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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.