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Overview

Background: 

 

Heart diseases are a major cause of death worldwide. Loss of cardiomyocytes (CMs) due to aging or disease is irreversible. Current therapeutic regimes are palliative, and in end-stage heart failure, transplantation remains the last resort but is significantly hampered by a severe shortage of donors. Cell replacement therapy represents one possible alternative, but significant hurdles must be overcome.

 

Self-renewing pluripotent human embryonic stem cells (hESCs) can differentiate into all cell types, including CMs. Direct reprogramming of adult somatic cells to induced pluripotent stem cells (iPSCs) has advanced the field of personalize medicine. The availability of hESC/iPSCs have enabled researchers to gain novel biological insights and to pursue heart regeneration. Despite these promises, substantial hurdles remain for translating pluripotent stem cells (PSCs) into cell-based therapies and for improved disease modeling, cardiotoxicity testing and drug screening.

 


Local Advances: 

 

In a series of studies, we have shown that hESC-CMs have 1) immature Ca2+-handling, with an attenuated transient and heart failure-like U-shaped Ca2+ propagation wavefronts due to the lack of t-tubules; 2) immature electrical properties; 3) a small physical size (~10-fold less than adult CMs); 4) an absence of ordered organization at the sub-, single- and multi-cellular levels; 5) high cell heterogeneity, even from directed cardiac differentiation, consisting of a mixture of pacemaker, atrial and ventricular derivatives; 6) sub-lineage specification is poorly understood; 7) no convenient cardiac/chamber-specific surface marker for robust purification; 8) poor graft survival; 9) poor understanding of immunobiology; and 10) an uncertain durability in terms of safety and efficacy.

On-going Projects: 


Modeling congenital heart diseases with human induced pluripotent stem cells

 

Congenital heart disease (CHD) is the most common birth defect affecting about 1% of live births.  However, their genetic bases are complex and not well-defined.  Ethnic differences in the incidence of different types of CHD have been well reported.  In particular, children of Asian ethnicity have been reported to have a greater incidence of varying degrees of right ventricular hypoplasia.  CHD often occurs in the setting of multiple congenital anomalies including limb anomalies, abnormal facial features, and cognitive defects.  For example, the CHD Tetralogy of Fallot (TOF) is a cyanotic heart defect often associated with extracardiac anomalies, progressive mental retardation, and development of psychiatric disease.  Tricuspid atresia (TA) is another important hypoplastic right heart syndrome which accounts for 1% to 3% of congenital heart defects.  It is characterized by complete obstruction of the RV inflow, RV hypoplasia, and pulmonary outflow obstruction that varies from mild pulmonary stenosis to complete atresia. Single cell RNA-sequencing technologies provide a unique set of tools to gain novel molecular insights into CHDs, hence unraveling novel disease mechanism and pathogenesis and could potentially lead to identification of novel therapies for these diseases.  Using single cell transcriptome profiling and bioinformatics, we sought to investigate the defects of CHD during cardiac development using hiPSCs as a model, by identifying altered cell states during the cardiac developmental process of CHDs.  

 

Establishing a human cell based disease model for dilated cardiomyopathy for developing novel drug targets unique to Southern Chinese

 

Dilated cardiomyopathy (DCM) is a genetically heterogenous disease which could lead to heart failure and sudden cardiac death. To date, over 50 genetic mutations have been associated with DCM.  However, routine genetic testing is not commonly done in patients clinically diagnosed with DCM and the genetic basis of the disease in the Southern Chinese population is unknown.  Human pluripotent stem cells (hPSC) have the ability to differentiate into cardiomyocytes (CMs),and is a potential unlimited source for engineered tissues for disease modeling and drug discovery. Our aim is to combine the advantage of our access to DCM patient samples in the Sourthern China, Next Generation Sequencing (NSG) and our engineered cardiac tissue platform, to develop novel biomarkers for new drug discovery by systematically comparing single-cell transcriptomes of hPSC-derived CMs and their engineered tissues from normal and disease samples.  The collected data will prove to be beneficial for establishing patient-specific therapy unique to the Southern Chinese population.  


Please see also here.

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