Cocktail of Molecules Regenerates Beating Heart Cells

By on February 27, 2014
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The survival rate for stroke victims is higher due to improved signs of early detection and healthy lifestyle changes in terms of smoking, diet and exercise. However, this leaves over one million stroke survivors in the United States alone with chronic heart failure. This condition prevents the heart from beating at full capacity due to the muscle lost during a stroke. Heart muscle is composed of cells with one unique nucleus called cardiomyocytes. In the latest issue of Cell Reports, scientists at Gladstone Institutes reveal a “molecular cocktail” that reprograms skin cells into cardiac muscle cells.

Previous methods of regenerative medicine are extremely complex and do not guarantee complete transformation of cells. Sheng Ding, PhD, professor of pharmaceutical chemistry at UCSF and investigator at Gladstone, modified the original process that used four to seven genetic factors to induce beating heart cells.

“…[I]n my lab,” Ding said, “we set out to see if we could perform a similar transformation by eliminating — or at least reducing — the reliance on this type of genetic manipulation.”

In earlier studies, Ding’s team identified “small molecules” that power the transfer of skin cells into neurons and insulin-producing pancreatic cells. They predicted that a similar concept could be applied to the heart cells, and searched for chemical compounds from the skin cells of adult mice that could replace the genetic factors in transformation. A four compound mix, SPFC, reprogrammed the skin cells into cells that showed twitching and contractile movements similar to that of normal heart cells. This transition occurs without ever inducing a pluripotent state in a process called transdifferentiation, reducing the risk of tumor formation. The complete transformation required a single transcription factor called Oct4.

Cells reprogrammed by the mix generated promising results within only 20 days.

“Remarkably,” Ding said, “additional analysis revealed that these cells showed the same patterns of gene activation and electric signaling patterns normally seen in the ventricles of the heart.” Ventricular heart cells are the most commonly lost cells during strokes. Therefore, the researchers believe they are inching closer towards the regeneration of cardiac muscle.

Further investigation is needed to define the exact mechanism of reprogramming accomplished by SCFP and Oct4, because a large network of signaling molecules and inhibitors contribute to the overall process. Current hypotheses include a signaling inhibition that destabilizes the phenotype of the skin cells and prevents endoderm induction.

Methodical innovations in regenerative medicine can bypass ethical obstacles and provide efficient pharmaceutical treatments for cell reprogramming. With time, the creation of Frankenstein’s monster may not be left in science fiction after all.

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