Developmental
& Stem Cell
Biology

"Ten years ago most people doubted
that the heart could regenerate at all. Thanks
to ground breaking studies, we can now
dream of new medicines that will augment
the human heart's innate ability to regenerate
the muscle cells lost after a heart attack,"

- Professor Richard Harvey 

Professor Richard Harvey 

head, development & stem cell biology laboratory

research overview

Key Research Areas

  • Heart development
  • Congenital heart disease
  • Transcription factor function
  • Cardiac systems biology
  • Cardiac stem cells and regeneration
  • Human disease modelling using pluripotent stem cells  

Research Overview 

The Harvey lab focuses on the development, function and regeneration of the mammalian heart, and the different layers of information – developmental, cellular, molecular, genetic and epigenetic – that guide these processes. In humans, the heart begins to beat after the first few weeks of embryonic life when it is still a simple muscular tube. As heart structure develops through the formation of valves and specialised pumping and electrical systems, it meets the increasing demands of the growing embryo.

Cardiovascular disease is a major cause of death and disability. Led by Professor Richard Harvey, the lab is seeking to understand how gene defects cause heart abnormalities in babies, and how this information can be used to help families. The lab also studies cardiac stem cells and stromal cells in the adult heart and how they might be targeted therapeutically for heart regeneration. 

research projects

There are a number of key projects underway in the Developmental and Stem Cell Biology Laboratory, led by Professor Richard Harvey:

1. Genetic basis of mammalian heart development and congenital heart disease

Our previous research has helped to define the key cardiac transcription factors and pathways regulating heart development, and the patterning principals that govern its morphogenesis. We continue to use the mouse model harnessing the ability to make subtle genetic manipulations, as well as patient-specific induce pluripotent stem cells as human disease models. We are currently focusing on how development of epicardial cell behaviour is regulated by transcription factors such as NKX2-5, and how ventricular chamber architecture is defined by the interactions between the NOTCH and NEUREGULIN signalling pathway in endocardium and myocardium, respectively.

2. Genetic basis of congenital heart disease in humans

It is becoming increasingly evident that many congenital malformations of the heart, which are common in babies, can be traced back to the very earliest stages of heart development, arising as behavioural defects in stem and progenitor cell populations in the embryo. Understanding the connections between congenital heart malformations and embryonic mechanisms is one of our key goals, and we use both mouse models and human genetic screening to further this goal. Genome sequencing of patients with congenital heart disease is a powerful and exciting discovery tool, although functional genomics approaches are essential to study the impact of gene variants on development and disease.

3. Cardiac gene regulatory networks

We seek to contextualise heart development and disease in a framework of thinking that takes into account the hierarchy of regulatory systems (systems biology). Such systems are regulated in part by conserved transcription factors that bind to cis-regulatory DNA elements in gene promoters and enhancers. We are using the technique of DamID for genome-wide transcription factor target gene identification, adapting it to a core set of cardiac-restricted and ubiquitous regulatory transcription factors. DamID has also allowed us to study how transcription factor mutations found in congenital heart disease patients have their impact at a genome-wide level. We discovered that mutant proteins can alter the expression of hundreds of targets not normally regulated by the wild type protein. We are now using this DamID to probe the logic of gene regulatory networks in heart development.

4. Biology of endogenous cardiac stem cells and prospects for cardiac regeneration

Unlike the hearts of fish and certain amphibian species, the adult mammalian heart is not regarded as a regenerative organ. However, fetal and neonatal hearts can regenerate after genetic or ischemic injury. Much effort is now being focused on understanding the mechanisms of heart regeneration in these permissive contexts and the barriers to regeneration in the adult human heart. Recently we have begun to explore the biology of endogenous cardiac stem cells and the prospects for harnessing their properties to ultimately stimulate heart regeneration. This is an exciting time in regeneration biology and our program is attempting to uncover new approaches to treating heart disease through regenerative medicine. We have developed a mouse model of enhanced cardiac repair after myocardial infarction through growth factor delivery. We are applying single cell tracking and transcriptomics, which allow us to probe cardiac cell types and how they interact in the regenerative setting at an unprecedented level.

5. Using pluripotent stem cells to model congenital heart disease 

 The ability to create patient-derived induced pluripotent stem cells (iPSCs) that can be propagated indefinitely and differentiated into virtually any cell type in vitro, represents a major shift in our ability to model human disease. This technology, developed just a decade ago, makes it possible to recreate specific disease-relevant tissue types from the patient’s own cells in order to understand the genetic origins of disease, as well as disease gene-environment and gene-drug interactions. We have established the iPSC system and are exploring the genetic basis of one of the most severe cardiac congenital abnormalities – hypoplastic left heart (HLH). HLH babies have hearts with an underdeveloped left ventricle and face a series of invasive surgeries aimed at establishing partial functionality to the crippled heart. They face a lifetime of uncertainty and a high risk of cardiac failure. Using the iPSC model, we have investigated the cardiac cell functionality and gene expression in 10 HLH families and discovered a common disease pathway that is now being further characterised. This finding presents the possibility of developing drugs that target this pathway to stimulate heart growth and help restore functionality in HLH neonates.


laboratory members & collaborators

Laboratory Members 

Bernice Stewart, Personal Assistant 

Dhanushi Abeygunawardena, PhD Student

Ann-Kristin Altekoester, PhD Student

Hana Fonoudi, PhD Student

Nona Farbehi – PhD Student

Gonzalo del Monte, Senior Postdoctoral Scientist 

Vaibhao Janbandhu, Postdoctoral Scientist 

Ralph Patrick, Postdoctoral Scientist 

Aude Dorison, Postdoctoral Scientist 

Junjie Du, Senior Staff Scientist 

Bharti Shewale, Research Assistant

Arne Adam, Research Assistant 

Renuka Gupta, Research Assistant

Collaborators 

Eldad Tzahor, Weizmann Institute

 Bin Zhou, Albert Einstein College of Medicine

David Winlaw, The Children’s Hospital at Westmead

Didier Stainier, Max Planck Institute for Heart and Lung Research

Nenad Bursac, Duke University

Jason Kovacic, Mt Sinai School of Medicine

Patrick Tam, The Children’s Medical Research Institute

Robert Nordon, University of New South Wales

Mat Francois, Institute of Molecular Bioscience

David Elliott, Murdoch Childrens Research Institute

James Hudson, University of Queensland

publication highlights

1. Harvey RP, Krieg PA, Robins AJ, Coles LS, Wells JRE. Non-tandem arrangement and divergent transcription of chicken histone genes. Nature 1981; 294:49-53

2. Harvey RP, Whiting JA, Coles LS, Krieg PA, Wells JRE. H2A.F: an extremely variant histone H2A sequence expressed in the chicken embryo. Proceedings of the National Academy of Sciences (USA) 1983; 80:2819-23

3. Rebagliati MR, Weeks DL, Harvey RP, Melton DA. Identification and cloning of localised maternal RNAs from Xenopus eggs. Cell 1985; 42:769-77

4. Harvey RP, Melton DA. Microinjection of synthetic Xhox-1A homeobox mRNA disrupts somite formation in developing Xenopus embryos. Cell 1988; 53:687-97 

5. Lints TJ, Parsons LM, Hartley L, Lyons I, Harvey RP. Nkx-2.5: a novel murine homeobox gene expressed in early heart progenitor cells and their myogenic descendants. Development 1993; 119:419-31

6. Lyons I, Parsons LM, Hartley L, Li R, Andrews J, Robb L, Harvey RP. Myogenic and morphogenetic defects in the heart tubes of murine embryos lacking the homeo box gene Nkx2-5. Genes & Development 1995; 9:1654-66. [Journal Cover]

7. Hentsch B, Lyons I, Li R, Hartley L, Lints T, Adams JM, Harvey RP. Hlx homeo box gene is essential for an inductive tissue interaction that drives expansion of embryonic liver and gut. Genes & Development 1996; 10:70-79

8. Biben C, Harvey RP. Homeodomain factor Nkx2-5 controls left/right asymmetric expression of bHLH gene eHand during murine heart development. Genes and Development 1997; 11:1357-69. [Journal Cover]

9. Ranganayakulu G, Elliot DA, Harvey RP, Olson EN. Divergent roles for Nk-2 class homeobox genes in cardiogenesis in flies and mice. Development 1998; 125:3037-48

10. Semsarian C, Wu M-J, Ju Y-K, Marciniec T, Yeoh T, Allen DG, Harvey RP, Graham RM. Skeletal muscle hypertrophy is mediated by a Ca2+ -dependent calcineurin signalling pathway. Nature 1999; 400:576-81

11. Christoffels VM, Habets PEMH, Franco D, Campione M, de Jong F, Lamers WH, Bao Z-Z, Palmer S, Biben C, Harvey RP, Moorman AFM. Chamber formation and morphogenesis in the developing mammalian heart. Developmental Biology 2000; 223:266-78

12. Chen F, Kook H, Milewski R, Gitler AD, Lu MM, Li J, Nazarian R, Schnepp R, Jen K, Biben C, Runke G, Mackay J, Novotny J, Schwartz RJ, Harvey RP, Mullins MC, Epstein JA. Hop is an unusual homeobox gene that modulates cardiac development. Cell 2002; 110:713-23

13. Elliott DA, Kirk E, Yeoh T, Chander S, McKenzie F, Taylor P, Grossfield P, Fatkin D, Jones O, Hayes P, Feneley M, Harvey RP. Cardiac homeobox gene NKX2-5 mutations and congenital heart disease: Associations with atrial septal defect and hydroplastic left heart syndrome. Journal of the American College of Cardiology 2003; 41:2072-76

14. Stennard FA, Costa MW, Lai D, Biben C, Preis JI, Dunwoodie SL, Elliott DE, Prall OWJ, Black BL, Fatkin D, Harvey RP. Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaption. Development 2005; 132:2451-462

15. Elliott DA, Solloway MJ, Wise N, Biben C, Costa M, Furtado MB, Lange M, Dunwoodie S, Harvey RP. A tyrosine-rich domain within homeodomain transcription factor Nkx2-5 is an essential element in the early cardiac transcriptional regulatory machinery. Development 2006; 133:1311-22

16. Prall OW, Menon MK, Solloway MJ, Watanabe Y, Zaffran S, Bajolle F, Biben C, McBride JJ, Robertson BR, Chaulet H, Stennard FA, Wise N, Schaft D, Wolstein O, Furtado MB, Shiratori H, Chien KR, Hamada H, Black BL, Saga Y, Robertson EJ, Buckingham ME, Harvey RP. An Nkx2-5/Bmp2/Smad1 negative feedback loop controls heart progenitor specification and proliferation. Cell. 2007 Mar 9;128(5):947-59

17. Kirk EP, Sunde M, Costa MW, Rankin SA, Wolstein O, Castro MK, Butler TL, Hyun C, Guo G, Otway R, Mackay JP, Waddell LB, Cole AD, Hayward C, Keogh A, Macdonald P, Griffiths L, Fatkin D, Sholler GF, Zorn AM, Feneley MP, Winlaw DS, Harvey RP. Mutations in cardiac T-box factor gene TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis, and cardiomyopathy. American Journal of Human Genetics 2007; 81:280-91

18. Yadava RS, Frenzel I–I, McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thorton CA, Prall OWJ, Harvey RP, Mahadevan MS. RNA toxicity in myotonic muscular dystrophy induces NKX2-5 expression. Nature Genetics 2008; 40:61-6.

19. Drenckhahn J-D, Schwarz QP, Gray S, Laskowski A, Kiriazis H, Ming Z, Harvey RP, Du X-J, Thorburn DR, Cox TC. Compensatory growth of healthy cardiac cells in the presence of diseased cells restores cardiac tissue homeostasis during heart development. Developmental Cell 2008; 15:521-33 [Journal Cover]

20. Furtado MB, Solloway MJ, Jones VJ, Costa MW, Biben C, Wolstein O, Preis JI, Sparrow DB, Saga Y, Dunwoodie SL, Robertson EJ, Tam PP, Harvey RP. BMP/SMAD1 signaling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4. Genes Dev. 2008 Nov 1;22(21):3037-49

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