- Blood-derived lipid signal S1P boosts cardiomyocyte differentiation rate above 90%

- Animal tests confirm restored heart function and reduced fibrosis

Director Son Mi-young (back) and researcher Yu Won-dong conduct a related experiment. [Korea Research Institute of Bioscience and Biotechnology]
Director Son Mi-young (back) and researcher Yu Won-dong conduct a related experiment. [Korea Research Institute of Bioscience and Biotechnology]

South Korean researchers have developed a technology that makes immature cardiomyocytes derived from stem cells beat as strongly and regularly as adult heart cells. The team pushed the cardiomyocyte differentiation rate above 90 percent and confirmed cardiac function recovery in animal models of myocardial infarction.

The Korea Research Institute of Bioscience and Biotechnology announced Thursday that a research team led by Son Mi-young and Lee Mi-ok had identified S1P — a lipid signaling molecule found in blood — as a key signal that promotes the differentiation and maturation of cardiomyocytes.

The heart has very limited capacity to regenerate once damaged. Research into converting human pluripotent stem cells (hPSC) into cardiomyocytes has been active in recent years, but cells produced by conventional methods remain in an immature state — unable to beat as strongly or regularly as adult heart cells, with differentiation efficiency varying widely depending on the type of stem cell used.

The research team noticed that adding bovine serum to stem cells improved their differentiation into cardiomyocytes. By analyzing the serum's components, they identified S1P, a bioactive lipid signaling molecule, along with S1PR1, the receptor that recognizes it.

When human pluripotent stem cells were treated with S1P or a substance that activates S1PR1, more than 90 percent differentiated into cardiomyocytes. The resulting cells grew larger, and the muscle structures responsible for cardiac contraction became more densely aligned. Their beating signals and electrical properties also grew more regular and stronger, closely resembling those of adult cardiomyocytes.

The team also conducted experiments using the gene-editing tool CRISPR-Cas9 to remove the S1PR1 gene. In those cases, normal cardiomyocyte differentiation did not occur even when S1P was applied — confirming that the S1P-S1PR1 signaling pathway plays a critical role in cardiomyocyte differentiation and functional maturation.

A schematic diagram showing enhanced function of human pluripotent stem cell-derived cardiomyocytes and myocardial infarction recovery through activation of S1P-S1PR1 signaling (AI-generated image). [Korea Research Institute of Bioscience and Biotechnology]
A schematic diagram showing enhanced function of human pluripotent stem cell-derived cardiomyocytes and myocardial infarction recovery through activation of S1P-S1PR1 signaling (AI-generated image). [Korea Research Institute of Bioscience and Biotechnology]

When cardiomyocytes produced using this technology were transplanted into animal models of myocardial infarction, the pumping function of the damaged heart recovered. Fibrosis — the hardening of heart tissue — also decreased, and the transplanted cells were confirmed to have engrafted in the cardiac tissue.

The ability to stably produce high-quality human cardiomyocytes would allow researchers to evaluate the cardiac toxicity and efficacy of new drug candidates in an environment closely resembling the human body. In the longer term, the technology could also be applied to cell therapy aimed at replenishing cardiomyocytes lost to myocardial infarction.

However, additional verification is needed before clinical application. Researchers must confirm that the same effects can be achieved across a range of human pluripotent stem cell lines and secure the technology for mass production and quality control. Safety validation — including long-term survival of transplanted cells and the potential for arrhythmia or tumor development — as well as large-animal studies, also remain to be completed.

"We simultaneously improved both the differentiation efficiency and functional maturity of stem cell-derived cardiomyocytes by harnessing a signaling molecule found in blood," Son said. "We expect this to be used in evaluating the safety and efficacy of new drugs using human-derived heart models, as well as in developing cardiac regenerative medicine technologies."

The findings were published in the international journal Experimental & Molecular Medicine.


nbgkoo@heraldcorp.com