Cardiac
Regeneration

"I was inspired to work in heart
research when I was a medical student
in Japan. I was seeing patients who
were suffering from heart disease and
I couldn't help noticing how badly
they struggled to recover"


- Dr Kazu Kikuchi 

Dr Kazu Kikuchi

Head, Cardiac Regeneration Laboratory

research Overview

Key Research Areas

  • Cardiomyocyte dedifferentiation and proliferation mechanisms
  • Roles of non-myocytes in heart regeneration
  • Immune regulation of organ regeneration
  • Developing tools that facilitate regeneration research

Research Overview 

The major interest of the Cardiac Regeneration Laboratory is to understand the mechanisms of heart regeneration. In mammals and indeed humans, the heart does not undergo regeneration after damage, such as from a heart attack. Instead, the damaged tissue is replaced by fibrotic scar tissue, which provides a quick repair from the damage, but fails to restore cardiac function and increases susceptibility to heart failure. By contrast, some vertebrates such as salamander and fish are known to naturally regenerate heart muscle with little scar formation after injury. The Kikuchi Laboratory uses the zebrafish, a small tropical freshwater fish which is highly amenable to genetic manipulations, to study the molecular and cellular regulations of heart muscle regeneration. The group has a long-term objective of finding out how this type of regeneration might be used to repair damaged human hearts.


research projects

There are 2 key projects underway in the Cardiac Regeneration Laboratory, led by Dr Kazu Kikuchi;

1. Cardiomyocyte dedifferentiation and proliferation mechanisms

A previous study led by Kikuchi showed that regenerating a damaged zebrafish heart muscle is surprisingly not based on stem cells, but involves the activation and dividing of the existing heart cells (called cardiomyocytes). Mice also have some ability to repair damaged heart muscle by using a similar mechanism to the zebrafish The Kikuchi Laboratory is further investigating the molecular mechanisms that induce the growth of new heart cells in the injured zebrafish heart. It is hoped that the results from this project may lead to the development of molecules that stimulate new heart cells to grow in the damaged human heart.

2. Immune regulation of organ regeneration 

A previous study led by Kikuchi showed that regenerating a damaged zebrafish heart muscle is surprisingly not based on stem cells, but involves the activation and dividing of the existing heart cells (called cardiomyocytes). Mice also have some ability to repair damaged heart muscle by using a similar mechanism to the zebrafish The Kikuchi Laboratory is further investigating the molecular mechanisms that induce the growth of new heart cells in the injured zebrafish heart. It is hoped that the results from this project may lead to the development of molecules that stimulate new heart cells to grow in the damaged human heart.

Laboratory members & collaborators

Laboratory 

Subhra Prakash Hui, Postdoctoral Scientist 

Masahito Ogawa, Postdoctoral Scientist 

Kaiming Luo, PhD Student 

Delicia Zhe Sheng, Senior Research Assistant

David Zheng, Research Assistant 

Maki Nakayama, Research Assistant 

Collaborators

Shane Grey, Garvan Institute of Medical Research

Daniel Hesselson, Garvan Institute of Medical Research

Kylie Webster, Garvan Institute of Medical Research

Jonathan Sprent, Garvan Institute of Medical Research

Christopher Goodnow, Garvan Institute of Medical Research

Simon Barry, University of Adelaide

Xiangjian Zheng, University of Sydney

Stefan Oehlers, University of Sydney

publication highlights

1. Sugimoto K, Hui SP, Sheng DZ, Kikuchi K. Dissection of zebrafish shha function using site-specific targeting with a Cre-dependent genetic switch. eLIFE DOI: 10.7554/eLife.24635.

2. Sugimoto K, Hui SP, Sheng DZ, Gonzalez-Rajal A, Nakayama M, Kikuchi K. Zebrafish Foxp3a is required for the maintenance of immune tolerance. Developmental and Comparative Immunology 73:156-62 (2017).

3. Xiang M. S. W., Kikuchi K, Endogenous mechanisms of cardiac regeneration. International Review of Cell and Molecular Biology 326:67-131 (2016).

4. Karra K, Knecht A, Kikuchi K, Poss KD. Myocardial NF-κB activation is essential for zebrafish heart regeneration. Proceedings of the National Academy of Sciences of USA 112:13255-13260 (2015).

5. Kikuchi K. Dedifferentiation, transdifferentiation, and proliferation: mechanisms underlying cardiac regeneration in zebrafish. Current Pathobiology Reports 3:81-88 (2015).

6. Kikuchi K. Advances in understanding the mechanism of zebrafish heart regeneration. Stem Cell Research 13:542-555 (2014).

7. Nachtrab G, Kikuchi K, Tornini VA, and Poss KD. Transcriptional components of anteroposterior positional information during zebrafish fin regeneration. Development. 140:3754-64 (2013)

8. Fang Y, Gupta V, Karra R, Holdway JE, Kikuchi K, Poss KD. Translational profiling of cardiomyocytes identifies an early Jak1/Stat3 injury response required for zebrafish heart regeneration. Proceedings of the National Academy of Sciences of USA 110:13416-21 (2013).

9. Guner-Ataman B, Paffett-Lugassy N, Adams MS, Nevis KR, Jahangiri L, Obregon P, Kikuchi K, Poss KD, Burns CE, Burns CG. Zebrafish second heart field development relies on ALPM progenitor specification and nkx2.5 function. Development 140:1353-63 (2013).

10. Kikuchi K*, Poss KD* (*Co-correspondence author). Cardiac regenerative capacity and mechanisms. Annual Review of Cell and Developmental Biology 28:719-41 (2012). 

11. Wang J, Panakova D, Kikuchi K, Holdway JE, Gemberling M, Burris J, Singh SP, Dickson A, Lin YF, Sabeh K, Werdich A, Yelon D, MacRae C, Poss KD. The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development 138:3421-30 (2011).

12. Kikuchi K, Gupta V, Wang J, Holdway JE, Wills AA, Fang Y, and Poss KD. tcf21+ epicardial cells adopt non-myocardial fates during zebrafish heart development and regeneration. Development 138:2895-902 (2011).

13. Kikuchi K, Holdway JE, Major RJ, Blum N, Dahn RD, Begemann G, Poss KD. Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration. Developmental Cell 2011. 20:397-404 (2011).

14. Liu J, Bressan M, Hassel D, Huisken J, Staudt D, Kikuchi K, Poss KD, Mikawa T, Stainier DYR. A dual role for ErbB2 signaling in cardiac trabeculation.  Development 137:3867-75 (2010).

15. Yin C, Kikuchi K, Hochgreb T, Poss KD, Stainier DYR. Hand2 regulates extracellular matrix remodeling essential for gut-looping morphogenesis in zebrafish. Developmental Cell 18:973-84 (2010).

16. Kikuchi K, Holdway JE, Werdich AA, Anderson RM, Fang Y, Egnaczyk GF, Evans T, MacRae CA, Stainier DYR, Poss KD. Primary contribution to zebrafish heart regeneration by gata4+ cardiomyocytes. Nature 464:601-5 (2010). 

17. Lepilina A*, Coon AN*, Kikuchi K, Holdway JE, Roberts RW, Burns CG, Poss KD (*Co-first author). A dynamic epicardial injury response supports progenitor cell activity during zebrafish heart regeneration. Cell 127:607-19 (2006).   

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