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Zhong Wang

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Primary Appointment: Cardiac Surgery
Other PIBS Depts.: Cell and Developmental Biology
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  Our long-term goal is to develop stem cell based heart therapies to effectively prolong and improve the life of heart patients. We are tackling a few roadblocks in heart regeneration. One roadblock is the poor understanding of the molecular mechanism of cardiac stem/progenitor cell (CPC) specification and differentiation. The second roadblock is the inefficient strategies to produce CPCs and engineered cardiac tissues suitable for heart regeneration. The third roadblock is the lack of appropriate large animal models for preclinical studies.

Project One: Epigenetic control of multipotent cardiac progenitor cell differentiation.

Rudimentary knowledge about CPC differentiation mechanisms remains a major roadblock to developing cell-based heart therapies. We propose that understanding the function of epigenetic factors and the chromatin signatures of key cardiac genes in CPCs could be an essential step toward elucidating the mechanisms of CPC differentiation.

ATP-dependent chromatin remodelers mediate one critical epigenetic mechanism. These large multiprotein complexes open up chromatin to modulate transcription factor access to DNA. SWI/SNF, one of the major types of chromatin remodelers, plays a key role in various aspects of development, including heart development and disease. To decipher SWI/SNF-mediated epigenetic mechanisms in CPC differentiation, we have focused on a key regulatory subunit BAF250a that mediates SWI/SNF assembly/recruitment and controls nucleosome density as well as histone methylation and ubiquitylation.

We propose to determine the function of BAF250a in regulating SHF CPC differentiation (Aim 1), to test the hypothesis that BAF250a is essential for the assembly and recruitment of cSWI/SNF complex to its targets (Aim 2), and to test the hypothesis that BAF250a-mediated epigenetic modifications control CPC differentiation by regulating the promoter accessibility of key cardiac transcription factors (Aim 3). We have applied an integrated strategy combining genetics, cell biology, molecular biology, and biochemistry in these studies. These studies will generate novel insights into epigenetic mechanisms that govern CPC differentiation and may have significant implications in understanding and treating heart disease. A five-year R01 was awarded to support this project (April 2012 to March 2017).

Project Two: Determine the therapeutic potential of cardiac progenitor cells in large animal models with lineage tracing and tissue engineering.

To pursue stem cell-based heart therapies in a more clinically relevant setting, we have generated a series of genetically modified cell reporter systems in rabbits and swine. For the first time in the field, we generated constitutive and stable expression of ROSA26-tdTomato knockin swine, which will enable precise quantification of transplanted cells versus host cells. Moreover, to increase the efficiency of cell delivery, survival and integration, we have developed cutting-edge injectable nanofibrous hollow microspheres (NF-HMS, in collaboration with Dr. Peter Ma) and show that NF-HMS greatly increase the CPC engraftment in infarcted hearts. We also developed novel technology for controlled release of growth factors within scaffolds to enhance CPC-mediated heart regeneration.

Our studies may help reveal the etiology of related heart diseases and provide clues to develop modern medical treatments such as small molecule drugs, gene or stem cell/progenitor cell therapies against these diseases.