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Scarring critically impairs regeneration
Immune systems appear critical to regeneration. Research from the MDI Biological Laboratory in Bar Harbor, Maine, shows that heart regeneration in salamanders depends on their own white blood cells.
The most compelling question in regenerative medicine — why some organisms can regenerate any body part while others cannot — may lie with the body's innate immune system. This is according to a new study of heart regeneration in the axolotl, or Mexican salamander, an organism who takes the prize as a champion regenerator.
Research conducted by James Godwin PhD, found new heart muscle formation in adult axolotls following laboraory induced heart attacks, depends on macrophages - a type of white blood cell. If macrophages became exhausted, salamanders began to form scar tissue which blocked heart regeneration. Godwin's paper was published in Regenerative Medicine in partnership with Australia Regenerative Medicine Institute.
There are significant implications for human health from this study as salamanders and humans evolved from a common ancestor. It's possible the ability to regenerate is also built into our genetic code.
Godwin's research demonstrates scar formation is critical to blocking regeneration. "The scar shoots down the program for regeneration," he explains, "No macrophages means no cardiac regeneration."
Godwin hopes to activate human regeneration through use of drug therapies derived from macrophages, or therapies that trigger genetic programs controlling formation of macrophages, to promote scar-free healing. His team is already looking at molecular targets influencing gene programming.
"If humans could get over the fibrosis hurdle in the same way that salamanders do, the system that blocks regeneration in humans could potentially be broken. We don't know yet if it's only scarring that prevents regeneration or if other factors are involved. But if we're really lucky, we might find that the suppression of scarring is sufficient in and of itself to unlock our endogenous ability to regenerate."
The prevailing view in regenerative biology has been that the major obstacle to heart regeneration in mammals is insufficient proliferation of cardiomyocytes, or heart muscle cells. But Godwin found that cardiomyocyte proliferation is not the only driver of effective heart regeneration. His findings suggest that research efforts should pay more attention to the genetic signals controlling scarring.
The extraordinary incidence of disability and death from heart disease, which is the world's biggest killer, is directly attributable to scarring. When a human experiences a heart attack, scar tissue forms at the site of the injury. While the scar limits further tissue damage in the short term, over time its stiffness interferes with the heart's ability to pump, leading to disability and ultimately to terminal heart failure.
Godwin believes in addition to regenerating heart tissue following heart attack, unlocking dormant capabilities for regeneration by suppressing scarring has potential application for tissue and organ loss through traumatic injury, surgery and diseases.The next step is to study the function of macrophages in salamanders and compare them with human and mouse counterparts. Ultimately, Godwin would like to understand why macrophages produced by adult mice and humans don't suppress scarring the same way as in axolotls and identify molecular pathways to exploit for human therapies.
In dramatic contrast to the poor repair outcomes for humans and rodent models such as mice, salamanders and some fish species are able to completely regenerate heart tissue following tissue injury, at any life stage. This capacity for complete cardiac repair provides a template for understanding the process of regeneration and for developing strategies to improve human cardiac repair outcomes. Using a cardiac cryo-injury model we show that heart regeneration is dependent on the innate immune system, as macrophage depletion during early time points post-injury results in regeneration failure. In contrast to the transient extracellular matrix that normally accompanies regeneration, this intervention resulted in a permanent, highly cross-linked extracellular matrix scar derived from alternative fibroblast activation and lysyl-oxidase enzyme synthesis. The activation of cardiomyocyte proliferation was not affected by macrophage depletion, indicating that cardiomyocyte replacement is an independent feature of the regenerative process, and is not sufficient to prevent fibrotic progression. These findings highlight the interplay between macrophages and fibroblasts as an important component of cardiac regeneration, and the prevention of fibrosis as a key therapeutic target in the promotion of cardiac repair in mammals. npj Regenerative Medicine (2017) 2:22 ; doi:10.1038/s41536-017-0027-y
All authors: J. W. Godwin, R. Debuque, E. Salimova and N. A. Rosenthal
Godwin's research is supported by an Institutional Development Award (IDeA) to the MDI Biological Laboratory from the National Institute of General Medical Sciences of the National Institutes of Health under grant numbers P20GM0103423 and P20GM104318.
About the MDI Biological Laboratory
Our scientists are pioneering new approaches to regenerative medicine focused on drugs that activate our natural ability to heal, and that slow age-related degenerative changes. Our unique approach has identified new drugs with the potential to treat major diseases, demonstrating that regeneration could be as simple as taking a pill. As innovators and entrepreneurs, we also teach what we know. Our Maine Center for Biomedical Innovation prepares students for 21st century careers and equips entrepreneurs with the skills and resources to turn great ideas into successful products. For more information, please visit mdibl.org.
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The ability of the axolotl, or Mexican salamander, to regenerate the form and function of almost any body part makes it a popular model for the study of the genetic pathways for regeneration.
Image Credit: MDI Biological Laboratory