Developmental& RegenerationBiology

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 cardiovascular system begins to function after the first few weeks of embryonic life when the heart is just a simple muscularised vessel. It then begins to develop complexity through the formation of valves and specialised pumping, neurohormonal, electrical and metabolic systems that increase the heart’s efficiency and responsiveness to intrinsic and extrinsic cues, and to satisfy the increasing demands of the growing embryo, neonatal and adult. Thus, heart form and function develop in exquisite choreography, integrating cross-regulatory circuits including biomechanical cues associated with muscle contraction and blood flow.

Cardiovascular disease is a major cause of death and disability. Led by Professor Richard Harvey, the lab is seeking to understand the cellular and molecular principles that guide heart development and patterning, and how gene defects cause heart abnormalities in babies. These studies contribute to our understanding of tissue complexity, adaptation and repair in the adult heart, and how such processes might be targeted therapeutically to augmen heart repair and regeneration. Ultimately, we seek to exploit our molecular and genetic knowledge to help individuals and families impacted by cardiovascular diseases.

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

1. Genetic basis of mammalian heart development

Our research has helped to define the key cardiac transcription factors and gene regulatory networks 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 1) how ventricular chamber architecture is defined – we have developed an entirely new model of how this occurs through the interactions between the NOTCH and NEUREGULIN signalling pathway (Del Monte Nieto et al., Nature 2018); and 2) how cardiac interventricular septation occurs. Through these studies we hope to reveal the basis of common congenital septal defects in human babies.

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 of the embryo (Prall et al., Cell 2007). 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, and we collaborate extensively with paediatric cardiac surgeon David Winlaw and cardiogenomics expert Sally Dunwoodie to understand the genetic basis of congenital heart disease subtypes, and to bring this information back to patients and their families (Alankarage et al., Genet Med 2019).

3. Cardiac gene regulatory networks

We seek to contextualise heart development and disease in a framework of systems biology. Heart development is regulated in part by transcription factors that bind to conserved DNA elements in gene promoters and enhancers. This level of network control is hardwired into the genome. Aligned with our suite of functional genomics tools, we are using the technique of DamID for genome-wide transcription factor target gene identification, an important first step in understanding their regulatory networks (Bouveret et al., eLife 2015). DamID has allowed us to study how transcription factor mutations found in congenital heart disease patients have their impact at a genome-wide level. We made that remarkable discovery that transcription factor mutant proteins, even those that lack DNA-binding ability, can alter the expression of hundreds of genes not normally regulated by the wild type protein, a type of gain-of-function which destabilises regulatory networks. We are now using DamID as a functional genomics tool to understand the impact of different classes of congenital heart disease mutation.

4. 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 makes it possible to recreate specific disease-relevant tissue types from a patient’s own cells in order to understand the origins of disease, as well as disease gene-environment and gene-drug interactions. In collaboration with Professor David Winlaw, 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 are born with hearts that have an underdeveloped left ventricle and face a series of invasive surgeries partially restore heart function. They face a lifetime of uncertainty and a high risk of heart failure. Using the iPSC model, we have investigated the cardiac cell functionality and gene expression in 10 HLH families and discovered both common and individual-specific disease pathways that are now being characterised further.

5. Cardiac repair and regeneration

Unlike the hearts of fish and certain amphibian species, the adult mammalian heart is not regarded as a regenerative organ. However, mammalian fetal and neonatal hearts can regenerate. 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. We previously participated in one of the key early studies in mice suggesting that heart regeneration through cardiomyocyte renewal might be possible in human hearts, e.g. after an acute heart attack (D’Uva et al., Nature Cell Biology 2015). We are also exploring the biology of cardiac mesenchymal progenitor and stromal cells, and prospects for targeting these cells to stimulate heart repair and regeneration (Chong et al., Cell Stem Cell 2011; Thavapalachandran et al., Sci Trans Med, 2021; Janbandhu et al., Cell Stem Cell 2022). This requires understanding their many roles in homeostasis, repair processes and pathological fibrosis, which accompanies virtually all forms of heart disease. We are harnessing the power of single cell transcriptomics to define tissue heterogeneity and cell dynamics in cardiac homeostasis and disease at the single cell level, to identify new therapeutic targets for regulation of pathological fibrosis (Farbehi et al., eLife 2019). It is an exciting time to be working in regeneration biology and our program is attempting to uncover new approaches to treating heart disease through regenerative medicine.

Peer Reviewed Journal Articles:

1. 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.
2. 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; https://pubmed.ncbi.nlm.nih.gov/7628699 [doi:10.1101/gad.9.13.1654]
3. 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; https://pubmed.ncbi.nlm.nih.gov/9192865... [doi:10.1101/gad.11.11.1357]
4. 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. [doi:10.1006dbio.2000.9753] (Field-Weighted Citation Impact: 5.77)
5. Harvey RP. Patterning the vertebrate heart. Nature Reviews Genetics 2002; 3:544-56. [doi:10.1038/nrg843] (Field-Weighted Citation Impact: 2.41
6. 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. [doi:10.1016/S0735-1097(03)00420-0] (Field-Weighted Citation Impact: 3.42)
7. Prall OWJ, 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; 128:947-959. [doi:10.016/j.cell.2007.01.042] (Field-Weighted Citation Impact: 7.26)
8. 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. [doi:10.1086/519530] (Field-Weighted Citation Impact: 3.60)
9. Furtado MB, Solloway MJ, Jones V, Costa MW, Biben C, Wolstein O, Preis JI, Sparrow DB, Saga Y, Dunwoodie SL, Robertson EJ, Tam PPL, Harvey RP. BMP/SMAD1 signalling sets a threshold for the left/right pathway in lateral plate mesoderm and limits availability of SMAD4. Genes and Development 2008; 22:3037-49. [doi:10.1101/gad/1682108]
10. Chong JJH, Chandrakanthan V, Xaymardan M, Asli NS, Li J, Heffernan C, Menon MK, Ahmed I, Scarlett CJ, Rashidianfar A, Biben C, Zoellner H, Colvin EK, Pimander J, Biankin AV, Zhou B, Pu WT, Prall OWJ, Harvey RP. Adult cardiac-resident MSC-like stem cells with a proepicardial origin. Cell Stem Cell 2011; 9:527-540. [doi:10.1016/j.stem.2011.10.002] (Field-Weighted Citation Impact: 6.86)
11. D’Uva G, Aharonov A, Lauriola M, Weisinger K, Bassat E, Kaine D, Lysenko M, Rajchman D, Konfino T, Hegesh J, Brenner O, Neeman M, Yarden Y, Leor J, Sarig R, Harvey RP, Tzahor E. ERBB2 triggers mammalian heart regeneration by promoting cardiomyocyte dedifferentiation and proliferation. Nature Cell Biology 2015 17:627-638. [doi:10.1038/ncb3149] (Field-Weighted Citation Impact: 10.96)
12. Bouveret R, Waardenberg AJ, Schonrock N, Ramialison M, Doan T, de Jong D, Bondue A, Kaur G, Fonoudi H, Chiann-mun C, Wouters M, Bhattacharya S, Plachta N, Dunwoodie SL, Chapman G, Blanpain C,Harvey RP. NKX2-5 mutations causative for congenital heart disease retain functionality and are directed to hundreds of targets. eLife 2015 https://pubmed.ncbi.nlm.nih.gov/2614693... [doi:10.7554/eLife.06942]
13. Zamir L,#, Singh R#, Nathan E, Patrick R, Yifa O, Arraf A, Schultheiss T, Han J DJ, Peng G, Jing N, Tam PPL, Harvey RP*, Tzahor E*. Nkx2.5 marks angioblasts that contribute to hemogenic endothelium of the endodardium and dorsal aorta. eLife 2017 6:e20994. [doi:10.7554/elife.20994] #contributed equally; *co-corresponding authors
14. Del Monte Nieto G, Ramialison M, Adam AS, Wu B, Aharonov A, D’Uva G, Bourke LM, Pitulescu ME, Chen H, de la Poma JL, Shou W, Adams RH, Harten SK, Tzahor E, Zhou B, Harvey RP. Control of cardiac jelly dynamics by NOTCH and NRG1 defines the building plan for trabeculation. Nature 2018 557: 439-445. [doi:10.1038/s41586-018-0110-6] (Field-Weighted Citation Impact: 3.37)
15. Alankarage D, Ip E, Szot J, Munro J, Blue G, Harrison K, Cuny H, Enriquez A, Troup M, Humphreys D, Harvey RP, Sholler G, Graham RM, Ho J, Kirk E, Pachter N, Chapman G, Winlaw D, Giannoulatou E, Dunwoodie SL. Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genetics in Medicine 2019 21:1111-1120 [doi: 10.1038/s41436-018-0296-x]
16. Farbehi N, Patrick R, Dorison A, Xaymardan M, Wystub-Lis K, Janbandhu V, Ho JWK, Nordon RE, Harvey RP. Single-cell expression profiling reveals dynamic flux of cardiac stromal, vascular and immune cells in health and injury. eLife 2019 pii: e43882 [doi:10.7554/eLife.43882] (Field-Weighted Citation Impact: 11.08)
17. Thavapalachandran S, Grieve SM, Hume RD, Le TYL, Raguram K, Hudson JE, Pouliopoulos J, Figtree GA, Dye RP, Barry AM, Brown P, Lu J, Coffey S, Kesteven SH, Mills RJ, Rashid FN, Taran E, Kovoor P, Thomas L, Denniss AR, Kizana E, Asli N, Xaymardan M, Feneley MP, Graham RM, Harvey RP, Chong JJH. Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction. Science Translational Medicine 2020 12, eaay2140 [science.org/doi/10.1126/scitranslmed]
18. Lu P, Wang Y, Wang Y, Liu Y,Wang Y, Wu B, Zheng D, Harvey RP, Zhou B. Perinatal angiogenesis from pre-existing coronary vessels via DLL4/NOTCH1 signalling. Nature Cell Biology 2021 9: 967-977 [doi: 10.1038/s41556-021-00747-1]
19. Janbandhu V, Tallapragada V, Patrick R, Li Y, Abegunawardena D, Humphries DT, Martin EMMA, Ward AO, Contreras O, Farbehi N, Yao E, Du J, Dunwoodie S, Bursac N, Harvey RP. Hif-1a suppresses ROS-induced proliferation of cardiac fibroblasts following myocardial infarction. Cell Stem Cell 2022 29, 1-17 [doi: 10.1016/j.stem.2021.10.009]

Textbooks:

1. Harvey RP, Rosenthal N (Eds). Heart Development. Academic Press, San Diego 1999. [>1,680 copies sold] [ISBN:0-12-329860-1]
2. Harvey RP, Rosenthal N (Eds). Heart Development and Regeneration. Academic Press, San Diego, 2010 [doi:10.1016/C2009-1-62569-7]