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Is an Extracellular Matrix Component the Key to Adult Cardiac Regeneration?

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Review of “The extracellular matrix protein Agrin promotes heart regeneration in mice” from Nature by Stuart P. Atkinson

For some researchers, regenerating the cardiomyocytes (CMs) of the heart represents the “holy grail” of regenerative medicine, given the countless millions of people around the globe suffering from heart disease. Recent encouraging research has centered round neonatal mice, where CMs can proliferate and repair cardiac injuries for around one week [1].

While studying how the composition of the extracellular matrix (ECM) surrounding CMs changes during this first week, the team from the laboratory of Eldad Tzahor (Weizmann Institute of Science, Rehovot, Israel) discovered that one component, Agrin, may represent the key to cardiac regeneration during neonatal periods [2]. Furthermore, their studies suggest that ECM modulation may represent a novel means to treat adult heart disease.

Bassat et al. initially discovered that ECM derived from neonatal mouse hearts induced CM proliferation and that the ECM component Agrin played a key role. Agrin, expressed by cardiac endothelial cells (ECs), directly stimulated CM proliferation in vitro partly by suppressing CM maturation and promoted cardiac regeneration in neonates. Excitingly, intramyocardial injection of Agrin also induced cardiac regeneration and improved cardiac function following an experimental myocardial infraction in both juvenile and adult hearts.

So how does Agrin inhibit CM maturation and promote cardiac regeneration? The authors discovered that, in part, Agrin functions by destabilizing the Dystrophin-glycoprotein complex (DGC), a large multicomponent complex that mediates interactions between the cytoskeleton, membrane, and extracellular matrix, via binding to the α-dystroglycan (Dag1) Agrin receptor. This reduced level of DGC stability then promotes myofibril disassembly and the activation of downstream signaling molecules including Yap and ERK, a model supported by several recent studies [3-6].

While the authors believe that Agrin may represent a relatively simple, safe, and effective means of repairing damaged adult human hearts, further analysis of important ECM components may reveal further components that further enhance cardiac regeneration. 

In Agrin, have we found the “holy grail” of regenerative medicine? Stay tuned to the Stem Cells Portal to find out!

References

  1. Porrello ER, Mahmoud AI, Simpson E, et al. Transient regenerative potential of the neonatal mouse heart. Science 2011;331:1078-1080.
  2. Bassat E, Mutlak YE, Genzelinakh A, et al. The extracellular matrix protein agrin promotes heart regeneration in mice. Nature 2017;547:179-184.
  3. Morikawa Y, Zhang M, Heallen T, et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci Signal 2015;8:ra41.
  4. D'Uva G, Aharonov A, Lauriola M, et al. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nat Cell Biol 2015;17:627-638.
  5. Yahalom-Ronen Y, Rajchman D, Sarig R, et al. Reduced matrix rigidity promotes neonatal cardiomyocyte dedifferentiation, proliferation and clonal expansion. Elife 2015;4:
  6. Reischauer S, Arnaout R, Ramadass R, et al. Actin binding GFP allows 4D in vivo imaging of myofilament dynamics in the zebrafish heart and the identification of Erbb2 signaling as a remodeling factor of myofibril architecture. Circ Res 2014;115:845-856.