In a new study published in iScience, scientists at the department of pharmaceutical sciences at the University of Houston reported a protocol that reprograms human heart muscle cells (cardiomyocytes) into cardiac Purkinje cells, capable of conducting electrical signals throughout the heart.

The evidence presented in the study indicates that the new method may restore electrical conduction in the heart and improve cardiac function. Implanting specialized cardiac Purkinje cells into diseased hearts, instead of cardiomyocytes, will enable curative repair and rhythmic heartbeats. The study advances the quest for an optimized cell therapy for heart regeneration and can facilitate the development of new drugs for heart disease.

If your heart fails, you might be administered ACE (angiotensin-converting enzyme) or PDE (phosphodiesterase) inhibitors, or beta-blockers, such as carvedilol or metoprolol. Unfortunately, most of these drugs have severe side effects and are only effective in some patients. More to the point, none of these drugs prevents the death of heart muscle cells and the formation of scar tissue in the heart, which cause most heart failures. In fact, the only curative option for end-stage heart failure is transplant, which is risky, expensive, and in most cases, unfeasible.

Regenerative medicine holds the promise of offering a cure for cardiovascular diseases (CVD). However, regenerating failing hearts by directly implanting cardiomyocytes is not the ideal solution.

“This is because, often the cardiac myocytes implanted cannot be electrically activated in synchrony by the recipient’s heart and will contract at a different pace from the rest of the heart, inducing arrhythmias,” said senior author of the study, Bradley McConnell, PhD, professor of pharmacology at the University of Houston.

Instead, implanting cells that can synchronously contract and relax with every heartbeat as it pulses from pacemaker tissues through the muscular walls of the heart (myocardium), would offer a better option. An example of such a cell would be cardiac Purkinje cells which are a building block of the cardiac conduction system (CCS).

Cardiac Purkinje Cells
The researchers used a cocktail of small molecules on human cardiomyocytes to differentiate them into cardiac Purkinje cells. [Adapted from Prodan N, et al., iScience, 2022]
“We are the first to demonstrate the successful direct reprogramming of human cardiomyocyte cell lines (AC16-CMs and iPSC-CMs) into Purkinje-like cells using a unique cocktail of small molecules,” said McConnell and, Nicole Prodan, a PhD student in McConnel’s lab. “Direct reprogramming is a technique that produces an epigenetically unstable plastic state to facilitate the conversion of a fully differentiated and matured cell into a different new cell type.”

“Our small molecule treatment of human cardiomyocytes leads to Purkinje differentiation resulting in key Purkinje cell gene expression and conduction of fast electrical signals, comparable to native Purkinje cells,” said Prodan.

The investigators showed that the differentiation protocol generated Purkinje cells that were genetically and functionally similar to native cardiac Purkinje cells. The cultured cells expressed key cardiac Purkinje genes such as CNTN2, ETV1, PCP4, IRX3, SCN5a, and HCN2 and conducted electrical signals with increased velocity.

McConnell’s team collaborated with Robert Schwartz, PhD, and Preethi Gunaratne, PhD, professors of biology and biochemistry at the University of Houston, on this study.

Every 36 seconds a person dies due to cardiovascular disease in the United States. By 2035, CVD is expected to affect 130 million people. At present, there are no treatments that prevent the death of cardiac cells, the underlying basis of CVD.

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