Doubling stem cell chromosomes produces heart cells with stronger, faster contractions

The Regenerative Medicine Project at our institute is advancing therapeutic strategies for various diseases by introducing a range of modifications to human induced pluripotent stem (iPS) cells.

The researchers have established iPS cells with doubled chromosomes (tetraploid iPS cells) via cell fusion. By differentiating these tetraploid iPS cells into cardiomyocytes, they succeeded in developing a technology that replicates the chromosome doubling that occurs naturally in vivo during cardiomyocyte maturation, thereby enhancing cardiac function.

The research findings were published online in the journal Communications Biology on Monday, Aug. 17, 2026.

Human iPS cells, which can be generated from the cells of our own bodies and possess the ability to differentiate into any cell type, have opened up a wide range of possibilities for diverse medical applications. A research group led by project leader Yuichiro Miyaoka of the Regenerative Medicine Project at our institute is developing therapeutic approaches for diseases by applying genetic modifications to these human iPS cells.

Doubling chromosomes to improve cardiac cell maturity

In this study, the research group—consisting of Ittetsu Nakajima (then a graduate student at Institute of Science Tokyo), project leader Miyaoka (who also serves as an associate professor at Graduate School of Medical and Dental Sciences, Institute of Science Tokyo, and as a visiting associate professor at Graduate School of Humanities and Sciences, Ochanomizu University), and Mitsuyoshi Shimane of Nanion Technologies Japan K.K.—established iPS cells with doubled chromosome numbers (tetraploid iPS cells) via cell fusion.

By differentiating these tetraploid iPS cells into cardiomyocytes, they replicated the chromosome doubling process that occurs during in vivo cardiomyocyte maturation, thereby developing a technology to enhance myocardial function.

A major hurdle for clinical and medical applications of iPS cell–derived cardiomyocytes has been that they remain immature, resembling an embryonic or fetal state. Addressing this issue, this study focused on the fact that cardiomyocytes double their chromosomes as they mature. By generating tetraploid cardiomyocytes, the team obtained cardiomyocytes possessing functions closer to those of mature cardiac cells. This breakthrough is expected to contribute to diverse medical applications, including transplantation therapies for heart failure, efficacy and safety testing for novel drug candidates, and the construction of disease models to elucidate disease mechanisms.

Normal iPS cells are diploid, and cardiomyocytes derived from these diploid iPS cells mostly remain diploid. Consequently, they cannot replicate the tetraploidization of cardiomyocytes that occurs during maturation in the human body. To address this issue, this study generated cardiomyocytes with doubled chromosomes by first tetraploidizing the iPS cells themselves via cell fusion, and then differentiating them into cardiomyocytes. As expected, the tetraploid iPS cell–derived cardiomyocytes exhibited more mature characteristics.

A natural process missing in cultured cardiomyocytes

Most cells in the human body are diploid, possessing 23 pairs (a total of 46) of chromosomes. We exist as diploid organisms by inheriting one copy of autosomes 1 through 22, and one sex chromosome (the 23rd chromosome), from each parent. However, in certain cell types such as cardiomyocytes and hepatocytes (liver cells), a phenomenon called “polyploidization” (chromosome doubling) occurs, in which the number of chromosome sets increases as the cells mature. In fact, approximately 80% of adult cardiomyocytes are tetraploid, containing four copies of each of the 23 chromosomes.

Human iPS cells can differentiate into a wide variety of cell types. Among these, cardiomyocytes hold promise for clinical application, with clinical trials for transplantation already underway. However, a persistent challenge for medical application has been that conventional iPS cell–derived cardiomyocytes remain immature and exhibit fetal-like properties.

Our team focused on the fact that conventional iPS cell–derived cardiomyocytes rarely undergo the chromosome doubling that naturally accompanies maturation. The researchers hypothesized that if they could generate tetraploid cardiomyocytes from iPS cells, they could significantly improve the functional capabilities of these cardiac cells.

Cell fusion before differentiation

Conventional technologies were unable to directly tetraploidize cardiomyocytes derived from iPS cells. In this study, instead of attempting to tetraploidize cardiomyocytes after their differentiation from diploid iPS cells, the team conceived the idea of tetraploidizing the iPS cells themselves first, and then differentiating them into cardiomyocytes.

To achieve this, they fused diploid iPS cells using Sendai virus particles—which have a well-known cell-fusing effect and are commonly used in cell fusion protocols—to establish tetraploid iPS cells. The resulting tetraploid iPS cells were slightly larger than conventional diploid iPS cells, stably maintained their four sets of chromosomes, and retained their pluripotency.

When the researchers differentiated these tetraploid iPS cells into cardiomyocytes, they exhibited a larger cell size compared to those derived from diploid iPS cells ). This is consistent with in vivo behavior, where cell size increases during maturation.

Mature gene profiles and stronger contractions

Next, they analyzed gene expression profiles using RNA-sequencing (RNA-seq). In tetraploid-derived cardiomyocytes, the expression of cell cycle–related genes was significantly downregulated compared to diploid-derived counterparts. In the human body, cardiomyocytes actively proliferate during the diploid fetal stage, but they stop dividing and become tetraploid as they mature. These results indicate that tetraploid-derived cardiomyocytes possess gene expression profiles that closely resemble those of mature cardiomyocytes.

Furthermore, because cardiomyocytes require a substantial amount of energy to contract, their mitochondria increase and their function improves as they mature. Our analysis of the mitochondria revealed an increase in both mitochondrial quantity and functional capacity.

Additionally, to conduct electrophysiological analysis, they measured electrical impedance. As cardiomyocytes attached to the bottom of the culture plate beat, their internal cellular structures shift, causing an increase in electrical impedance. The measurements demonstrated that the tetraploid-derived cardiomyocytes contracted more strongly and rapidly than the diploid-derived ones. Strong and fast contraction is another key characteristic of mature cardiomyocytes, and this analysis further supported the trend of enhanced maturity in the tetraploid-derived cardiomyocytes.

Potential applications beyond cardiac cells

This research has established a technology to produce mature cardiomyocytes from tetraploid iPS cells. By overcoming the limitations associated with the immaturity of conventional diploid iPS cell–derived cardiomyocytes, this technology is expected to contribute to the advancement of regenerative medicine and drug discovery.

Furthermore, this approach is likely to prove beneficial for research and regenerative applications involving other cell types that undergo chromosome doubling as part of their natural maturation process, such as hepatocytes (liver cells), skeletal muscle cells, megakaryocytes (platelet-producing cells), and osteoclasts (bone-resorbing cells).

Who’s behind this story?

Gaby Clark

MA in English, copy editor since 2021 with experience in higher education and health content. Dedicated to trustworthy science news.

Full profile →

Andrew Zinin

Master’s in physics with research experience. Long-time science news enthusiast. Plays key role in Science X’s editorial success.

Full profile →