Understanding why some Mexican tetra fish regenerate their hearts after injury and why others develop scars may bring scientists one step closer to developing strategies to heal the human heart, according to new research published in Cell Reports and carried out by scientists at University College London and the University of Oxford.
Complete regeneration of the adult heart after injury is an exclusive feature in the animal kingdom and species such as the zebrafish have a scar-free regeneration process, with the wound tissue completely being replaced by new, functional cardiac muscle, making them a useful model organism for heart research in the past. However, it is difficult to identify genes purely regulating heart regeneration versus scarring while comparing different species with separate physiologies. This is where the researchers decided to focus on two populations of the same species, the Mexican tetra. The first population live close to the surface of rivers in Northern Mexico and can successfully heal their heart like zebrafish. The second population is blind and translucent, occupying the cave systems of Mexico but lack the ability to regenerate their hearts.
"Millions of years ago, some surface fish living in rivers flooded into caves, became trapped when river levels retreated and lost their eyes and pigment to adapt to cave life," says co-senior author Mathilda Mommersteeg, a developmental scientist at the University of Oxford. "We have discovered that, like zebrafish, the river surface fish regenerate their heart, while some cavefish cannot and form a permanent scar.
Mommersteeg and her team bred both surface and cavefish in the laboratory, performing surgery on some fish to remove a piece of their hearts. After surgery, surface fish slowly regenerated the missing tissue, while cavefish developed a scar. They then cross-bred both populations and performed the same surgery with their offspring showing different levels of regeneration, indicating that the ability to heal heart tissue is heritable in these fish.
"We have identified three regions in the DNA that contain genes that make the difference between regeneration or scarring after heart injury," says co-senior author Yoshiyuki Yamamoto, a developmental biologist at University College London. The researchers now want to know which genes in these regions are directly responsible for heart regeneration and why at some point along the evolutionary scale cavefish lost their ability to regenerate. "The next step is to find out what the reason is that surface fish can regenerate their hearts, but cavefish cannot," says Mommersteeg. "What is it that happened during their adaptation to cave life that stopped them from regenerating their hearts?"
Mommersteeg concluded by saying "Heart failure is a cruel and debilitating illness that more than half a million people across the UK are living with. It's early days but we're incredibly excited about these remarkable fish and the potential to change the lives of people with damaged hearts."
By Ellis Moloney
William T. Stockdale, Madeleine E. Lemieux, Abigail C. Killen, Juanjuan Zhao, Zhilian Hu, Joey Riepsaame, Noémie Hamilton, Tetsuhiro Kudoh, Paul R. Riley, Ronny van Aerle, Yoshiyuki Yamamoto, Mathilda T.M. Mommersteeg. (2018). Heart Regeneration in the Mexican Cavefish. Cell Reports; 25 (8): 1997 DOI: 10.1016/j.celrep.2018.10.072
This work was supported by British Heart Foundation (BHF) project grants PG/12/39/29626 (Y.Y. and M.T.M.M.) and PG/15/111/31939 (M.T.M.M.), the Biotechnology and Biological Sciences Research Council (BB/C517041/1) (Y.Y.), a BHF non-clinical PhD fellowship (FS/14/73/31107) (A.C.K. and M.T.M.M.), the BHF Centre of Regenerative Medicine (RM/13/3/30159), the BHF Centre of Research Excellence, Oxford (RE/13/1/30181), and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement 715895, CAVEHEART, ERC-2016-STG,