Module 1: Endogenous Cardiac Stem Cells

 Module Leader Professor Richard Harvey
 Host Organisation
 Victor Chang Cardiac Research Institute, NSW

Module description

Heart attack, stroke, and related diseases are the leading cause of death in the Western world, outstripping deaths due to all cancers combined. Improvements to medical therapy for acute coronary artery disease (myocardial infarction, MI) has lead to an epidemic of heart failure, a condition that is expected to increase exponentially.

The Module’s principal aim is to establish a quantitative and comparative framework for the analysis of endogenous cardiac stem cell populations in development, health, disease and aging. The Module will use this framework to interrogate the relationships, origins and biology of these cells, seeking to discover ways to augment cardiac regeneration or cardiac cell therapy.

The Module has initially focused on a population of colony forming cells that occupy a perivascular niche and resemble bone marrow MSCs. These cells are multipotent for mesodermal lineages ex vivo and in vitro. They undergo considerable flux in numbers and, importantly, quality, in disease, aging and regenerative models. The Module has defined factors or conditions that improve the cardinal stem cell features of long term self renewal and clonogenicity, and these factors are candidates for regeneration therapies. Under the proposed Stream, the Module will continue to define the properties of these stem cells and expand the perspective to include real time cell lineage tracking and pre-clinical investigations.

Photo of Module members (left to right): James Chong, Helena  Malinowska, Munira Xaymardan, Naisana Asli & Vashe Chandrakanthan

Aims

  1. To define the lineage origins of resident cardiac stem cells in development, health and disease.
  2. To define the effects of Pdgfra signalling on cardiac stem cell maintenance, activation, and rejuvenation using Lab-on-a-Chip single cell fate mapping.
  3. To explore the effects of novel rejuvenation therapies on heart repair.

Module Leader biography

Professor Richard Harvey, PhD, FAA (Australia), received his PhD in 1982, after further training at Harvard University for three years and spending 10 years at the Walter and Eliza Hall Institute of Medical Research in Melbourne, he joined the Victor Chang Cardiac Research Institute (VCCRI) in 1998, where he is currently Co-Deputy Director and Head of the Developmental Biology Division.

Professor Harvey’s research interests include cardiac developmental biology and stem cells. In 2001, he received the Hazel Croke Research Award from the NHF; in 2004, the RT Hall Prize, the highest senior investigator award of the Cardiac Society of Australia and New Zealand; in 2005, the Julian Wells Medal and Oration, conferred by the Executive Committee of the Lorne Genome Meeting; and in 2007 the Evelyn Hall Award of the National Heart Foundation. In 2007 he was elected member of the Australian Academy of Science. He is on the editorial boards of Developmental Cell, Developmental Biology, Developmental Dynamics, Trends in Cardiovascular Medicine and Stem Cell Research. He is also an Associate Member of EMBO and is currently an NHMRC Australia Fellow.

Contact details

 E-mail  r.harvey@victorchang.edu.au
 Phone   +61 2 9295-8620
 Web  www.victorchang.edu.au/research/ProfRichardHarvey.cfm?cid=71

Selected publications

  1. Von Both I, Silvestri C, Erdemir T, Lickert H, Walls JR, Henkelman RM, Rossant J, Harvey RP, Attisano L, Wrana JL. Foxh1 is essential for development of the anterior heart field. Developmental Cell 2004; 7:31-345. (IF=12.43; Citations 55)
  2. 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. (IF=7.29; Citations 36)
  3. 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; 133:1311-1322 [Journal Cover]. (IF=7.29; Citations 5)
  4. Kirk EP, Hyun C, Thompson PC, Lai D, Castro ML, Biben C, Buckley MF, Martin IC, Moran C, Harvey RP. Quantitative trait loci modifying cardiac atrial septal morphology and risk of patent foramen ovale in the mouse. Circulation Research 2006; 98:651-658. (IF=9.72; Citations 1)
  5. 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 orchestrates cardiac progenitor cell specification and proliferation in the second heart field. Cell 2007; 128:947-959. (IF=29.88; Citations 17)
  6. 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 TBX20 are associated with diverse cardiac pathologies, including defects of septation and valvulogenesis, and cardiomyopathy. American Journal of Human Genetics 2007; 81:280-291. (IF= 11.09; Citations 5)
  7. Siero F, Biben C, Martinez-Munoz L, Mellado M, Ransohoff RM, Li M, Woehl B, Leung H, Groom J, Batten M, Harvey RP, Martinez-A, Mackay CR, Mackay F. Disrupted cardiac development but normal hematopoiesis in mice deficient in the second CXCL12/SDF-1 receptor, CXCR7. Proceeding of the National Academy of Science (USA) 2007: 104:14759-764. (IF=9.6; Citations 4)
  8. Yadava RS, Frenzel I–I, McCardell CD, Yu Q, Srinivasan V, Tucker AL, Puymirat J, Thorton CA, Prall OWJ, Harvey RP, Mahadeven MS. RNA toxicity in mytonic muscular dystrophy induces NKX2-5 expression. Nature Genetics 2008; 40:61-68. (IF=25.55; Citations 0)
  9. 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; 15:521-533 [Journal Cover] (IF=12.43).
  10. 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; 22:3037-3049 (IF=14.79)