Cardiology; Cardiovascular Diseases; Heart; Physiology; Stem Cells; Tissue Engineering
Stem Cell Center, Yale: Tissue Specific Stem Cells
Our research laboratory has been focused on establishing novel cellular and animal models of human cardiovascular diseases for the purpose of elucidating causative mechanisms and identifying potential therapeutic interventions to treat those diseases. Through a close collaboration with several clinicians at Yale, we are able to obtain cells from a variety of tissues procured from healthy subjects and patients with cardiovascular diseases. These cells include dermal fibroblast cells derived from skin punch biopsies or peripheral mononuclear blood cells, which are isolated and reprogrammed into induced pluripotent stem (iPS) cells by introducing stem cell factors before being re-differentiated into functional cardiovascular cells. In this way, we have the ability to derive an unlimited amount of human cardiovascular cells for use in our investigations into the specifics of cardiovascular disease mechanisms and the discovery of potential therapeutic treatments by performing high-throughput drug screening, as well as the generation of patient-specific, autologous cardiovascular tissues for organ repair.
Specialized Terms: Heart; Stem cell; ES cell; iPS cell; Physiology; Tissue engineering; Small molecule; Patient; Disease; Cardiovascular
Extensive Research Description
Our research laboratory has been focused on establishing novel cellular and animal models of human cardiovascular diseases for the purpose of elucidating causative mechanisms and identifying potential therapeutic interventions to treat those diseases. Our research covers the following areas:
1. Vascular disease mechanism and drug screening: Having patient-specific vascular smooth muscle cells (SMCs) available facilitates the study of disease and development of novel therapeutic interventions. We were the first to describe the development of a human induced pluripotent stem cell (iPSC) line from a patient with supravalvular aortic stenosis (SVAS). SVAS iPSC-SMCs recapitulate key pathological features of patients with SVAS and provide a promising strategy to study disease mechanisms and to develop novel therapies. The objectives of our recently funded Connecticut Regenerative Medicine Research Program (2015-2019) are to obtain mechanistic insight into how elastin and candidate drug vinblastine inhibit the hyperproliferation of SVAS iPSC-SMCs and to screen for additional small molecules that ameliorate the hyperproliferative defect in SVAS. By studying SVAS, a particular disease with an intrinsic defect in SMC proliferation, we may gain insights into the disease mechanisms and develop novel therapies for multiple vascular proliferative diseases. Rotation students are welcome to join this project and learn vascular disease mechanism and drug screening using patient stem cell modeling.
2. Vascular tissue engineering and repair: The availability of unlimited supply of iPSC-derived SMCs and endothelial cells (ECs) has also allowed for the generation of 3D vascular tissue for disease studies and blood vessel repair (awarded NIH R01 program 2013-2018). We have engineered 3D tissue rings from hiPSC-SMCs using a facile one-step self-assembly technique in collaboration with Dr. Marsha Rolle group. The tissue rings are mechanically robust and can be used for vascular tissue engineering, disease modeling and drug screening.
3. Cardiac disease modeling and mechanism: Human iPSC potentially provide a unique resource for generating patient-specific cardiomyocytes to study cardiac disease mechanisms and treatments. We were the first group to report that small molecule Wnt inhibitors IWP1 or IWP4-based, highly efficient production of functional cardiomyocytes from embryonic stem cells (ESCs) or iPSCs. We have used iPSC approach to study the functional consequences of sarcomeric and stretch-sensing mutations in hypertrophic cardiomyopathy (HCM; thickening of the heart tissue, affecting 1 out of 500 people). We have recently derived iPSCs from patients with MYH7(sarcomeric) and MLP (stretch-sensing) mutations. We will investigate the disease mechanism by producing engineered heart tissue constructs (EHTs) that can be precisely stretched in vitro in collaboration with Dr. Stuart Campbell group. This project is supported by an awarded NIH R01 program (2016-2020). Rotation students can join this project, gain experience in studying cardiac disease mechanism, and learn how to design potential drug screening approach to rescue/treat this devastating heart disease.
4. Cardiac repair and regeneration based on cardiac progenitor cells: We have also established robust cardiac differentiation approach in human ESCs and iPSCs to derive ISL1+ cardiovascular progenitor cells (ISL1-CPCs), a CPC population representative of an authentic cardiac origin, for cardiac repair. We show that ISL1-CPCs have important physiological effects to improve heart contractile function, reduce scar size and increase blood vessel formation in the mouse model. Thus, our findings indicate that the ISL1-CPC approach may represent a significant advance in the heart repair field. Future efforts will be made to translate ISL1-CPC heart repair from mouse to large animal models. This project is supported by a Department of Defense Award (another grant is pending and other proposals are in preparation). Rotation students joining this project will learn how to isolate ISL1-CPCs from human ESCs and iPSCs, generate cardiac progenitor-based tissue, and gain experience in cardiac repair and regeneration.
5. Preclinical modeling of cardiovascular repair and regeneration: We have generated robust iPSC lines from pigs for preclinical studies.The availability of pig iPSC will enable us to engineer cardiovascular tissues and then test in pigs, which closely mimic human cardiovascular physiology. Our studies will provide critical preclinical knowledge for the application of autologous stem cell-based cardiovascular repair and regeneration therapies.
- Oscar Bartulos, PhD, Zhen Wu Zhuang, MD, Yan Huang, PhD, Nicole Mikush, BS, Carol Suh, MS, Alda Bregasi, MD, Lin Wang, MS, William Chang, MD, PhD, Diane S. Krause, MD, PhD, Lawrence H. Young, MD Jordan S. Pober, MD, PhD, Yibing Qyang, PhD ISL1 Cardiovascular Progenitor Cells for Cardiac Repair after Myocardial Infarction. JCI Insight 2016 (Accepted and In Press).
- Liqiong Gui, Biraja C. Dash, Jiesi Luo, Lingfeng Qin, Liping Zhao, Kota Yamamoto, Takuya Hashimoto, Hongwei Wu, Alan Dardik, George Tellides, Laura E. Niklason, Yibing Qyang Implantable Tissue-Engineered Blood Vessels from Human Induced Pluripotent Stem Cells. Biomaterials 2016 (Accepted and In Press).
- Biraja C. Dash, Karen Levi, Jonas Schwan, Jiesi Luo, Oscar Bartulos, Hongwei Wu, Caihong Qiu, Ting Yi, Yongming Ren, Stuart Campbell, Marsha W. Rolle, Yibing Qyang Tissue-Engineered Vascular Rings from Human iPSC-Derived Smooth Muscle Cells . Stem Cell Reports 2016 (Accepted and In Press).
- Misra A, Sheikh AQ, Kumar A, Luo J, Zhang J, Hinton RB, Smoot L, Kaplan P, Urban Z, Qyang Y, Tellides G, Greif DM. Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis. J Exp Med. 2016 Mar 7;213(3):451-63. doi: 10.1084/jem.20150688. Epub 2016 Feb 8.
- Biraja C. Dash, Zhengxin Jiang, Carol Suh, Yibing Qyang (2015). Induced Pluripotent Stem Cell-derived Vascular Smooth Muscle Cells: Methods and Application. Biochemical Journal 2015, 465(2):185-94.
- Abrahimi P, Chang WG, Kluger MS, Qyang Y, Tellides G, Saltzman WM, Pober JS. Efficient Gene Disruption in Cultured Primary Human Endothelial Cells by CRISPR/Cas9. Circ Res. 2015, 117(2):121-8
- Sivarapatna A, Ghaedi M, Le AV, Mendez JJ, Qyang Y, Niklason LE. Arterial specification of endothelial cells derived from human induced pluripotent stem cells in a biomimetic flow bioreactor. Biomaterials, 2015, 53:621-33.
- Suh CY, Wang Z, Bártulos O, Qyang Y. Advancements in Induced Pluripotent Stem Cell Technology for Cardiac Regenerative Medicine. J Cardiovasc Pharmacol Ther. 2014, 19;19(4):330-339.
- Esra Cagavi, Oscar Bartulos, Carol Y. Suh, Baonan Sun, Zhichao Yue, Zhengxin Jiang, Lixia Yue, Yibing Qyang. Functional cardiomyocytes derived from Isl1 cardiac progenitors via Bmp4 stimulation. PLOS ONE 2014, 9(12):e110752.
- Dunworth WP, Cardona-Costa J, Cagavi E, Kim JD, Fischer JC, Meadows S, Wang Y, Cleaver O, Qyang Y, Ober EA, Jin SW. Bone Morphogenetic Protein 2 Signaling Negatively Modulates Lymphatic Development in Vertebrate Embryos. Circ Res. 2014, 114(1):56-66.
- Li W, Li Q, Qin L, Ali R, Qyang Y, Tassabehji M, Pober BR, Sessa WC, Giordano FJ, Tellides G (2013). Rapamycin Inhibits Smooth Muscle Cell Proliferation and Obstructive Arteriopathy Attributable to Elastin Deficiency. Arterioscler Thromb Vasc Biol. 2013, 33(5):1028-35.
- X. Ge, Y. Ren, Z. Yue, K. Kim, M. Lee, W. Li, P. Amos, E. Bozkulak, W. Zheng, H. Zhao, K. Martin, D. Kotton, G. Tellides, I. Park, L. Yue, Y. Qyang (2012). Modeling Supravalvular Aortic Stenosis Syndrome Using Human Induced Pluripotent Stem Cells. Circulation 2012, 126 (14):1695-1704.
- Jun-Dae Kim, Hyeseon Kang, Bruno Larrivee, Min Young Lee, Marcel Mettlen, Sandral L. Schmid, Beth L. Roman, Yibing Qyang, Anne Eichmann, and Suk-Won Jin (2012). Context-Dependent Proangiogenic Function of Bone Morphogenetic Protein Signaling Is Mediated by Disabled Homolog 2. Developmental Cell 2012, 23:1-8.
- A. Alcon, E. Bozkulak, Y. Qyang. Regenerating functional heart tissue for myocardial repair. Cellular and Molecular Life Sciences 2012, 69(16):2635-56.
- Min Young Lee, Baonan Sun, Simon Schliffke, Zhichao Yue, Mingyu Ye, Jere Paavola, Esra Cagavi Bozkulak, Peter J. Amos, Yongming Ren, Rong Ju, Yong Woo Jung, Xin Ge, Lixia Yue, Barbara E. Ehrlich, Yibing Qyang. Derivation of functional ventricular cardiomyocytes using endogenous promoter sequence from murine embryonic stem cells. Stem Cell Research 2012, 8(1):49-57.
- Peter J. Amos, Esra Cagavi Bozkulak, Yibing Qyang (2012). Methods of Cell Purification: A Critical Juncture for Laboratory Research and Translational Science. Cells Tissues Organs 195(1-2):26-402011. PMID: 21996576
- Min Young Lee, Esra Cagavi Bozkulak, Simon Schliffke, Peter J. Amos, Yongming Ren, Xin Ge, Barbara E. Ehrlich, Yibing Qyang (2011).High density cultures of embryoid bodies enhanced cardiac differentiation of murine embryonic stem cells. Biochemical and Biophysical Research Communications 2011, 416(1-2):51-7.
- Ren Y, Lee MY, Schliffke S, Paavola J, Amos PJ, Ge X, Ye M, Zhu S, Senyei G, Lum L, Ehrlich BE, Qyang Y (2011). Small molecule Wnt inhibitors enhance the efficiency of BMP-4-directed cardiac differentiation of human pluripotent stem cells. J Mol Cell Cardiol 2011, 51(3): 280-7.
- Yibing Qyang, Silvia Martin-Puig, Murali Chiravuri, Susanna Chen, Huansheng Xu, Lei Bu, Xin Jiang, Lizhu Lin, Anne Granger, Alessandra Moretti, Leslie Caron, Xu Wu, Jonathan Clarke, Makoto M. Taketo, Karl-Ludwig Laugwitz, Randall T. Moon, Peter Gruber, Sylvia M. Evans, Sheng Ding, and Kenneth R. Chien. The Renewal and Differentiation of Isl1+ Cardiovascular Progenitors Are Controlled by a Wnt/beta-Catenin Pathway. Cell Stem Cell 2007, 1:165-179.
- Moretti, A., Caron, L., Nakano, A., Lam, J.T., Bernshausen, A., Chen, Y., Qyang, Y., Bu, L., Sasaki, M., Martin-Puig, S., Sun, Y., Evans, S.M., Laugwitz, K.L. and Chien, K.R. Multipotent embryonic isl1+ progenitor cells lead to cardiac, smooth muscle, and endothelial cell diversification. Cell, 2006, 127:1151-1165.
- *Kim, H., *Yang, P., *Qyang, Y., H. Lai, H. Du, J.S. Henkel, K. Kumar, S. Bao & S. Marcus. Genetic and molecular characterization of Skb15, a highly conserved inhibitor of the Fission Yeast PAK, Shk1. (2001). Mol. Cell 2001, 7:1095-1101. (*contributed equally.)
- *Yang, P., *Qyang, Y., Bartholomeusz G., Zhou X., Marcus S. (2003).The novel RhoGAP family protein, Rga8, provides a potential link between Cdc42/PAK and Rho signaling pathways in the fission yeast, Schizosaccharomyces pombe. J. Biol Chem. 278, 48821-4883. (*contributed equally.)
- Qyang, Y., X. Luo, T. Lu, P.M. Ismail, D. Krylov, C. Vinson & M. Sawadogo. Cell-type-dependent activity of the ubiquitous transcription factor USF in cellular proliferation and transcriptional activation. Mol. Cell. Biol. 1999, 19:1508-1517.