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Cardiac regeneration

Stem cells have the potential to treat heart diseases by transforming into heart cells and blood vessels or by producing protective factors. The human heart cells produced from stem cells can be used to grow whole tissues of human heart, which might then be developed to replace and support damaged hearts through surgical transplantation, and to test new heart attack drugs.

Research overview

In order to utilise human stem cells to treat heart disease effectively, our lab has a multidisciplinary approach to enhance stem cell cardiomyogenesis, improve survival and functionality of stem cell-derived heart cells, and optimise their delivery to the damaged heart. Studies include identify suitable stem cell sources, cardiac differentiation, stem cell secretomes, cytoprotective, tissue assembly and transplantation strategies.

Moreover, we have successfully developed a human heart model in the dish using human heart cells generated from patient-specific stem cells. This human heart model has allowed us to test new drugs that have potential to protect the heart from injury, and to study genetic mutations that can cause heart disease.

Research Themes

Cardiac stem cell secretomes

Cardiac stem cell therapy has great potential for repair of ischaemic heart disease. We have recently identified a new population of human cardiac stem cells which are positive for W8B2 antigen and it shows better cardioreparative benefit in vitro than do other adult stem cells from non-cardiac tissues. This benefit has been attributed to their secretion of cytokines, growth factors mRNA and miRNA (the secretome). We aim to explore the cardioreparative secretome constituents (growth factors, cytokines, extracellular vesicles and exosomes) of W8B2+ cardiac stem cells and to harness their paracrine activities to treat ischaemic heart disease.

Relevant publications:
Zhang Y, Sivakumaran P, Newcomb AE, Hernandez D, Harris N, Khanabdali R, Liu GS, Kelly DJ, Pébay A, Hewitt AW, Boyle A, Harvey R, Morrison WA, Elliott DA, Dusting GJ, Lim SY. Cardiac repair with a novel population of mesenchymal stem cells resident in the human heart. Stem Cells. 2015:33:3100-3113.
Khanabdali R, Rosdah A, Dusting GJ, Lim SY. Harnessing the secretome of cardiac stem cells as therapy for treat ischaemic heart disease. Biochem. Pharmcol. 2016 (Epub Feb 21)

Mitochondrial morphology in regulating stem cell survival and cardiogenesis

Mitochondrial shape change (fusion or fission) allows them to maintain their integrity and efficient bioenergetics of the organelle, as well as influencing cell survival and differentiation. We aim to evaluate whether new drugs that regulate mitochondrial shape (i) enhance stem cell survival, and (ii) promote stem cell differentiation into cardiac lineage.

Relevant publications:
Rosdah AA, Holien JK, Delbridge LMD, Dusting GJ, Lim SY. Mitochondrial fission – a drug target for cytoprotection or cytodestruction? Pharmacol. Res. Prespective. 2016:4:e00235
Ong SB, Subrayan S, Lim SY, Yellon DM, Davison SM, Hausenloy DJ. Inhibiting mitochondrial fission protects the heart against ischemia reperfusion injury. Circulation. 2010:121: 2012-2022.

Human cardiomyocytes and engineered heart tissue for disease modeling and drug testing

Pluripotent stem cells can provide an unlimited source of functional human cardiomyocytes for drug discovery and pharmacological safety testing, especially induced pluripotent stem cells which are generated by reprogramming adult somatic cells (such as skin cells). This allows for autologous patient-specific stem cells, and subsequently cardiomyocytes to be derived in a large scale to assess patient-specific drug responses (personalised medicine). These human cardiomyocytes can also be used to engineer 3D vascularized human heart tissue for transplantation to replace and support the infarcted myocardium.  

Relevant publications:
Lim SY, Sivakumaran P, Crombie D, Dusting GJ, Pébay A, Dilley RJ. Trichostatin-A enhances differentiation of human induced pluripotent stem cells to cardiogenic cells for cardiac tissue engineering. Stem Cells Transl. Med. 2013:2:715-725  
Chan EC, Kuo SM, Kong AM, Morrison WA, Dusting GJ, Mitchell GM, Lim SY*, Liu GS*. Three dimensional collagen scaffold promotes intrinsic vascularisation for tissue engineering applications. Plos one. 2016:11(2):e0149799.
Lim SY, Hernández D, Dusting GJ. Growing vascularised heart tissue from stem cells. 2013. J Cardiovasc Pharmacol. 2013:62:122-129.

Student Projects

Staff

  • Dr Shiang (Max) Lim
  • Dr Jarmon Lees
  • Dr Anne Kong (part-time)
  • Dr Ayeshah Rosdah (PhD student)
  • Mr Andrew Treller (Honours student)
  • Mr Alexander Murdoch (Honours student)

Publication Highlights

  1. Fang L, Hung SSC, Yek J, El Wazen L, Nguyen T, Khan S, Lim SY, Hewitt AW, Wong RCB. A simple cloning-free method to efficiently induce gene expression using CRISPR/Cas9. Mol. Ther. Nucleic Acids. 2018:14:184.
  2. Hernández D, Millard R, Sivakumaran P, Kong AM, Mitchell GM, Pébay A, Shepherd RK, Dusting GJ, Lim SY.  Influence of continuous electrical stimulation on development of human cardiomyocytes from induced pluripotent stem cells. Cond. Med. 2018:1(6):306-12.
  3. Hoque A, Sivakumaran P, Bond ST, Ling NXY, Kong AM, Scott J, Bandara N, Hernández D, Liu GS, Wong RCB, Ryan MT, Hausenloy DJ, Kemp BE, Oakhill JS, Drew BG, Pébay A, Lim SY. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discov. 2018:4:39.
  4. Nie S, Wang X, Sivakumaran P, Chong MMW, Liu X, Karnezis T, Bandara N, Takov K, Nowell CJ, Wilcox S, Shambrook M, Hill AF, Harris NC, Newcomb AE, Strappe P, Shayan R, Hernández D, Clarke J, Hanssen E, Davidson SM, Dusting GJ, Pébay A, Ho JWK, Williamson N, Lim SY. Biologically active constituents of the secretome of human W8B2+ cardiac stem cells. Sci Rep. 2018:8(1):1579.
  5. Rosdah AA, Bond ST, Sivakumaran P, Hoque A, Oakhill JS, Drew BG, Delbridge LMD, Lim SY. Mdivi-1 Protects Human W8B2+ Cardiac Stem Cells from Oxidative Stress and Simulated Ischemia-Reperfusion Injury. Stem Cells Dev. 2017:26(24):1771-80.
  6. Crombie DE, Curl CL, Raaijmakers AJ, Sivakumaran P, Kulkarni T, Wong RCB, Minami I, Evans-Gallea MV, Lim SY, Delbridge L, Corben LA, Dottori M, Nakatsuji N, Trounce IA, Hewitt AW, Delatycki MB, Pera MF, Pébay A. Friedreich's ataxia induced pluripotent stem cell-derived cardiomyocytes display electrophysiological abnormalities and calcium handling deficiency. Aging. 2017:9(5):1440-1452.
  7. Bandara N, Gurusinghe S, Lim SY, Chen H, Chen S, Wang D, Hilbert B Wang LX, Strappe P. Molecular control of nitric oxide synthesis through eNOS and caveolin-1 interaction regulates osteogenic differentiation of adipose derived stem cells by modulation of Wnt/β-catenin signalling. Stem Cell Res Ther. 2016:7(1):182.
  8. Rosdah AA, Holien J, Delbridge LMD, Dusting GJ, Lim SY. Mitochondrial fission – a drug target for cytoprotection or cytodestruction? Pharmacol. Res. Prespective. 2016:4(3):e00235.
  9. Khanabdali R, Rosdah A, Dusting GJ, Lim SY. Harnessing the secretome of cardiac stem cells as therapy for treat ischaemic heart disease. Biochem. Pharmcol. 2016:113:1-11.
  10. Zhan W, Marre D, Mitchell GM, Morrison WA, Lim SY. Tissue engineering by intrinsic vascularization in an in vivo tissue engineering chamber. JoVE. 2016:111:e54099.
  11. Bandara N, Gurusinghe S, Chen H, Chen S, Wang L, Lim SY, Strappe P. Minicircle DNA-mediated endothelial nitric oxide synthase gene transfer enhances angiogenic response of bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther. 2016:7(1):48. .
  12. Chan EC, Kuo SM, Kong AM, Morrison WA, Dusting GJ, Mitchell GM, Lim SY*, Liu GS*. Three dimensional collagen scaffold promotes intrinsic vascularisation for tissue engineering applications. Plos one. 2016:11(2):e0149799. *equal authors .
  13. Hernández D, Millard R, Sivakumaran P, Wong RCB, Crombie DE, Hewitt AW, Liang H, Hung SSC, Pébay A, Shepherd RK, Dusting GJ, Lim SY. Electrical stimulation promotes cardiac differentiation of human induced pluripotent stem cells. Stem Cell Int. 2016:1718041. .
  14. Zhang Y, Sivakumaran P, Newcomb AE, Hernandez D, Harris N, Khanabdali R, Liu GS, Kelly DJ, Pébay A, Hewitt AW, Boyle A, Harvey R, Morrison WA, Elliott DA, Dusting GJ, Lim SY. Cardiac repair with a novel population of mesenchymal stem cells resident in the human heart. Stem Cells. 2015:33:3100-13.
  15. Hsiao ST, Dilley RJ, Dusting GJ, Lim SY. Ischemic preconditioning for cell-based therapy and tissue engineering. Pharmacol. Ther. 2013:142(2):141-53.