Haodi Wu, PhD

Research Interests

The long-term goal of Wu lab is to understand the molecular mechanisms underlying the development, disease, and senescence of cardiac cells, and to identify therapeutic targets to rectify the pathogenesis and aging in the heart. For that purpose, we mainly use human induced pluripotent stem cell (iPSC) platform as well as the cutting edge molecular, cellular, and physiological technologies to study the biology of heart cells in health and disease, and to discover novel drugs/approaches for translational applications.

Direction 1: Understand the genetic mechanisms of cardiomyopathy and heart failure

We will focus in two types of cardiomyopathies: 1: Hypertrophic cardiomyopathy (HCM) is characterized by the thickened ventricle walls and impaired relaxation. And without proper management, these patients are likely to develop the heart failure with preserved ejection fraction, which shows diastolic dysfunction. 2: Dilated cardiomyopathy (DCM) is characterized by enlarged ventricular dimensions and impaired contractility. DCM is the most common cause of heart failure with reduced ejection fraction, which shows systolic disfunction.

Although many familiar mutations have been identified for both DCM and HCM, the underlying mechanism for these mutations has not been well studied, and thus, our treatment are still focusing in relieve the symptoms rather than target the molecular basis. One of the applications of our iPSC is to model the pathogenesis in vitro, which will help us to better understand DCM and HCM mechanism.

Direction 2: iPSC models as a platform for better diagnosis and drug discovery

Cardiac arrhythmias are related to genetic mutations and drug exposure, which affects the ion homeostasis in the cardiomyocytes and may lead to serious consequences in patients. Moreover, proarrhythmic effect is a major cause of failure during drug development. The iPSCs provide us a unique platform to better evaluate the arrhythmic risk of both genetic mutations and drugs. The dataset from the different patient-specific iPSC line and drug treatment groups can be used to train a machine learning model (classifier), which will help us identify the potential arrhythmia risks based on the experimental data. The computational tool will optimize the utility of the massive dataset in modern iPSC modeling research, help to identify cardiotoxicity during drug development, and facilitate the evaluation of potential cardiac risk and drug response with the patient-specific iPSC model.

Direction 3: Understand the relation between functional SNPs and cardiac risks of disease and aging

Genetic polymorphism is one of the main contributing factors for the heterogeneity of cardiac risks and aging in different populations. And there are a great number of SNPs that have been identified as cardiac risk-related from our Genome-Wide Association Study (GWAS) study. However, the understanding of whether and how these SNPs contribute to the pathogenesis, phenotype presentation, and drug response is very limited. Mainly due to the lack of screening methods and standardized platforms. Using a specialized Reel-sequencing method, the unbalanced interaction of wide type and mutated alleles with nuclear protein factors in the target cell types can be identified. These allele-specific interactions of protein factors and SNPs in the non-coding DNA region indicate potential roles in transcriptional regulation, which can be further validated with CRISPR/Cas9 genome-editing, iPSCs, and animal models. These studies will decode the relation between SNP and cardiac risks and help us develop better therapeutic strategies for different populations.

 

 

Selected Publications

View Dr. Wu's full publication on PubMed.

 

  • Chirikian O, Goodyer WR, Dzilic E, Serpooshan V, Buikema JW, McKeithan W, Wu H, Li G, Lee S, Merk M, Galdos F, Beck A, Ribeiro AJS, Paige S, Mercola M, Wu JC, Pruitt BL, Wu SM. CRISPR/Cas9-based targeting of fluorescent reporters to human iPSCs to isolate atrial and ventricular-specific cardiomyocytes. Sci Rep. 2021 Feb 4;11(1):3026. doi: 10.1038/s41598-021-81860-x. PubMed PMID: 33542270; PubMed Central PMCID: PMC7862643.
  • Kim BB, Wu H, Hao YA, Pan M, Chavarha M, Westberg M, St-Pierre F, Wu JC, Lin, MZ. A red fluorescent protein with improved monomericity enables ratiometric voltage imaging with ASAP3. 2020. BioRxiv: doi: https://doi.org/10.1101/2020.10.09.328922
  • Liu Q, Wu H, Luo QJ, Jiang C, Duren Z, Van Bortle K, Zhao MT, Zhao B, Liu J, Marciano DP, Lee-McMullen B, Zhu C, Narasimha AM, Gruber JJ, Lipchik AM, Guo H, Watson NK, Tsai MS, Furihata T, Tian L, Wei E, Li Y, Steinmetz LM, Wong WH, Kay MA, Wu JC, Snyder MP. Tyrosine kinase inhibitors induce mitochondrial dysfunction during cardiomyocyte differentiation through alteration of GATA4-mediated networks. 2020. BioRxiv: doi: https://doi.org/10.1101/2020.05.04.077024
  • Li LL, Guo QJ, Lou HY, Liang JH, Yang Y, Xing X, Li HT, Han J, Shen S, Li H, Ye H, Wu H, Cui B, Wang SQ. Nanobar Array Assay Revealed Complementary Roles of BIN1 Splice Isoforms in Cardiac T-Tubule Morphogenesis. Nano Lett. 2020 Sep 9;20(9):6387-6395. doi: 10.1021/acs.nanolett.0c01957. Epub 2020 Aug 10. PubMed PMID: 32787151.
  • Buikema JW, Lee S, Goodyer WR, Maas RG, Chirikian O, Li G, Miao Y, Paige SL, Lee D, Wu H, Paik DT, Rhee S, Tian L, Galdos FX, Puluca N, Beyersdorf B, Hu J, Beck A, Venkamatran S, Swami S, Wijnker P, Schuldt M, Dorsch LM, van Mil A, Red-Horse K, Wu JY, Geisen C, Hesse M, Serpooshan V, Jovinge S, Fleischmann BK, Doevendans PA, van der Velden J, Garcia KC, Wu JC, Sluijter JPG, Wu SM. Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes. Cell Stem Cell. 2020 Jul 2;27(1):50-63. e5. doi: 10.1016/j.stem.2020.06.001. PubMed PMID: 32619518; PubMed Central PMCID: PMC7334437.
  • Wnorowski A, Sharma A, Chen H, Wu H, Shao NY, Sayed N, Liu C, Countryman S, Stodieck LS, Rubins KH, Wu SM, Lee PHU, Wu JC. Effects of spaceflight on Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Structure and Function. Stem Cell Reports. 2019 Dec 10;13(6):960-969. doi: 10.1016/j.stemcr.2019.10.006. Epub 2019 Nov 7. PubMed PMID: 31708475; PubMed Central PMCID: PMC6915842.
  • Wu H, Yang H, Rhee JW, Zhang JZ, Lam CK, Sallam K, Chang ACY, Ma N, Lee J, Zhang H, Blau HM, Bers DM, Wu JC. Modeling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. Eur Heart J. 2019 Dec 1;40(45):3685-3695. doi: 10.1093/eurheartj/ehz326. PubMed PMID: 31219556.
  • Kernik DC, Morotti S, Wu H, Garg P, Duff HJ, Kurokawa J, Jalife J, Wu JC, Grandi E, Clancy CE. A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources. J Physiol. 2019 Sep;597(17):4533-4564. doi: 10.1113/JP277724. Epub 2019 Jul 27. PubMed PMID: 31278749; PubMed Central PMCID: PMC6767694.
  • Zhang H, Tian L, Shen M, Tu C, Wu H, Gu M, Paik DT, Wu JC. Generation of Quiescent Cardiac Fibroblasts from Human Induced Pluripotent Stem Cells for In Vitro Modeling of Cardiac Fibrosis. Circ Res. 2019 Aug 16;125(5):552-566. doi: 10.1161/CIRCRESAHA.119.315491. Epub 2019 Jul 10. PubMed PMID: 31288631; PubMed Central PMCID: PMC6768436.
  • Lee J, Termglinchan V, Diecke S, Itzhaki I, Lam CK, Garg P, Lau E, Greenhaw M, Seeger T, Wu H, Zhang JZ, Chen X, Gil IP, Ameen M, Sallam K, Rhee JW, Churko JM, Chaudhary R, Chour T, Wang PJ, Snyder MP, Chang HY, Karakikes I, Wu JC. Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature. 2019 Aug;572(7769):335-340. doi: 10.1038/s41586-019-1406-x. Epub 2019 Jul 17. PubMed PMID: 31316208; PubMed Central PMCID: PMC6779479.