Setting the clocks ahead for cardiac cells

Researchers determine a method for accelerating the maturation of iPSCs into cardiomyocytes

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MADISON, Wis.—Stem cells have long been—and continue to be—a key point of interest for their regenerative potential, particularly as research with induced pluripotent stem cells (iPSC) has advanced and allowed for more precise tuning to encourage stem cells to differentiate into the preferred cell type.
In hopes of being able to accelerate this process, recent work out of the University of Wisconsin-Madison (UWM) has detailed how polyinosine-polycytidylic acid (pIC) can be used to speed up cellular maturation in induced pluripotent stem cells (iPSC) that are differentiating into cardiac muscle cells. The work was published in the journal Stem Cells in an article titled “Epigenetic priming of human pluripotent stem cell-derived cardiac progenitor cells accelerates cardiomyocyte maturation.”
Polyinosine-polycytidylic acid is a double-stranded RNA molecule that triggers a cell’s defense system. This compound, which is approved by the FDA, is often used as to boost vaccines and chemotherapy, as noted in a press release by UWM’s Kelly April Tyrrell.
Tissue generated from iPSCs, like organ-on-a-chip technology, offers the ability to study disease progression and test therapeutics more accurately. Cardiac tissue and function is of particular interest, but it offers a unique difficulty—as noted by Tim Kamp, leader of the Stem Cells study, immature cardiac cells cannot contract as strongly as their adult counterparts, and the electrical aspects of their beating and metabolism are also different.
“If you want to know how drugs, such as beta blockers, work in the adult heart, it’s better to test those in more mature, human iPSC-derived cardiomyocytes (cardiac muscle cells),” noted Kamp, who is director of the University of Wisconsin–Madison Stem Cell and Regenerative Medicine Center and a professor of medicine in the School of Medicine and Public Health.
“Cardiac development is regulated by the cardiac gene network, including transcription factors (TFs). According to our current understanding of cardiac development, cardiac TFs are sequentially expressed during cardiac commitment in hPSCs. Expression levels of each gene are strictly regulated by epigenetic modifications. DNA methylation, histone modification, and noncoding RNAs significantly influence cardiac differentiation. These complex circuits of genetic and epigenetic factors dynamically affect protein expression and metabolic changes in cardiac differentiation and maturation,” the authors explained in their paper.
UWM M.D./Ph.D. student Mitch Biermann, lead author on the study, realized that iPSC-derived cardiac cells mature at different rates in vitro, while other researchers noted “that cardiomyocytes in the heart and in blood vessels of rats matured according to the same clock,” as per Tyrrell’s release.
As a result, Biermann shifted his focus to epigenetics to look closer at the cellular timing of the cells. He found that when pIC was added to early cardiac progenitor cells (CPCs)—the intermediate step between stem cells and differentiated cardiomyocytes, according to a Stem Cells press release—the CPCs matured into beating heart cells a full two days sooner than cells that were not treated. Even when Biermann removed the cells from pIC after 48 hours, the effects continued, resulting in cardiac cells that “were larger in size, had better contractility, were electrically more efficient, exhibited mature metabolic characteristics and had better-developed structures when compared to cells without pIC,” as noted by Tyrrell. The mechanism responsible for this was deemed to be the JAG1 gene—pIC increased expression of the gene.
As the authors explained in their paper, “Cell variation in hPSCs is also a major problem for clinical applications. The differentiation potential of hPSCs has been shown to vary between lines … One of current topics in this field is epigenetic memory, which significantly affects the heterogeneity of hPSCs. DNA methylation also varies between cell lines, causing variations in their potentials for lineage‐specific differentiation. If hiPSCs are used as a source, the original epigenetic state remains, possibly affecting differentiation pathways … Epigenetic memories are observed in cardiac developmental programs as well. The early disruption of the epigenome significantly affected cardiac differentiation in vivo. Therefore, appropriate epigenomic priming appears to be a major requirement for efficient and pertinent cardiac differentiation from hPSCs.”
“Developing fully mature cells from pluripotent sources has been a major translational hurdle, said Dr. Jan Nolta, editor-in-chief of Stem Cells. “The significant progress in maturing cardiomyocytes, reported in this manuscript, is highly important in moving the therapy closer to clinical application.”
According to Kamp, there are still several issues to address in this approach—namely that the pIC-treated cardiomyocytes are not an exact match for adult cardiac cells, and whether or not this method will work with other types of cells as well. The question also remains as to whether the accelerated cells will continue to age faster than untreated cells, though at present Kamp reported that no “aberrant effects” have been seen. Biermann noted that the team is interested in exploring these primed CPCs in models of heart attack as well as “in-vitro uses for mature hPSC-CMs such as studying disease mechanisms, drug responses and basic human cardiomyocyte biology.”

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