Parenting 101: How to raise bioengineered heart tissue

Stem cells are a promising treatment for heart disease, a leading cause of death in the United States. Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) could replace diseased myocardium tissue, but the newly generated cells more closely resemble embryonic cardiomyocytes than adult cells. This discrepancy could cause regions of the heart to contract out of sync, a condition called arrhythmia.

Instead of yelling at the cells to “grow up,” Kumar et al. investigated transcription factors that could encourage hPSC-CMs maturation. The authors developed a vector that combines the identified factors to improve compatibility with adult cardiomyocytes.

Environmental factors can mature hPSC-CMs through stretching and electrical stimulation; however, manipulating genetic factors to mature cells is a relatively new idea.

Transcription factors are proteins that bind to DNA to regulate gene expression. By RNA sequencing hPSC-CMs isolated at different times, the researchers identified transcription factors that were more common or active in the mature cells.

“We identified five transcription factors that mature hPSC-CMs. Some improved cell size, others improved calcium flux, and one improved mitochondrial function,” said author Aditya Kumar. “To improve all three facets, we constructed a new vector that combined their effects. RNA-sequencing data from these cells demonstrated that, in particular, KEH overexpression induced numerous maturation-associated calcium handling, ion channel, mitochondrial, and cytoskeletal gene changes.”

Implementing these results can improve heart disease treatment, and this process can be applied to identify transcription factors in other stem cell progenies.

“Ultimately, we hope this work and others can be utilized to produce more mature hPSC-CMs that are more translatable in the clinic,” Kumar said.

Source: “Systematic discovery of transcription factors that improve hPSC-derived cardiomyocyte maturation via temporal analysis of bioengineered cardiac tissues,” by Aditya Kumar, Starry He, and Prashant Mali, APL Bioengineering (2023). The article can be accessed at https://doi.org/10.1063/5.0137458 .