The heart's limitations
Two signaling pathways interact to constrain the mammalian heart's ability to self-renew
Two seemingly disparate signaling pathways -- one that controls organ size in fruit flies and another important for the growth of embryos -- interact in embryonic mouse hearts to restrict cell proliferation and control heart size.
| Wild-type (left) and Hippo mutant (right)|
neonate mouse hearts
Courtesy of Todd Heallen, Janelle Heallen and James Martin, Texas A&M Health Science Center
Mammalian hearts have only a scant capacity to regenerate heart muscle cells, known as cardiomyocytes, to repair tissue damaged as a result of a heart attack or heart disease. The new research, linkurl:published today (April 21) in Science,
;http://www.sciencemag.org/ suggests it may be possible to interfere with signaling pathways that limit such regeneration to therapeutically promote the production of muscle cells in damaged hearts.
"It's a fine piece of fundamental developmental biology," said linkurl:Michael Schneider,;http://www1.imperial.ac.uk/medicine/people/m.d.schneider/ head of the National Heart and Lung Institute at the Imperial College London, who was not involved in the study, that could help "fuel a resurgence in interest in cell cycle approaches to cardiac repair."
Little is known about the genetic regulation of heart size, especially in mammals. But in Drosophila,
a signaling pathway called Hippo inhibits cell proliferation and promotes cell death in several organs, controlling their size. Mammals have signaling kinases homologous to the Hippo proteins, but their involvement in mammalian heart size regulation has remained unclear.
linkurl:James Martin;http://www.ibt.tamhsc.edu/faculty/bio-jmartin.html and colleagues at the Texas A&M Health Science Center assessed the role of the Hippo signaling pathway in mouse embryos to see if it might play a role in heart size. The team made conditional knockouts of Hippo signaling proteins in cardiomyocytes, resulting in "massive Hippo hearts," says Martin -- organs up to 2.5 times the size of normal mouse hearts.
Follow-up microarray experiments revealed the upregulation of genes in the Wnt signaling pathway, a network of proteins well known for its role in embryogenesis and implicated in cardiomyocyte differentiation and growth. Embryonic mice deficient in both pathways developed hearts that were normal in size, the team found, suggesting that the Hippo pathway normally suppresses Wnt signaling, which encourages cardiomyocyte proliferation.
"These two pathways are really critical for growth, telling a cell when to grow and when not to grow," said Martin. "Connecting these two pathways has been really interesting."
Next the researchers plan to look at the function of Hippo and Wnt pathways in newborn and adult mouse hearts. linkurl:A study in February;http://www.ncbi.nlm.nih.gov/pubmed/21350179 demonstrated that newborn mice have the ability to produce new cardiomyocytes to repair damage right after birth, but they lose this ability at about seven days old. "We wonder if Hippo is involved in that loss of ability to repair," said Martin.
The new results raise the possibility that scientists could repress growth-restricting pathways in human hearts to stimulate new cardiomyocyte growth following heart attacks or heart disease, an area of research that scientist have backed away from in the last few years in favor of stem cell therapies. But these new findings, together with the newborn mice study and linkurl:recent research;http://www.ncbi.nlm.nih.gov/pubmed/20336145 showing that zebrafish hearts grow new cells through proliferation of cardiomyocytes, not stem cells, are "three stakes in the ground that will drive interest" in the field, says Schneider, who wrote an accompanying perspective in Science.
"We just needed new pathways to look at, and Hippo is a relatively new heart pathway that people haven't been thinking about too much," agreed Martin. "I think it's going to be valuable."
Heallen, T., et al., "Hippo Pathway Inhibits Wnt Signaling to Restrain Cardiomyocyte Proliferation and Heart Size," Science, 332:458-61, 2011.
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