Zebrafish Extracellular Matrix Produces Enhanced Regeneration in Mouse Hearts

The big question in the study of the comparative biology of regeneration is the degree to which mammals retain the mechanisms needed for the exceptional regeneration found in species such as zebrafish and salamanders. The individuals of these highly regenerative species are capable of regrowing fins, limbs, and major portions of internal organs. Has evolution removed this machinery from mammals, or only buried it, leaving it dormant and awaiting activation? This experiment, in which the molecular signals provided via transplanted extracellular matrix material from zebrafish are shown to enhance heart regeneration in mice, argues for the latter theory. The heart in mammals is among the least regenerative of tissues, and does not recover well from damage, but there is considerable room for improvement in the healing processes for all mammalian tissues. Zebrafish and other highly regenerative species heal without scars and without loss of function, something that cannot be said for mammals.

Many lower forms of life on earth exhibit an extraordinary ability to regenerate tissue, limbs, and even organs - a skill that is lost among humans and other mammals. Now, researchers have used the components of the cellular "scaffolding" of a zebrafish to regenerate heart tissues in mammals, specifically mice, as well as exhibiting promising results in human heart cells in vitro. The researchers found that a single administration of extracellular matrix (ECM) material from zebrafish hearts restored the function of the heart and regenerated adult mouse heart tissues after acute myocardial infarction. The study also found that the zebrafish ECM protected human cardiac myocytes - specialized cells that form heart muscle - from stresses.

ECM are the architectural foundations of tissues and organs; not only do they provide a "scaffolding" on which cells can grow and migrate, they assist in the signaling necessary for the organ to develop, grow, or regenerate. In mammals, the heart quickly loses the ability to regenerate after the organism is born, except for a brief period after birth. In lower animals, such as zebrafish, the heart retains that ability throughout their lives: up to 20 percent of a zebrafish's heart can be damaged or removed, and within days the heart's capacity has been fully restored. The researchers first separated the ECM from the cells so that the recipient heart would not reject the treatment. They did this by freezing the zebrafish cardiac tissue, causing the cell membranes to burst and allowing the researchers to retrieve the ECM, a process called decellularization. They then injected the ECM into the hearts of mice with damaged heart muscles and watched the hearts repair themselves. It is difficult to inject foreign cells into a body because the body will recognize them as foreign and reject them. That's not the case with ECM because it is composed of collagen, elastin, carbohydrates and signaling molecules and has no cell surface markers, DNA or RNA from the donor, and so the recipient is less likely to reject the treatment.

Restored function starts almost immediately, and healing is noticeable as early as five days after treatment; within a week, his team could see the heart beating more strongly than the hearts of the untreated animals. The researchers tested the effectiveness of ECM from normal zebrafish and from zebrafish with damaged hearts, in which the ECM had already begun the healing process. They found that while both types of ECM were effective in repairing damage to the mice hearts, the ECM obtained from the zebrafish hearts that were healing were even more potent in restoring heart function in the mice. The researchers are now working on a process to regenerate nerves in mammals using the same process and hope to expand the heart treatments to larger animals in a future study.

Link: http://www.news.pitt.edu/news/how-do-you-mend-broken-heart


Very good news indeed! Now we need to find what signals from the ECM are responsible for the regeneration.

Posted by: Antonio at November 23rd, 2016 9:04 AM

It will be interesting to see how far the regenerative capabilities go when applied to mammals. As you highlight the heart isn't noted for its regenerative properties. There should be some grounds for optimism that if this works in mice, and can be replicated by further studies, it should work in humans, given that our last common ancestor was "only" 80 million years ago. It would be surprising if humans had lost the capability through evolution yet mice had retained it.

Posted by: Neil at November 23rd, 2016 3:32 PM

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