However, in mouse models, neonatal hearts regenerate quickly after injury.

How does a newborn’s heart recover? What ingredients are required for regeneration? Dr. Miao Kui began asking these questions as a postdoctoral fellow in Eric Olson’s lab at the University of Texas Southwestern Medical Center. Carrying out research in his laboratory in the Department of Cardiology at Boston Children’s Hospital, Cui has discovered factors that support heart regeneration. These include the routes cancers use to escape attack.

Could interventions reactivate some of these factors to treat cardiomyopathy in children and heart disease in adults?

Neonatal heart examination

Early on, Cui and Olson identified a unique subpopulation of cardiomyocytes that retains regenerative potential. Cui examined RNA-seq data from so-called CM4 cells in a mouse model and identified several regeneration-friendly factors.

One is a transcription factor known as NFYa, which is involved in mitochondrial metabolism and is key to the activation of genes involved in cell proliferation in the developing fetal heart. As explained recently, developmental cells, Loss of NFYa reduced immature regenerative cells. Increase in mature non-regenerating cardiomyocytes. Mitochondrial metabolic disorders. and mental growth failure.

Another transcription factor, Nrf1, controls genetic programs involved in adaptation to cellular stress. As detailed by Cui and his colleagues, nature communications, loss of Nrf1 prevented neonatal heart regeneration. Conversely, increasing Nrf1 expression in adult mouse hearts protected the heart from ischemia/reperfusion injury. Cui is investigating this promising lead further.

heart regeneration, immunosuppression, cancer

The latest research was conducted at UT Southwestern and co-led by Dr. Stephanie Vargas Aguilar. Nature cardiovascular researchidentified the PD-1/PD-L1 pathway, a surprising factor that helps newborn hearts regenerate. This well-known pathway suppresses the immune system. Cancer uses it to avoid immune attacks by the body’s T cells. In oncology, it is the target of many checkpoint inhibitors.

Researchers found that in the neonatal heart, activation of the PD-1/PD-L1 pathway maintains an immunosuppressive environment that allows regeneration.

“We found a systematic downregulation of PD-1 and PD-L1 in the postnatal immune system,” notes Cui, who also holds a position in the Department of Genetics at Harvard Medical School. “During pregnancy, high she-PD-1/PD-L1 activity may be beneficial in escaping maternal immune responses. However, after the mouse is born, her PD-1 is low to prevent infection. / It is important to reduce PD-L1 levels quickly.”

When the researchers suppressed the pathway in neonatal mice with heart injuries, they observed increased inflammation and T cell activation, and impaired heart regeneration.

“We hypothesized that T cell activation promotes cardiomyocyte death,” Cui says. She thinks the findings may also explain why cancer patients receiving immune checkpoint inhibitors often develop myocarditis.

Exploring therapeutic approaches

Cui’s next step is to find a way to upregulate the PD-1/PD-L1 pathway in the heart through gene therapy or cell therapy (transplantation of neonatal-like T cells) to regenerate heart tissue after a heart attack. It’s about research.

That’s just one potential therapeutic target Cui wants to study. Her lab aims to uncover additional factors through systematic investigations of the gene networks that control regeneration. The goal is to overexpress them through gene therapy in animal models and see their effects on heart development and recovery from stress and injury.

Cui also hopes to translate his research to human heart tissue, in collaboration with Sarah Morton, MD, of the Department of Neonatal Medicine. Morton’s research focuses on the genetics of congenital heart disease (CHD). The pair will investigate whether CHD patients have mutations in genes that Cui believes are associated with heart regeneration.

“We are looking forward to this collaboration,” says Morton. “Understanding how genetic mutations contribute to heart regeneration and resilience can help understand differences in outcomes among CHD patients and enable new treatment options to improve their health. It may become.”

Learn more about our cardiology research and neonatal genomics programs.