Professor Li, Ronald Adolphus 李登偉
Professor Li is the Founding Director of the Stem Cell & Regenerative Medicine Consortium and SY and HY Cheng Professor in Stem Cell Biology & Regenerative Medicine. He was the two-time recipient of Top Young Faculty Research Award and Top Prize for Young Investigator Award from Johns Hopkins Medicine, Young Investigator Award from the Heart Rhythm Society, Career Development Award from the Cardiac Arrhythmias Research and Education Foundation, etc. Professor Li has over 100 publications in the areas and his lab has received funding from the National Institute of Health (NIH), California Institute of Regenerative Medicine, Research Grants Council (RGC), etc. He serves as a panel member or reviewer of major funding bodies such as the NIH, American Heart Association, Association Francaisecontre les Myopathies, United States-Israel Binational Science Foundation, Research Grant Council of HK, Stem Cell Consortium, A*STAR/Biopolis of Singapore, Wellcome Trust and MRC of the UK, etc.
Professor Li’s group focuses on electrophysiology and construction of an unlimited library of “custom-tailored” human heart cells and higher-ordered engineered tissues for in vitro diagnostics and transplantation. Their work on cardiac differentiation (bio-artificial pacemaker) has been recognized by the American Heart Association as Best Basic Study of 2005, Ground-Breaking Study of 2006, and Late-breaking studies of 2003, 2004 and 2007. Professor Li has over 100 publications in the areas with funding received from the National Institute of Health (NIH), California Institute of Regenerative Medicine, Research Grants Council (RGC), etc.
Cell-based Heart Regeneration (T13-706/11)
Heart diseases are a major cause of death worldwide. Loss of cardiomyocytes (CMs) due to aging or diseases is irreversible. Current therapeutic regimes are palliative; in end-stage heart failure, transplantation remains the last resort but is significantly hampered by a severe shortage of donors. Human embryonic stem cells (hESCs) can self-renew while maintaining their pluripotency to differentiate into all cell types, including CMs. Direct reprogramming of adult somatic cells to induced pluripotent stem cells (iPSCs) has been achieved. The availability of hESC/iPSCs has enabled researchers to gain novel biological insights and to pursue heart regeneration. Despite these promises, substantial hurdles remain for translating into cell-based therapies and other applications (e.g., disease modeling, cardiotoxicity and drug screening). Based on our team’s own work in the past decade, we have identified the following MAJOR SCIENTIFIC GAPS: Human embryonic and induced pluripotent stem cell derived cardiomyocytes (hESC/iPSC‐CMs) have immature properties, a small physical size (~10‐fold less than adult CMs), poor structural organization at the sub‐, single‐ and multi‐cellular levels, poorly‐defined immunobiology and sub‐lineage specification, with uncertain safety and efficacy for therapeutics that limits their use in promoting good health. To address these, our laboratory has the following key directions:
Direction 1. ENGINEERING HUMAN CARDIAC MUSCLE AND CHAMBER
Rationale and Goals: HESC‐CMs differentiated in vitro lack the sub‐cellular organization and higher order structural 3‐dimensionality seen in adult heart tissues. We hypothesize that engineered human heart muscles and chambers (collectively termed as engineered cardiac tissues or ECTs) can be optimally biofabricated to recapitulate key structural and functional features in the native human heart; ECT efficacy can be further enhanced by micro‐environmental cues. Optimization of ECTs will not only provide powerful tools for disease modeling, drug/cardiotoxicity screening and clinical translations, but physiologic 3D environment also promises to reveal novel insights not possible with conventional rigid 2D culture systems.
Direction 2 – BIOLOGY OF CELL ENGINEERING
Rationale and Goals: Adult CMs are bi‐ or multi‐nucleated, ~200μM in length and ~2‐300pF in size; hESC‐CMs are mono‐nucleated, ~10‐15 times smaller, and refuse to grow in physical size by undergoing physiological hypertrophy even after long‐term culturing (>150 days); Ca2+ signaling is one of the most poorly defined areas in hESC‐VCM biology; and developmentally, bi‐nucleated CMs arise from the absence of cytokinesis after karyokinesis during the final round of (incomplete) cell division. We hypothesize that reverse‐engineered increase of physical size by laser‐mediated fusion of hESC‐CMs can drive maturation; that TRP, nuclear/perinuclear Ca2+ signaling and IP3R play a pivotal role in cardiac differentiation, ventricular specification and maturation by mediating local Ca2+ events; and we will test if enhanced mitochondrially derived ROS production promotes maturation.
Direction 3. PRE‐CLINICAL TRANSLATION
Rationale and Goals: While rodents are convenient models for proof‐of‐concept experiments, significant species differences prevent direct clinical extrapolations:
1) The small size and fast heart rate of rodents (>400bpm vs. ~80 bpm for humans) result in poor spatial and temporal resolution (particularly for electrophysiology; the fast heart rate in the recipient mouse heart can override/mask any arrhythmogenic or pacing properties of the transplanted human donor cells).
2) Clinical irrelevant timing for cell transplantation (e.g., immediately after MI is an unlikely clinical setting). We hypothesize that implantable, non‐viral, cell‐based bio‐SAN display more superior functions and safety than our published gene‐based bio‐SAN.
To test the hypotheses that hESC‐VCMs driven to maturation (as ECTs, or by electrical, mechanical and/or metabolic stimuli) display improved i) safety and ii) efficacy after in vivo transplantation in MI.
|Awardees||Award Date||Honours / Awards / Prizes||Category|
|2006-06-01||1 of 10 chosen participants of the Mid-Career Leadership Program (MCLP): UC Davis School of Medicine||Research Achievement|
|2007-06-01||Late-breaking Basic Science (Stem Cells) Study of 2007 (one of five chosen): Genetically-driven Maturation of hESC-derived cardiomyocytes completely ablates post-transplantation arrhythmias.: American Heart Association.||Research Achievement|
|2010-06-01||Convener for the field of Stem Cell & Regenerative Medicine in Hong Kong, appointed by the Research Grant Council of HK, Theme-based Research.: Research Grant Council of HK||Research Achievement|
|2003-06-01||Late-breaking Basic Science Study (one of five chosen) of 2003: hESC-based biopacemaking.: American Heart Association||Research Achievement|
|2007-06-01||Chancellor (campus-wide) Award Nominee (1 or 2 School of Medicine Faculty nominated by Dean Claire Pomeroy), 2007.: University of California||Research Achievement|
|2010-06-01||SY and HY Cheng Endowed Professorship in Stem Cell & Regenerative Medicine.: The University of Hong Kong, The University of Hong Kong||Research Achievement|
|2006-06-01||BEST Basic Science Paper of 2005: Human Embryonic Stem Cell-based Biopacemaker. Circulation,: American Heart Association.||Research Achievement|
|2006-06-01||Ground-breaking Paper of 2006 (one of three chosen): Bioartificial sinus node. Circulation: American Heart Association.||Research Achievement|
|2004-06-01||Late-breaking Basic Science Study (one of five chosen) of 2004: Gene-based biopacemaking: American Heart Association||Research Achievement|
|2018-04-01||U of Waterloo Distinguished Alumnus of Faculty of Science 2017: U of Waterloo||Research Achievement|
|2007-03-01||Probing the external S5-Pore region of HCN-encoded pacemaker channel by cysteine scanning mutagensis.: HBHA conference 2007 Young Investigator Award (Poster category)||Research Achievement|
|2004-06-01||First Prize, Basic Research Faculty Award, Department of Medicine: The Johns Hopkins University||Research Achievement|
|2015-12-01||Hong Kong Spirit: Innovating for Good Award: South China Morning Post||Research Achievement|
|2016-11-01||Nikkei Asia Prizes - Science and Technology Nomination: Nikkei Asia Prizes -||Research Achievement|
|Term Period||Position||Professional Societies|
|Invited Reviewer||Translationeel Adult Stamcelonderzoek ' program. Laan van Nieuw Oost-Indië 334, 2593 CE Den Haag Postbus 93245, 2509 AE Den Haag www.zonmw.nl.|
|2009||Panel Member||Electrical Signaling, Ion Transport and Arrhythmia (ESTA) study section, National Heart, Lung and Blood Institute, National Institute of Health|
|2008||Invited Consultant||Consortium of ENCyclopedia of DNA Elements (ENCODE), National Human Genome Research Institute, National Institute of Health.|
|2008||Panel Member||Special Emphasis Panel, Progenitor Cell Biology Consortium Planning Award, National Heart, Lung and Blood Institute, National Institute of Health.|
|2006, 2008||Invited Reviewer||Association Française contre les Myopathies, Paris, France|
|2008||Funding Committee Panelist||American Heart Association’s Jon Holden DeHaan Foundation of Cardiac Myogenesis Research Center|
|2002-||Member||Cardiac Muscle Society|
|2009 - 2012||Panel Member||Career Development Award (K02 and K08) Grant Review Panel, National Heart, Lung and Blood Institute, National Institute of Health.|
|2014||Invited Reviewer||National Research Program for Biopharmaceuticals (NRPB) Human Disease iPS Cells Service Consortium, Taiwan R.O.C.|
|2014||Invited Reviewer||European Research Projects on Rare Diseases,German Federal Ministry for Education and Research (BMBF)|
|2008, 2011||Invited Reviewer||Medical Research Council (MRC), London, United Kingdom.|
|2009||Panel Member||Specialized Review Panel for Program Project Grant (PPG), National Heart, Lung and Blood Institute, National Institute of Health.|
|Invited Reviewer||European Research Projects on Rare Diseases, German Federal Ministry for Education and Research (BMBF) and the E-Rare group of national research funding agencies|
|2014||Invited Reviewer||Regenerative Medicine by Future Science Group Ltd, United Kingdom|
|2008||Panel Member||Specialized Review Panel for Program Project Grant (PPG; Cardiac Regeneration from Stem Cells), National Heart, Lung and Blood Institute, National Institute of Health.|
|2002-||Basic Science Council Member||American Heart Association|
|2006, 2008||Invited Reviewer||United States - Israel Binational Science Foundation|
|2002-||Member||International Society of Stem Cell Research|
|2002-||Member||Federation of American Societies for Experimental Biology (FASEB)|
|2009||Panel Member||NHLBI RC2 (GO) grants, " Characterizing Differentiated Stem Cells ". National Institute of Health|
|2002-||Member||American Society for Biochemistry and Molecular Biology (ASBMB)|
|2011||Panel Member||Special Emphasis Panel, USD$76M initiative: From GWAS to iPSC: Next Generation Genetic Association Studies (U01) Award. (http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-11-006.html), National Heart, Lung and Blood Institute, National Institute of Health.|
|2009||Panel Member||Special Emphasis Panel, USD$76M initiative: Progenitor Cell Biology Research Hubs (U01) Award (http://grants.nih.gov/grants/guide/rfa-files/RFA-HL-09-004.html), National Heart, Lung and Blood Institute, National Institute of Health.|
|2009||Panel Member||NHLBI RC2 (GO) grants, " Characterizing Differentiated Stem Cells ". National Institute of Health|
|2006||5-member Funding Committee||Stem Cell Consortium, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore (Chair: Roger Pedersen, Cambridge University, UK).|
|2011||Invited Reviewer||R&D Excellence Awards, Kentucky Science and Engineering Foundation (KSEF), Lexington KY, United States.|
|2009||Panel Member||Committee 3A, American Heart Association, Western Affiliate.|
|2009||Panel Member||Stem Cell Consortium, Agency for Science, Technology and Research (A*STAR), Biopolis, Singapore,|
|2002-||Member||American Society of Gene Therapy|
|2002-||Member||Heart Rhythm Society|
|Invited Reviewer||The Israel Science Foundation (ISF), Israel|
|2006||Invited Reviewer||Welcome Trust, London, United Kingdom|
|2004, 2008-2011||Invited Reviewer||Research Grant Council, Hong Kong|
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