Boston, MA - Local delivery of periostin, an extracellular matrix protein, can induce the reentry of differentiated cardiomyocytes into the cell cycle, and these stimulated mononucleated cardiomyocytes are capable of going through full cell division, a new study has shown [1]. After experimental MI in an animal model, investigators also showed that cardiomyocyte cell-cycle reentry and mitosis were associated with improved ventricular remodeling and myocardial function, reduced infarct size and fibrosis, and increased angiogenesis.

"This is a novel approach to how one might think about treating heart failure," explained lead investigator Dr Bernhard Kühn (Children's Hospital Boston, MA). "Currently medical therapy is approaching a ceiling, where we're treating with ACE inhibitors, beta blockers, and so forth, and while these are very important, the increment of benefit with each drug is getting smaller and smaller. The way out and around that is to make more myocardium."

The study is published online in the July 15, 2007 issue of Nature Medicine.

Speaking with heartwire, Kühn said the loss of cardiomyocytes after an MI typically results in heart failure. In stimulating cardiomyocytes to reenter the cell cycle in response to extracellular signals after infarction, it might be possible to prevent this resulting loss of function. By applying various extracellular factors, such as periostin, which is derived from the skin around bone, investigators hoped to induce cell proliferation and enhance cardiac regeneration. The adult heart has only small amounts of periostin, said Kühn, noting it is largely present during fetal heart development as well as after injury to stimulate cells to begin dividing.

"Periostin was initially cloned from a cell line that was derived from cells that are around the bone, cells that make up the periosteum," he said. "Subsequently, it was discovered that in many other tissues, the expression of periostin is usually downregulated in adult life but upregulated after bone fracture, skeletal muscle injury, vessel injury, and also briefly upregulated after myocardial injury. Usually, though, it is absent in adult life, so the idea was to try a couple of different substances in the petri dish to see if they can stimulate cell-cycle reentry and division of differentiated cardiomyocytes. We tried a bunch of substances that made sense, and most of them didn't work, but periostin was one that did."

Investigators found that approximately 1% of cells entered the mitotic cell cycle, supporting the concept that differentiated cells can proliferate. As it turns out, cells with one nucleus are more likely to enter the cell cycle than those with two or more nuclei. Kühn said that the most differentiated cardiomyocytes have two nuclei, but data suggest that approximately 5% of adult cardiomyocytes are mononucleated and could potentially reenter the cell cycle. In addition, the researchers were able to characterize the receptor for periostin as well as the relevant intercellular signal transduction pathways.

The next stage involved moving on to an animal model to determine whether the proliferation of cells resulted in functional improvements. Looking at two time points, one week and 12 weeks, in rats with induced MI, investigators observed functional and structural improvements via the enhancement of cardiac repair or regeneration when they were treated with periostin. The rats had improved ejection fractions and improved ventricular remodeling, as well as decreased left-ventricular wall stress. There was also less fibrosis, a decreased infarct size, and improved angiogenesis. At the cellular level, the periostin-treated rats had an approximate 100-fold increase in the number of cells entering the mitotic cycle and also grew more cardiomyocytes.

Kühn told heartwire that periostin and the pathway it regulates might provide a target for new strategies to treat heart failure and possibly congenital heart defects in children.

"There are some data out there that suggest the number of mononucleated cells goes down with age and with disease," said Kühn. "It might be conceivable that if you consider the proliferation of cells we would start with a younger patient. What's against us here is that a lot of disease might be caused by genetic disorders and might also affect the cardiomyocytes, so we might be starting off with diseased cardiomyocytes, then making more diseased cardiomyocytes, which may or may not be good for you. It'll have to be tested."