Scarred hearts are reprogrammed to young healthy ones, new study reveals

Reprogrammed scars make the heart work like new again

Unlike the liver, the human heart cannot regenerate its parts. So when cardiac muscles die due to a heart attack, the heart is not able to replace them with healthy muscles. Instead, it employs fibroblasts, cells that specialize in producing connective and scar tissues.

Fibroblast cells turn dead muscles into hard scar tissues that hinder normal heart functioning. The researchers decided to reprogram fibroblasts using miRNAs to produce healthy rather than scar tissues. 

However, while working with mouse models, they realized that it was easy to reprogram juvenile fibroblasts. Still, on the other side, adult fibroblast cells were reluctant to receive reprogramming instructions from miRNAs. 

When the researchers dug deeper, they discovered that adult fibroblasts were resistant to reprogramming due to a protein oxygen sensor called Epas1. Interestingly, the transformation of juvenile fibroblasts into adults was also found to be dependent on Epas1.

So they first inhibited Epas1 and then used exosomes (vesicles containing genetic material) for delivering miRNAs to fibroblasts in mice who previously suffered heart attacks. As expected, adult fibroblasts didn't show any resistance this time.

“We reversed the fibroblast aging process, essentially making the fibroblasts think they were young again, and we converted more fibroblasts into cardiac muscle,” said one of the study authors, Professor Conrad Hodgkinson.

The approach allowed the study authors to turn scar tissues in mice's hearts into healthy tissues and made the hearts function again like normal healthy hearts. 

Reprogramming might work for all kinds of scars

This is the first study highlighting miRNAs' use for reprogramming fibroblasts. According to the researchers, if successful in humans, this approach could transform the lives of millions of heart patients across the globe. 

Moreover, they believe the same reprogramming method might also be used to reverse damage in other parts of the body. For instance, future studies might allow scientists to use miRNAs to repair scars and damage in the brain, skin, and other organs. 

The study is published in the Journal of Biological Chemistry. 

Study Abstract:

Directly reprogramming fibroblasts into cardiomyocytes improves cardiac function in the infarcted heart. However, the low efficacy of this approach hinders clinical applications. Unlike the adult mammalian heart, the neonatal heart has an intrinsic regenerative capacity. Consequently, we hypothesized that birth imposes fundamental changes on cardiac fibroblasts which limit their regenerative capabilities. In support, we found that reprogramming efficacy in vitro was markedly lower with fibroblasts derived from adult mice versus those derived from neonatal mice. Notably, fibroblasts derived from adult mice expressed significantly higher levels of pro-angiogenic genes. Moreover, under conditions which promote angiogenesis, only fibroblasts derived from adult mice differentiated into tube-like structures. Targeted knockdown screening studies suggested a possible role for the transcription factor Epas1. Epas1 expression was higher in fibroblasts derived from adult mice and Epas1 knockdown improved reprogramming efficacy in cultured adult cardiac fibroblasts. Promoter activity assays indicated that Epas1 functions as both a transcription repressor and activator, inhibiting cardiomyocyte genes while activating angiogenic genes. Finally, the addition of an Epas1 targeting siRNA to the reprogramming cocktail markedly improved reprogramming efficacy in vivo with both the number of reprogramming events as well as cardiac function being markedly improved. Collectively, our results highlight differences between neonatal and adult cardiac fibroblasts and the dual transcriptional activities of Epas1 related to reprogramming efficacy.