Lab-cultured Heart Tissues Derived from Stem Cells Deemed Suitable to Study FA

Lab-cultured heart tissues derived from patients’ stem cells are a suitable model to study the progression of Friedreich’s ataxia (FA) and to develop and test new therapies, a study says.

The study, “Correlation between frataxin expression and contractility revealed by in vitro Friedreich’s ataxia cardiac tissue models engineered from human pluripotent stem cells,” was published in Stem Cell Research & Therapy.

FA is a rare, genetic, progressive disorder that affects the nerves and muscles. The disease is caused by the repetition of three nucleotides — the building blocks of DNA — specifically, one guanine (G) and two adenines (A) in the first intron of the FXN gene. An intron is a region of the gene that does not encode for a protein.

This leads to a significant decrease in levels of frataxin, a protein involved in iron metabolism that is encoded by the FXN gene. That deficiency, in turn, leads to the accumulation of iron deposits inside cells of the heart and brain, compromising their normal function.

As a result, many FA patients develop heart disease that may progress to heart failure, the leading cause of death among people with the disorder.

“[Mouse] models have been developed to study disease [development] in the past two decades; however, differences between human and mouse physiology and metabolism have limited the relevance of animal studies in cardiac disease conditions,” the researchers said.

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In this study, a group of investigators from Novoheart, a biotech company focused on the use of stem cells for therapeutic purposes, and their collaborators set out to develop an in vitro model of FA that fully mimicked the effects the disorder has on a patient’s heart in an attempt to overcome the limitations posed by the use of animal models.

They first created heart cells (ventricular cardiomyocytes) derived from induced pluripotent stem cells — cells that are able to grow into any type of cell — obtained from healthy individuals and FA patients.

Then, after creating a sufficient number of heart cells, they placed them into two different scaffolds — Novoheart’s proprietary human ventricular cardiac tissue strip (hvCTS) and human ventricular cardiac anisotropic sheet (hvCAS) models — to grow and form a tissue similar to that found on the heart.

Between seven and 17 days later, they used heart cells growing on the hvCTS to assess their ability to contract, and those growing on the hvCAS to evaluate their electrical activity. These tests were performed in heart cells derived from FA patients and healthy individuals.

Results showed that heart cells derived from FA patients had a 70% reduction in the amount of frataxin transcripts (RNA molecules that serve as the template for production of the protein), and a 40-60% reduction in the levels of frataxin protein compared to heart cells derived from healthy donors.

After examining heart cells that had been placed on the hvCTS, investigators found that those derived from FA patients generated much less force and had difficulty contracting compared with those derived from healthy individuals.

High-resolution imaging of heart cells that had grown on hvCAS showed that cells from patients lacking frataxin had a series of defects in their electrical activity consistent with clinical symptoms of FA.

Finally, they showed that when they forced the expression of the FXN gene in heart cells from patients who lacked frataxin, these cells regained their ability to contract normally.

“In summary, we demonstrated that the clinical symptoms of contractile and electrophysiological dysfunction in FA patients can be recapitulated by human cardiac tissues [derived from patients’ pluripotent stem cells],” the researchers said.

“[T]he results of our rescue experiments underscore the potential of FXN restoration by small molecules or gene therapy as an effective therapeutic strategy for suppressing or even reversing the cardiac symptoms of FA,” they added.