Novel stem cell strategy regenerates myocardium after heart attack

A study in a rat model used a new form of stem cells to regenerate myocardial cells and improve cardiac function after a heart attack, according to a study published in The Journal of Physiology.

“This research could lead to new treatments for people after suffering a heart attack, as it shows how we can promote the regeneration of cells in the heart,” said investigator Changhao Wu, MB, MD, PhD, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.

Previous studies have indicated that stem cell therapy can improve cardiac function and prognosis, but investigators have been stymied in their efforts to effectively use stem cells for myocardial regeneration.  

The researchers for this study took a different strategy that included four novel steps.

First, they used cardiospheres instead of regular stem cells. Cardiospheres are a form of stem cells derived in vitro from in situ stem cells of cardiac tissue. They have an outer layer of “cardiac-committed” cells and an inner core of undifferentiated cardiac stem cells. This structure mimics the niche microenvironment of cardiac stem cells in the heart, and has been shown to lead to high rate of stem cell survival, the researchers noted.

However, cardiospheres are very small and, if implanted by conventional methods, could leak into the bloodstream and potentially cause an embolism. (The researchers addressed this problem in the final step.)

For the second step, Dr. Wu and colleagues reasoned that they could increase the activity of the cardiospheres by preconditioning them in pericardial fluid in the lab.

Third, to enhance viability of the cells during the trip between the lab and the operating room, the researchers coated the preconditioned cardiospheres with matrix hydrogel. This step preserved more than 90% of cardiospheres for up to 12 hours, the investigators found.

For the fourth and final step, they injected the cardiospheres directly into the pericardial cavity. Administering medicine into the pericardium is a common drug delivery method for treating heart disease, yet it has received little attention as a delivery route for stem cells, the researchers noted. They figured that the walls of the pericardium would prevent the cardiospheres from entering the circulatory system (and causing an embolism), but allow the cardiospheres to diffuse into the epicardium and begin regenerating heart muscle.

“The membranes separating the pericardium and tissue in the heart muscle have tightly packed cells to limit cell penetration. Therefore, one would imagine that it would be difficult for the stem cells to migrate,” Dr. Wu said.

But, the researchers found, the cardiospheres did migrate to myocardial tissue and infiltrated into the infarcted area, where they survived for at least 4 weeks. The researchers used cell staining to show that cardiospheres differentiated into cardiac muscle cells directly after transplantation in vivo.

“The migration of the implanted stem cells from pericardium into the area of the heart affected by heart attack is an important finding. We were very excited as this result showed that implanted stem cells can directly differentiate into heart muscle cells,” Dr. Wu said.

Functionally, cardiosphere transplantation significantly increased left ventricle ejection fraction by about 40%. It also increased survival. At 4 weeks after induced heart attack, only 52% of untreated control rats had survived, compared with 80% of the treated rats.

“This is the first demonstration of direct pericardial administration of preoptimized cardiospheres, and its effectiveness on myocardial infarction by functional and morphological outcomes with distinct mechanisms,” the authors concluded. “These findings establish a new strategy for therapeutic myocardial regeneration to treat myocardial infarction.”