Yiqiang Zhang
	Affiliation: JABSOM, Center for Cardiovascular Research Position: Assistant Professor Degree: PhD (Biomedical Sciences, University of Montreal, Canada) Phone: (808) 692-1480 Fax: (808) 692-1973 Email: yiqiang.zhang@hawaii.edu Address: 651 Ilalo Street, BSB-311D, Honolulu HI, 96813

Integrative Cellular Molecular Cardiobiology and Heart Regeneration

We study systems molecular regulations in cardiac growth and regeneration, stem cell and cardiomyocyte biology, and electrophysiology, using innovations in transgenic models, multi-omics (e.g., epigenetics, transcriptomics) and bioinformatics, functional physiology, and bioengineering.

INTRODUCTION
Our multi-disciplinary research covers cardiovascular molecular and cell biology and integrative pathophysiology and multi-omics sciences. We study cardiac and stem cell biology and heart regeneration, cardiac growth and disease mechanisms, cell cycle control, epigenetics and functional genomics, heart failure therapies, and electrophysiology and arrhythmias. By obtaining a better, in-depth understanding of mechanisms underlying endogenous heart growth and regeneration, as well as exogenous cardiac regeneration by innovative approaches in stem cell biology and bioengineering, we hope to develop novel and effective therapeutics to treat congestive and congenital heart diseases.



OVERVIEW
Heart cell hemostasis and regeneration undergo dynamic changes during development and in disease processes. Understanding the molecular and genetic pathways regulating cell lineage and functions is a crucial step in treating congenital and congestive heart diseases such as heart failure. Mammalian cardiomyocytes rapidly enter into a quiescent cell cycle state shortly after birth. Dr. Zhang's group first demonstrated that adult cardiomyocytes (ACMs) retain substantial cellular plasticity, capable of dedifferentiation, and can become more primitive to re-enter the cell cycle to proliferate, contributing to the endogenous myocardial regeneration in post-injury hearts, albeit at a low level. In addition, cardiomyocytes derived from pluripotent stem cells are great models and unlimited resources for exogenous heart regeneration. Still, molecular epigenetic regulations on cardiac cell biology and functions remain largely undetermined. An integrative system investigation in cell and molecular cardiobiology will reshape the future of preventing and treating heart disease.

GOALS AND APPROACHES
With the ultimate goal of treating degenerative heart diseases by promoting both endogenous and exogenous cardiac regeneration, the Zhang lab is working to determine the integrative cardiac and non-cardiac cellular processes and molecular pathways regulating cardiomyocyte differentiation, maturation, dedifferentiation, and cell cycle activities. His team uses state-of-the-art transgenic and reporter cells and animal models bridging to human health, cutting-edge multi-omics and bioinformatics approaches, together with advanced cellular, molecular, and bioengineering technologies.

CURRENT RESEARCH THEMES
Cardiomyocyte Growth, Dedifferentiation, and Cell Cycle Regulation
Based upon our early work in cardiomyocyte dedifferentiation, we have recently developed new multi-reporter transgenic mouse models for rigorous cardiomyocyte lineage tracing and real-time maturity (versus dedifferentiation) visualization (Figure 1). We continue studying molecular regulations of endogenous myocardial regeneration, namely cardiomyocyte dedifferentiation followed by proliferation, in injured (e.g., infarcted and hypertrophic) hearts. We use multi-disciplinary approaches, including high-throughput single-cell imaging, massive parallel single-nucleus RNA-seq and ATAC-seq, DNA methylome, and integrative cellular, molecular, and functional physiological analyses. We also use cell cycle-specific reporter systems and patient cardiac tissues to study heart cell hemostasis and mechanisms of endogenous myocyte renewal and regeneration.

Stem Cell and Cardiac Biology, Bioengineering, Cardiac Physiology, and Heart Regeneration
Pluripotent stem cells (e.g., induced pluripotent stem cells/iPSCs, or embryonic stem cells/ESCs) are the unique models used in cardiac development and heart regeneration research. We study cardiomyocyte differentiation, growth (maturation versus dedifferentiation), cell cycle (proliferation), cellular physiology, and how these processes are modulated by cellular cues such as bioengineered, nanopatterned surfaces (Figure 2), and their underlying molecular/epigenetic mechanisms. The overarching goals of our projects are to dissect molecular mechanisms regulating these multi-faceted processes in stem cells and heart cells and to generate important targets to enhance exogenous myocardial regeneration using cell therapies.

Integrative Functional Multi-Omics in Heart Diseases
We apply large-scale multi-omic approaches to discover and translate knowledge of treating cardiovascular diseases (Figure 3). By taking advantage of novel transgenic models for cell lineage, cell cycle, and specific molecular expression, and using both animal models and human biopsies, we study the integrative transcriptomic and epigenomic regulations (e.g., chromatin accessibility by ATAC-seq, histone and DNA modifications, and miRNA) in cardiac development and disease remodeling. Our systematic functional genomic work on global heart cell populations has the potential for comprehensive, in-depth knowledge and novel discoveries critical in treating heart failure and other cardiovascular diseases.

Figure 1: Modes of endogenous myocardial regeneration revealed in multi-reporter transgenic models for cardiomyocyte lineage tracking and maturity (vs dedifferentiation) reporting. Single-cell imaging using ImageStream revealed significantly increased BrdU+ cycling pre-existing myocytes in post-infarct hearts compared to sham, and that increase was preferentially in dedifferentiated BFPlow CMs.

Figure 2: Cardiac and Stem Cell Biology and Electrophysiology, and the roles of extracellular cues on myocyte maturity and functions revealed by assays using microelectrode arrays.

Figure 3: System cardiac genomics. A, t-SNE plot showing cell populations in normal and post-infarct triple-transgenic mouse hearts revealed by massive parallel single-nucleus RNA-seq (snRNA-seq) analysis. B, Integrative transcriptomic and DNA methylomic analysis of differentially expressed (DEGs) or methylated genes (DMGs) in dedifferentiated cardiomyocytes.



Selected publications:

1. Zhang Y, Gago-Lopez N, Li N, Zhang Z, Alver N, Liu Y, Martinson AM, Mehri A, MacLellan WR. Single-cell imaging and transcriptomic analyses of endogenous cardiomyocyte dedifferentiation and cycling. (Nature) Cell Discovery, 2019; 5: 30; June 4, 2019; PMCID: PMC6547664. DOI : 10.1038/s41421-019-0095-9
2. El-Nachef D, Oyama K, Wu YY, Liu Y, Zhang Y, MacLellan WR. Repressive histone methylation regulates cardiac myocyte cell cycle exit. J Mol Cell Cardiol. 2018; 121:1-12; PMID: 29800554 DOI: 10.1016/j.yjmcc.2018.05.013
3. Chen X*, Chakravarty T*, Zhang Y*, Li X, Zhong JF, Wang C. Single-cell transcriptome and epigenomic reprogramming of cardiomyocyte-derived cardiac progenitor cells. (Nature) Scientific Data. 2016; 3: 160079. PMID: 27622691 (*co-first author)
4. * Zhang Y, Zhong JF, Qiu H, MacLellan WR, Marban E, Wang C. Epigenomic reprogramming of adult cardiomyocyte-derived cardiac progenitor cells. (Nature) Sci. Rep. 2015; 5: 17686; doi: 10.1038/ srep17686. PubMed PMID: 26657817
5. * Zhang Y, Mignone J, MacLellan WR, Cardiac Regeneration and Stem Cells. Physiol. Rev. 2015; 95: 1189-204. PubMed PMID: 26269526
6. Gago-Lopez N, Awaji O, Zhang Y, Ko C, Nsair A, Liem D, Stempien-Otero A, MacLellan WR. THY-1 receptor expression differentiates cardiosphere-derived cells with divergent cardiogenic differentiation potential. Stem Cell Report, 2014;2:1-16. PMID: 24936447
7. Zhang Y, Matsushita N, Eigler T, Marban. Targeted microRNA interference promotes postnatal cardiac cell cycle re-entry. J Regenerative Med. 2013;2:2. PMID: 24910852
8. Malliaras K, Zhang Y, Seinfeld J, Galang G, Tseliou E, Cheng K, Sun B, Aminzadeh M, Marban E. Cardiomyocyte proliferation and progenitor cell recruitment underlie therapeutic regeneration after myocardial infarction in the adult mouse heart. EMBO Mol Med. 2013;5:191-209. PMID: 23255322
9. Li Z, Zhang C, Weiner LP, Chiou PY, Zhang Y, Zhong JF. Molecular characterization of heterogeneous mesenchymal stem cells with single-cell transcriptomes. Biotechnol. Adv. 2013;31(2):312-7. PMID: 23266308 )
10. Barth AS*, Zhang Y*, Li TS, Smith RR, Chimenti I, Terrovitis J, Davis D, Kizana E, Ho A, O'Rourke B, Wolff A, Gerstenblith G, Marban E. Functional impairment of human resident cardiac stem cells contributes to trastuzumab cardiotoxicity. Stem Cells Transl Med, 2012;1(4):289-97.. PMID: 23197808 (* equal first-author)
11. Li TS, Cheng K, Malliaras K, Matsushita N, Sun B, Marban L, Zhang Y, Marban E. Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovascular Res., 2011;89: 157-165. PMID: 20675298
12. Zhang Y, Li TS, Lee ST, Wawrowsky KA, Cheng K, Galang G, Malliaras K, Abraham RM, Wang C, Marban E. Dedifferentiation and proliferation of mammalian cardiomyocytes. PLoS One 2010; 5: e12559. PMID: 20838637

View a complete list of Publications in MyBibliography: Click here



OPPORTUNITIES

Positions

Our laboratory and institution provide a broad spectrum of learning opportunities for undergraduate students, graduate students and postdoctoral fellows in the following areas: Cellular Molecular Biology, Heart Diseases, Animal models, Stem Cell Research and Regenerative Medicine, Genomics and Epigenetics, Electrophysiology, and Bioengineering.

Our lab can only accept graduate students who have already been admitted to the University of Hawaii Manoa (UHM) graduate programs. Candidates are encouraged to apply through the Department of Anatomy, Biochemistry and Physiology, or other departments at the UHM. For undergraduate students, independent study for potential credit and completion of an undergraduate thesis are highly encouraged. Outstanding and motivated undergraduates with necessary knowledge and skills from all departments who can commit at least 12 hours per week and plan to stay with our lab during the academic year, can contact Dr. Zhang by e-mail and submit a CV and statement of interest as a single PDF.

Research Scientist and Post-docs interested in the opportunities are encouraged to contact Dr. Zhang directly by sending the following documents in a single PDF file via e-mail: 1) a cover letter outlining their research interests and career plans; 2) a CV including three references and their contact information; 3) any selected publications.