If heart attacks fail to kill their victim, they do succeed at killing heart cells, leaving a weaker heart more prone to failure in the future. Cell therapies can remedy damaged hearts by transplanting into them cardiovascular progenitor cells (CPCs) that replace the lost cells. Successful therapies depend on the CPCs differentiating into cardiomyocytes, but to date known the efficiency of the differentiation has been substandard for wide treatment. CiRA researchers in the Jun K. Yamashita laboratory have used iPS cells to find a type of CPC that when transplanted into mice almost exclusively produced cardiomyocytes, giving these cells great promise for future heart cell therapies.

"CPCs have been characterized by the expression of several transcription factors and surface markers. However, they differentiate to cardiomyocytes and other cell types," said Masafumi Takeda.

These other cells include endothelial cells, pericytes and mesenchymal cells , all of which are essential for the heart and vasculature, but not suitable for replacing the lost cardiomyocytes.

"For cell therapies, we want CPCs that differentiate to cardiomyocytes at 100%," he continued.

Takeda considered whether within CPCs there exists a specific subset that exclusively differentiates into cardiomyocytes. Subsets of progenitors that exclusively differentiate into one specific cell type are known in other systems like blood.

CPCs themselves rarely exist in the adult body but can easily be acquired from stem cells like iPS cells. By differentiating iPS cells and following protein expression patterns, Takeda found the differentiation potential of CPCs could be distinguished by the expression of CD82. He transplanted CD82+ CPCs, which he called cardiomyocyte-fated progenitors, into the hearts of live mice and found that almost all differentiated into cardiomyocytes.

"We found the differentiation efficiency was consistently over 95%. I do not know of any other progenitor that differentiates into cardiomyocytes at such a high rate," said Takeda.

CD82 is a glycoprotein that was first identified to have a suppressive role in prostate cancer. Since then, it has been found to have function in cell adhesion and cell motility. It also regulates exosomes, which led Takeda to the molecular mechanism through which CD82 enhances cardiomyocyte commitment.

"CD82 contributes to the inhibition of Wnt signaling through exosome activity. It is known that in normal heart development, Wnt inhibition is crucial for cardiomyocyte commitment," he said.

To prove this point, forcing the overexpression of CD82 in CPCs resulted in much higher rates of cardiomyocyte differentiation than normal CPCs.

Takeda says the finding of CD82 has important implications not only for heart therapies but also heart development.

"The high differentiation efficiency is exciting for cell therapies, because it means we can produce a pure population of cardiomyocytes. It also means we can study heart development more accurately."

• doi: 10.1016/j.celrep.2017.12.057