Mammalian hearts have almost no ability to grow latest heart muscle cells, called cardiomyocytes, after birth. Thus, dead tissue after an adult heart attack isn’t repaired with latest cardiomyocytes. It’s as a substitute replaced with scar tissue that weakens the pumping power of the center and infrequently results in heart failure.
One promising technique to remuscularize the injured heart is the direct cardiac reprogramming of heart fibroblast cells into cardiomyocytes. In a paper published in Circulation, University of Alabama at Birmingham researchers Yang Zhou, Ph.D., and Rui Lu, Ph.D., have identified TBX20 as the important thing missing transcription think about existing cocktails for direct cardiac reprogramming of human fibroblasts.
Adding TBX20 to the reprogramming cocktail MGT 133, they report, promoted cardiac reprograming and activated genes related to cardiac contractility, maturation and a ventricular location of the center muscle cell. Mechanistically, they found that TBX20 synergistically colocalizes with the MGT reprogramming aspects at cardiac gene enhancers, causing robust activation of goal genes.
Our study highlights the undocumented role of TBX20 as a significant regulator of direct human cardiac reprogramming. Enhancing the efficiency and quality of direct cardiac reprogramming from human fibroblasts is a critical step within the clinical translation of this technology.”
Yang Zhou, Ph.D., Researcher, UAB
A crucial area for future investigation, Zhou says, will probably be testing TBX20 in vivo for direct reprogramming.
Current cocktails for direct reprogramming of human fibroblasts suffer from low efficiency and insufficient production of functional cardiomyocytes. The UAB researchers identified TBX20 as probably the most underexpressed factor after they compared cardiomyocytes induced from fibroblasts with a current cocktail versus functional cardiomyocytes. The addition of TBX20 promoted cardiac reprogramming, as seen in activation of cardiac genes related to sarcomere structure, ion channels and heart contractions. A sarcomere is the smallest functional unit of striated muscle.
Human heart fibroblasts of the ventricle will probably be the first goal for evaluation of in vivo reprogramming. Zhou and colleagues showed that TBX20 was essential in reprogramming these fibroblasts to induced-cardiomyocytes, suggesting a therapeutic potential for TBX20.
Intimately, TBX20 primarily activated genes on the late stage of reprogramming, enhancing calcium flux, contractility and mitochondrial function within the induced-cardiomyocytes. Mitochondria are the energy source for heart muscle contractions. TBX20 appeared to assist the mitochondria within the induced-cardiomyocytes switch to an adult cardiomyocyte-like respiration.
Mechanistically, the UAB researchers found that TBX20 was sure to and activated cardiac gene enhancers. An enhancer is a brief regulatory element on DNA that may bind activator proteins to initiate transcription or increase the transcription of a specific gene goal. Transcription is the production of messenger RNA copied from the DNA gene to encode a protein. Enhancers often function at a distance from its gene goal.
This enhancer binding by TBX20, Zhou and colleagues found, required all three of the MGT cocktail aspects to assist activate cardiac genes. TBX20 alone was not sufficient to induce cardiac cell fate conversion; omission of any of the three MGT aspects substantially reduced reprogramming efficiency.
“Together, our findings show that TBX20 requires intact MGT aspects to advertise direct reprogramming and activate cardiac genes, they usually support the notion that direct cardiac reprogramming is a synergistically regulated process orchestrated by multiple aspects,” Zhou said.
Single-cell RNA sequencing profiling identified two major clusters of cells after reprogramming with TBX20. One was reprogrammed induced-cardiomyocytes, but the opposite group was only partially reprogrammed. The cluster of reprogrammed cardiomyocytes had gene expression profiles resembling ventricular cardiomyocytes.
At UAB, Zhou is an assistant professor within the Department of Biomedical Engineering, and Lu is an assistant professor within the Department of Medicine Division of Hematology and Oncology.
Source:
University of Alabama at Birmingham
Journal reference:
Tang, Y., et al. (2022) TBX20 improves contractility and mitochondrial function during direct human cardiac reprogramming. Circulation. doi.org/10.1161/CIRCULATIONAHA.122.059713.