Regenerative Heart Therapies

Scientists led by Duke-NUS Medical School in Singapore and the University of California, Los Angeles, (UCLA) in the United States have discovered a new control mechanism that can drive the maturation of human stem cell-derived heart muscle cells, providing fresh insight into the maturation process of heart muscle cells from fetal to adult form.

After birth, heart muscle cells undergo extensive changes to become fully mature adult cells, altering their form, function and physiology. However, the regulatory processes governing this maturation have been poorly understood thus far.

For regenerative therapies in particular, this lack of understanding has proven a major limitation as efforts to grow stem cell-derived heart muscle cells have not been successful at producing mature adult cells, capable of restoring or improving heart function.

Publishing in Circulation, the research team used transcriptomic analysis to pinpoint an RNA splicing regulator named RBFox1 that was highly elevated soon after birth in a newborn heart.

Analyses of published single-cell data also showed dramatic RBFox1 increase in maturing heart cells.

By expressing RBFox1 in immature human stem cell-derived heart cells, the researchers saw enhancements in key indicators of maturation, including cell size, sarcomere structure, contraction, calcium handling and oxygen usage.

RBFox1 expression also led to the development of characteristic electrical properties seen in adult cells.

Further analyses showed RBFox1 regulated splicing of RNA transcripts linked to heart cell contraction and sarcomere components.

While further research is needed to explore the mechanisms linking RBFox1-mediated RNA splicing with downstream maturation processes and phenotype, the study provides proof-of-concept that modulating RNA splicing can significantly impact heart muscle cell, or cardiomyocyte, maturation.

This opens possibilities for regulating maturation that could eventually be translated to therapeutic strategies.

Sources:

Jijun Huang, Josh Z. Lee, Christoph D. Rau, Arash Pezhouman, Tomohiro Yokota, Hiromi Miwa, Matthew Feldman, Tsz Kin Kong, Ziyue Yang, Woan Ting Tay, Ivan Pushkarsky, Kyungsoo Kim, Shan S. Parikh, Shreya Udani, Boon Seng Soh, Chen Gao, Linsey Stiles, Orian S. Shirihai, Bjorn C. Knollmann, Reza Ardehali, Dino Di Carlo, Yibin Wang. Regulation of Postnatal Cardiomyocyte Maturation by an RNA Splicing Regulator RBFox1. Circulation, 2023; 148 (16): 1263 DOI: 10.1161/circulationaha.122.061602

Duke-NUS Medical School. (2023, December 18). New discovery could aid regenerative heart therapies. ScienceDaily. Retrieved December 21, 2023 from www.sciencedaily.com/releases/2023/12/231218130026.htm

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