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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)
  • Mr Jarrod Skinner
  • Dr Ayeshah Rosdah (PhD student)
  • Mr RenJie Phang (Jack) Masters student
  • Mr Haoxiang Zhang (Alan) Masters student
  • Ms Yali Deng (Honours student)

Publication Highlights

  1. Kalkhoran SB, Kriston-Vizi J, Hernandez-Resendiz S, Crespo-Avilan GE, Rosdah AA, Lees JG, Da Costa JRS, Ling NXY, Holien JK, Samangouei P, Chinda K, Ping YE, Riquelme JA, Ketteler R, Yellon DM, Lim SY*, Hausenloy DJ*. Hydralazine protects the heart against acute ischemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission. Cardiovasc Res. 2021 Jan *joint senior authors 
  2. Hernández D, Millard R, Kong AM, Burns O, Sivakumaran P, Shepherd RK, Dusting GJ, Lim SY.  A tissue engineering chamber for continuous pulsatile electrical stimulation of vascularised cardiac tissues in vivoBioelectricity. 2020 Sep. 
  3. Rosdah AA, Smiles WJ, Oakhill JS, Scott JW, Langendorff CG, Delbridge LMD, Holien JK, Lim SY. New perspectives on the role of Drp1 isoforms in regulating mitochondrial pathophysiology. Pharmacol. Ther. 2020:107594. 
  4. Kompa AR, Greening DW, Kong AM, McMillan PJ, Fang H, Saxena R, Wong RCB, Lees JG, Sivakumaran P, Newcomb AE, Tannous BA, Kos C, Mariana L, Loudovaris T, Hausenloy DJ, Lim SY. Sustained subcutaneous delivery of secretome of human cardiac stem cells promotes cardiac repair following myocardial infarction. Cardiovasc Res. 2020 Apr 6. 
  5. Lees JG, Kong AM, Chen YC, Sivakumaran P, Hernández D, Pébay A, Harvey AJ, Gardner DK, Lim SY. Mitochondrial fusion by M1 promotes embryoid body cardiac differentiation of human pluripotent stem cells.  Stem Cells International. 2019:6380135. 
  6. Kong AM, Yap KK, Lim SY, Marre D, Pébay A, Gerrand YW, Lees JG, Palmer JA, Morrison WA, Mitchell GM. Bioengineering a tissue flap utilizing a porous scaffold incorporating a human induced pluripotent stem cell-derived endothelial cell capillary network connected to a vascular pedicle. Acta Biomater. 2019:94:281-94.  
  7. 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.  
  8. 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 ALim SY. Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells. Cell Death Discov. 2018:4:39.  
  9. Nie SWang XSivakumaran PChong MMWLiu XKarnezis TBandara NTakov KNowell CJWilcox SShambrook MHill AFHarris NCNewcomb AEStrappe PShayan RHernández DClarke JHanssen EDavidson SMDusting GJPébay AHo JWKWilliamson NLim SY. Biologically active constituents of the secretome of human W8B2+ cardiac stem cells. Sci Rep. 2018:8(1):1579.  
  10. 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):1440-52.  
  11. 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.  
  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. 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.  
  14. Hsiao ST, Dilley RJ, Dusting GJ, Lim SY. Ischemic preconditioning for cell-based therapy and tissue engineering. Pharmacol. Ther. 2014:142(2):141-53.