Cardiomyocyte spheres grown from stem cells raised mouse survival in the first two days after infarction from 36 to 92%, despite proving less mature than single cells
Cardiomyocyte spheres grown from stem cells raised mouse survival in the first two days after infarction from 36 to 92%, despite proving less mature than single cells
Danish biologists from Professor Ditte Caroline Andersen's laboratory at the University of Southern Denmark transplanted cardiomyocytes grown from stem cells into immunocompromised mice with induced infarction, either as dissociated single cells or as compact spheres of roughly 250 cells. Within the first two days, 92% of the mice receiving spheres survived, compared with 36% of those receiving single cells and 50% of vehicle controls. The results were posted as a preprint on bioRxiv on September 11.
After a myocardial infarction the heart loses up to one billion cardiomyocytes and cannot replace them: unlike skin or liver, the adult heart has almost no resident stem cells. Regenerative medicine grows replacement cardiomyocytes from induced pluripotent stem cells (iPSCs) and transplants them into the damaged heart; 12 clinical trials of this approach are already registered worldwide. Single dissociated cells tend to wash out of the injection site and die without cell-to-cell contact. Cardiac patches survive longer but integrate poorly with the host tissue. Spheres represent a compromise: aggregates of several hundred cells can be delivered through the same fine needle, yet the preserved intercellular contacts should help them survive the injection.
To compare the two delivery formats without immune interference, the authors used a new mouse strain, NXG B2m, which is in principle an ideal host for engraftment. These mice lack B cells, T cells, and natural killer cells, and the gene that normally helps cells display the MHC class I "self" marker is also knocked out.
The procedure itself turned out to be nearly lethal: of 49 mice, only 50% of vehicle controls and 36% of single-cell recipients survived the first two days. In the sphere group, 92% survived, a rate close to the 90–91% seen in wild-type mice after the same infarction surgery. Ethical constraints prevented the authors from adding more animals.
Necropsy of the mice that died ruled out vascular embolism: both cell formats settled in the same location, at the border of the scar. Among survivors at week 8, cardiac function and scar size were comparable across all groups. Spheres improved early survival but did not produce better cardiac recovery. The authors then assessed cell maturity and obtained a result opposite to what the prior literature had predicted: spheres had been thought to be more mature and therefore safer, yet by every marker examined they turned out to be less mature than single cells.
"Our results directly inform this debate: iPSC-cardiomyocyte maturity does not necessarily promote engraftment and recipient survival"the authors write. Their hypothesis is that immature cells, which contract more weakly, are safer for the rhythm of the beating recipient heart, whereas mature single cells can trigger fatal arrhythmia.
A similar pattern (55%, 55%, and 91% survival for the same three groups) was independently reported in 2022 by another group, confirming that the effect is reproducible. The present authors used cells from only one iPSC line, and the high mortality left them underpowered to demonstrate a difference in therapeutic effect on the heart itself, only in procedural survival.
In these mice, the format of the cell product determined whether the recipient survived the cardiac cell therapy procedure at all. The protection came precisely from the immaturity of the sphere cells, the very property that earlier work had expected to pose a risk rather than confer safety.