Heart regeneration a step closer as researchers identify progenitor cell exclusively for heart muscle.


Future therapies for failing hearts are likely to include stem-like cells and associated growth factors that regenerate heart muscle. Now, researchers from the University of Pennsylvania have just taken an important step towards that future by identifying a stem-like progenitor cell that produces only heart muscle cells.  The team state that they have defined the progenitor cell that is committed to making heart muscle and started to define the factors that make that cell grow and form heart muscle cells.  The study is published in the journal Science.

Previous studies show that evolution has left the mammalian heart with relatively little self-repair capacity compared to skin, bone, and other tissues, possibly because an extensive repair process would compromise the heart’s ability to keep working. Nevertheless, scientists have been trying to find ways to amplify the heart’s limited regenerative potential and have looked for clues in the embryonic phase of life, when the heart forms itself from stem-like cardiac progenitor cells (CPCs).

The team state that a major goal of the medical community has been to understand how CPCs give rise to the different cell types of the mature heart, which include muscle cells (cardiomyocytes) and endothelial cells that line cardiac chambers and valves. In particular, scientists have wanted to identify progenitor cells that have matured just beyond the ‘multipotent’ CPC state, so that they are committed to making just one type of cardiac cell.

In the current study the researchers identified a cardiac progenitor, which they term a cardiomyoblast, that gives rise exclusively to cardiomyocytes. The finding occurred somewhat unexpectedly while the lab was performing ‘lineage tracing’ experiments on mouse CPCs by marking different cells with fluorescent beacons and observing their fates as they proliferated and matured. The scientists found that CPCs expressing a particular protein called Hopx always went on to form cardiomyocytes.

At first the team thought that Hopx would also mark a multipotent progenitor cell, however, they were surprised to learn that it was marking only the cells that were going on to make heart muscle.

Hopx has previously been identified as a marker of progenitor cells in other tissues, including the gut, hair follicles, and lungs. Earlier studies from the team first linked it to heart development in a study published in 2002, noting that its deletion leads to severe heart defects in mice and zebrafish.

To find out more about Hopx’s role in heart development the current study overexpressed it in embryonic mouse hearts and observed that at an early phase of development this overexpression led to an increase in the number of cardiomyocytes. The results showed that Hopx exerts this effect by suppressing the activity of genes in the Wnt signaling pathway, which helps maintain some cells in a multipotent, stem-like state. By contrast, embryonic heart cells lacking Hopx showed higher levels of Wnt signaling and gave rise to far fewer myocytes.

Previous studies have shown that the suppression of Wnt signaling in multipotent progenitor cells typically induces them to move towards a more mature cell type. In the heart and other tissues, that process has been linked to the activity of another protein called Bmp. The current study found that for heart cell development, Hopx is a critical go-between, associating with Smad proteins to work as Bmp’s enforcers in the suppression of Wnt signaling.

The researchers state that their data findings expand the basic scientific knowledge of how the mammalian heart develops and should speed research in this area, not least because scientists now have a definitive marker, Hopx, that they can use to isolate the cardiomyoblast progenitors that specifically make heart muscle cells.  They go on to add that the study findings is expected to accelerate the development of future cardiac therapies, which might include the injection of cardiomyoblasts into damaged hearts and implantable bioengineered patches of heart muscle.

The researchers surmise that knowing how Hopx and other factors help generate myocytes in the embryonic heart might also lead to drugs that stimulate the adult heart to produce its own new myocytes.  They note that previous basic studies of how blood cells develop led to blockbuster medicines such as the red cell growth factor EPO, and the white cell booster GM-CSF.

A next step for the lab in this line of research is to see if the cardiomyoblasts and other factors that generate heart muscle cells in early life also do so to some extent in later life, after a heart attack or other injury.  The team hope that by understanding how it happens in the embryo will assist in finding the cells that play a similar role in the adult heart.

Source:  Perelman School of Medicine at the University of Pennsylvania 

 

Hopx expression during cardiogenesis.  GFP expression in Hopx 3XFlag/+ embryos representing endogenous Hopx expression at indicated time points.  Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts.  Epstein et al 2015.

Hopx expression during cardiogenesis.
GFP expression in Hopx 3XFlag/+
embryos representing endogenous Hopx expression at indicated time points. Integration of Bmp and Wnt signaling by Hopx specifies commitment of cardiomyoblasts. Epstein et al 2015.

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