Adult cardiac fibroblasts tell neighbouring myocytes to expand; embryonic fibroblasts say proliferate
Though cardiac muscle cells proliferate in embryos, they unfortunately lose this function as the heart matures. Adult cardiomyocytes tend to grow through hypertrophy (increased cell size) rather than hyperplasia (increased cell number), even though the latter process is often more desirable.
Publishing in Developmental Cell, researchers led by Deepak Srivastava at the Gladstone Institute of Cardiovascular Disease in San Francisco, California, have now identified the key factors and cell types responsible for cardiomyocyte proliferation and have helped explain the differences between the adult and embryonic behaviour of these cells1.
Previous research has shown that hypertrophy is promoted by the interactions of cardiomyocytes with factors secreted by cardiac fibroblasts, a population of cells embedded within the extracellular matrix2, 3. Srivastava's team developed a new co-culture system in which cardiac ventricular cardiomyocytes (as identified by the marker Nkx2.5 linked to yellow fluorescent protein) were co-cultured with embryonic cardiac fibroblasts. Cardiomyocytes cultured with embryonic cardiac fibroblasts proliferated more quickly than those cultured with adult cardiac fibroblasts, and cardiomyocytes co-cultured with the adult fibroblasts showed distinct signs of hypertrophy. Further investigation led to the identification of fibronectin, collagen and a heparin-binding EGF-like growth factor as likely substances that fibroblasts secrete to promote proliferation. In addition, the cell-surface receptor integrin 1, which is present in embryonic cardiomyocytes but not adult cardiomyocytes, seems to be required in order for cells to respond to these proliferative signals; when the gene for this protein is deleted in cardiac cells, developing mice die in utero or just after birth, and cells within their heart muscles are both less numerous and poorly integrated
Srivastava hopes to use this information to find ways to make adult cardiomyocytes proliferate. "The next step is to engineer the adult fibroblasts to secrete the embryonic-like factors and to put the appropriate receptor on the adult myocytes so they can receive that signal", he says. Should these techniques prompt appropriate growth, it could open up potential treatments for such diseases as cardiomyopathy and left ventricular hypertrophy.
"This promises to focus researchers in the hunt for the switches that modulate cardiac myocyte division", says Kit Parker of the Harvard School of Engineering and Applied Science in Cambridge, Massachusetts. Though the work needs to be verified with more sophisticated cell and tissue engineering methods, he says, "the paper is very interesting and suggests that communications between heterogeneous cell populations may be mediated by extracellular matrix and the integrin-mediated mechanotransduction pathways." The work shows not only how cells receive messages, but also that messages morph. "So this means that something is changing postpartum. The signaling pathway, with many of the same components, has different outcomes in the womb versus in the adult heart." He adds that his colleague Don Ingber at Children's Hospital Boston has found a similar phenomenon in the context of angiogenesis, and that potential applications to understanding this phenomenon are exciting. "When we identify the variable components, it opens up all kinds of therapeutic possibilities."
It's possible, says Srivastava, that the proliferation of progenitor cells in many tissues could be controlled by paracrine signalling, or secretions from nearby cells. "Since fibroblasts are in each organ, we think that the differences between embryonic and adult fibroblasts may be widely applied", he says. If so, any regenerative implications for this work could extend past the cardiac region.