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Ching Ling Lien, PhD

Title(s)Associate Professor Surgery and Biochemistry & Molecular Medicine
Phone+1 323 361 8377
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    Heart disease is among the leading causes of death for both adults and children. Mammalian hearts have very limited regenerative capacity and heal by scarring and hypertrophy after heart injury, which results in decreased cardiac performance. By contrast, zebrafish have remarkable regenerative capacity. The molecular mechanisms of zebrafish heart regeneration are not understood. The goal of my lab is to define the molecular and cellular mechanisms of heart regeneration in zebrafish with the long-term goal of enhancing regenerative capacity and replacing defective tissues in diseased human hearts.

    We use genetic and genomic approaches to dissect the process of zebrafish heart regeneration. Using gene expression profiling, we identified a set of genes that are differentially expressed during heart regeneration. We would like to address the following basic questions: How do these genes contribute to heart regeneration in zebrafish? Does regeneration recapitulate the developmental process? Are stem cells also involved in this regeneration process? The functions of these genes will be characterized in cultured cardiomyocytes in vitro, zebrafish embryos and regenerating hearts in vivo.

    Most zebrafish genes are highly conserved with mammalian homologues. However, zebrafish can regenerate heart but mammals can't. We would like to test the two possibilities that contribute to the incapability of regeneration: 1 mammalian hearts fail to express these genes upon injuries at the right time and place; 2. mammalian cardiomyocytes response to stimuli differently from zebrafish cardiomyocytes.

    Our work may lead to discovery of important factors/pathways that can contribute to pharmaceutical or cellular therapies for ischemic or congenital heart diseases.

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    Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Researchers can login to make corrections and additions, or contact us for help.
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    1. Yip JK, Harrison M, Villafuerte J, Fernandez GE, Petersen AP, Lien CL, McCain ML. Extended culture and imaging of normal and regenerating adult zebrafish hearts in a fluidic device. Lab Chip. 2019 Dec 24. PMID: 31872200.
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    2. Harrison MR, Feng X, Mo G, Aguayo A, Villafuerte J, Yoshida T, Pearson CA, Schulte-Merker S, Lien CL. Late developing cardiac lymphatic vasculature supports adult zebrafish heart function and regeneration. Elife. 2019 Nov 08; 8. PMID: 31702553.
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    3. Yeo S, Yoon C, Lien CL, Song TK, Shung KK. Monitoring of Adult Zebrafish Heart Regeneration Using High-Frequency Ultrasound Spectral Doppler and Nakagami Imaging. Sensors (Basel). 2019 Sep 22; 19(19). PMID: 31546705.
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    4. Wang K, Shen H, Gan P, Cavallero S, Kumar SR, Lien CL, Sucov HM. Differential roles of insulin like growth factor 1 receptor and insulin receptor during embryonic heart development. BMC Dev Biol. 2019 03 25; 19(1):5. PMID: 30909860.
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    5. Kapuria S, Yoshida T, Lien CL. Coronary Vasculature in Cardiac Development and Regeneration. J Cardiovasc Dev Dis. 2018 Dec 17; 5(4). PMID: 30563016.
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    6. Li Z, Tyrpak DR, Lien CL, MacKay JA. Tunable assembly of protein-microdomains in living vertebrate embryos. Adv Biosyst. 2018 10; 2(10). PMID: 31840042.
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    7. Schall KA, Holoyda KA, Isani M, Lien CL, Alam DA, Grikscheit TC. Corrigendum to "Inhibition of Fgf signaling in short bowel syndrome increases weight loss and epithelial proliferation." [surgery volume 161, number 3 (2017) 694-703]. Surgery. 2018 06; 163(6):1330-1331. PMID: 29452701.
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    8. Patterson M, Barske L, Van Handel B, Rau CD, Gan P, Sharma A, Parikh S, Denholtz M, Huang Y, Yamaguchi Y, Shen H, Allayee H, Crump JG, Force TI, Lien CL, Makita T, Lusis AJ, Kumar SR, Sucov HM. Frequency of mononuclear diploid cardiomyocytes underlies natural variation in heart regeneration. Nat Genet. 2017 Sep; 49(9):1346-1353. PMID: 28783163.
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    9. Gamba L, Amin-Javaheri A, Kim J, Warburton D, Lien CL. Collagenolytic Activity Is Associated with Scar Resolution in Zebrafish Hearts after Cryoinjury. J Cardiovasc Dev Dis. 2017 Feb 24; 4(1). PMID: 29367534.
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    10. Schall KA, Thornton ME, Isani M, Holoyda KA, Hou X, Lien CL, Grubbs BH, Grikscheit TC. Short bowel syndrome results in increased gene expression associated with proliferation, inflammation, bile acid synthesis and immune system activation: RNA sequencing a zebrafish SBS model. BMC Genomics. 2017 01 25; 18(1):23. PMID: 28118819.
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    11. Schall KA, Holoyda KA, Isani M, Schlieve C, Salisbury T, Khuu T, Debelius JW, Moats RA, Pollack HA, Lien CL, Fowler K, Hou X, Knight R, Grikscheit TC. Intestinal adaptation in proximal and distal segments: Two epithelial responses diverge after intestinal separation. Surgery. 2017 04; 161(4):1016-1027. PMID: 28011012.
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    12. Schall KA, Holoyda KA, Isani M, Lien CL, Al Alam D, Grikscheit TC. Inhibition of Fgf signaling in short bowel syndrome increases weight loss and epithelial proliferation. Surgery. 2017 03; 161(3):694-703. PMID: 27771159.
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    13. Rubin N, Harrison MR, Krainock M, Kim R, Lien CL. Recent advancements in understanding endogenous heart regeneration-insights from adult zebrafish and neonatal mice. Semin Cell Dev Biol. 2016 10; 58:34-40. PMID: 27132022.
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    14. Miguel JC, Maxwell AA, Hsieh JJ, Harnisch LC, Al Alam D, Polk DB, Lien CL, Watson AJ, Frey MR. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J Cell Sci. 2017 01 01; 130(1):90-96. PMID: 27026527.
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    15. Schall KA, Holoyda KA, Grant CN, Levin DE, Torres ER, Maxwell A, Pollack HA, Moats RA, Frey MR, Darehzereshki A, Al Alam D, Lien C, Grikscheit TC. Adult zebrafish intestine resection: a novel model of short bowel syndrome, adaptation, and intestinal stem cell regeneration. Am J Physiol Gastrointest Liver Physiol. 2015 Aug 01; 309(3):G135-45. PMID: 26089336.
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    16. Harrison MR, Bussmann J, Huang Y, Zhao L, Osorio A, Burns CG, Burns CE, Sucov HM, Siekmann AF, Lien CL. Chemokine-guided angiogenesis directs coronary vasculature formation in zebrafish. Dev Cell. 2015 May 26; 33(4):442-54. PMID: 26017769.
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    17. Cavallero S, Shen H, Yi C, Lien CL, Kumar SR, Sucov HM. CXCL12 Signaling Is Essential for Maturation of the Ventricular Coronary Endothelial Plexus and Establishment of Functional Coronary Circulation. Dev Cell. 2015 May 26; 33(4):469-77. PMID: 26017771.
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    18. Zhao Y, Cao H, Beebe T, Zhang H, Zhang X, Chang H, Scremin O, Lien CL, Tai YC, Hsiai TK. Dry-contact microelectrode membranes for wireless detection of electrical phenotypes in neonatal mouse hearts. Biomed Microdevices. 2015 Apr; 17(2):40. PMID: 25749638.
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    19. Kang BJ, Park J, Kim J, Kim HH, Lee C, Hwang JY, Lien CL, Shung KK. High-frequency dual mode pulsed wave Doppler imaging for monitoring the functional regeneration of adult zebrafish hearts. J R Soc Interface. 2015 Feb 06; 12(103). PMID: 25505135.
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    20. Shen H, Cavallero S, Estrada KD, Sandovici I, Kumar SR, Makita T, Lien CL, Constancia M, Sucov HM. Extracardiac control of embryonic cardiomyocyte proliferation and ventricular wall expansion. Cardiovasc Res. 2015 Mar 01; 105(3):271-8. PMID: 25560321.
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    21. Darehzereshki A, Rubin N, Gamba L, Kim J, Fraser J, Huang Y, Billings J, Mohammadzadeh R, Wood J, Warburton D, Kaartinen V, Lien CL. Differential regenerative capacity of neonatal mouse hearts after cryoinjury. Dev Biol. 2015 Mar 01; 399(1):91-99. PMID: 25555840.
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    22. Li R, Beebe T, Jen N, Yu F, Takabe W, Harrison M, Cao H, Lee J, Yang H, Han P, Wang K, Shimizu H, Chen J, Lien CL, Chi NC, Hsiai TK. Shear stress-activated Wnt-angiopoietin-2 signaling recapitulates vascular repair in zebrafish embryos. Arterioscler Thromb Vasc Biol. 2014 Oct; 34(10):2268-75. PMID: 25147335.
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    23. Cao H, Yu F, Zhao Y, Zhang X, Tai J, Lee J, Darehzereshki A, Bersohn M, Lien CL, Chi NC, Tai YC, Hsiai TK. Wearable multi-channel microelectrode membranes for elucidating electrophysiological phenotypes of injured myocardium. Integr Biol (Camb). 2014 Aug; 6(8):789-95. PMID: 24945366.
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    24. Gamba L, Harrison M, Lien CL. Cardiac regeneration in model organisms. Curr Treat Options Cardiovasc Med. 2014 Mar; 16(3):288. PMID: 24496965.
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    25. Lee J, Moghadam ME, Kung E, Cao H, Beebe T, Miller Y, Roman BL, Lien CL, Chi NC, Marsden AL, Hsiai TK. Moving domain computational fluid dynamics to interface with an embryonic model of cardiac morphogenesis. PLoS One. 2013; 8(8):e72924. PMID: 24009714.
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    26. Huang Y, Harrison MR, Osorio A, Kim J, Baugh A, Duan C, Sucov HM, Lien CL. Igf Signaling is Required for Cardiomyocyte Proliferation during Zebrafish Heart Development and Regeneration. PLoS One. 2013; 8(6):e67266. PMID: 23840646.
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    27. Park J, Cummins TM, Harrison M, Lee J, Zhou Q, Lien CL, Shung KK. High frequency photoacoustic imaging for in vivo visualizing blood flow of zebrafish heart. Opt Express. 2013 Jun 17; 21(12):14636-42. PMID: 23787651.
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    28. Zhou X, Sun L, Yu Y, Qiu W, Lien CL, Shung KK, Yu W. Ultrasound bio-microscopic image segmentation for evaluation of zebrafish cardiac function. IEEE Trans Ultrason Ferroelectr Freq Control. 2013 Apr; 60(4):718-26. PMID: 23549532.
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    29. Park J, Huang Y, Chen R, Lee J, Cummins TM, Zhou Q, Lien CL, Shung KK. Pulse inversion chirp coded tissue harmonic imaging (PI-CTHI) of Zebrafish heart using high frame rate ultrasound biomicroscopy. Ann Biomed Eng. 2013 Jan; 41(1):41-52. PMID: 22930467.
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    30. Lien CL, Harrison MR, Tuan TL, Starnes VA. Heart repair and regeneration: recent insights from zebrafish studies. Wound Repair Regen. 2012 Sep-Oct; 20(5):638-46. PMID: 22818295.
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    31. Kim J, Rubin N, Huang Y, Tuan TL, Lien CL. In vitro culture of epicardial cells from adult zebrafish heart on a fibrin matrix. Nat Protoc. 2012 Jan 19; 7(2):247-55. PMID: 22262006.
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    32. Park J, Lee J, Lau ST, Lee C, Huang Y, Lien CL, Kirk Shung K. Acoustic radiation force impulse (ARFI) imaging of zebrafish embryo by high-frequency coded excitation sequence. Ann Biomed Eng. 2012 Apr; 40(4):907-15. PMID: 22101757.
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    33. Tang M, Chen B, Lin T, Li Z, Pardo C, Pampo C, Chen J, Lien CL, Wu L, Ai L, Wang H, Yao K, Oh SP, Seto E, Smith LE, Siemann DW, Kladde MP, Cepko CL, Lu J. Restraint of angiogenesis by zinc finger transcription factor CTCF-dependent chromatin insulation. Proc Natl Acad Sci U S A. 2011 Sep 13; 108(37):15231-6. PMID: 21896759.
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    34. Kim J, Wu Q, Zhang Y, Wiens KM, Huang Y, Rubin N, Shimada H, Handin RI, Chao MY, Tuan TL, Starnes VA, Lien CL. PDGF signaling is required for epicardial function and blood vessel formation in regenerating zebrafish hearts. Proc Natl Acad Sci U S A. 2010 Oct 05; 107(40):17206-10. PMID: 20858732.
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    35. Wiens KM, Lee HL, Shimada H, Metcalf AE, Chao MY, Lien CL. Platelet-derived growth factor receptor beta is critical for zebrafish intersegmental vessel formation. PLoS One. 2010 Jun 25; 5(6):e11324. PMID: 20593033.
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    36. Sun P, Zhang Y, Yu F, Parks E, Lyman A, Wu Q, Ai L, Hu CH, Zhou Q, Shung K, Lien CL, Hsiai TK. Micro-electrocardiograms to study post-ventricular amputation of zebrafish heart. Ann Biomed Eng. 2009 May; 37(5):890-901. PMID: 19280341.
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    37. Sun L, Lien CL, Xu X, Shung KK. In vivo cardiac imaging of adult zebrafish using high frequency ultrasound (45-75 MHz). Ultrasound Med Biol. 2008 Jan; 34(1):31-9. PMID: 17825980.
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    38. Wu SM, Fujiwara Y, Cibulsky SM, Clapham DE, Lien CL, Schultheiss TM, Orkin SH. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell. 2006 Dec 15; 127(6):1137-50. PMID: 17123591.
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    39. Lien CL, Schebesta M, Makino S, Weber GJ, Keating MT. Gene expression analysis of zebrafish heart regeneration. PLoS Biol. 2006 Aug; 4(8):e260. PMID: 16869712.
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    40. Xin M, Davis CA, Molkentin JD, Lien CL, Duncan SA, Richardson JA, Olson EN. A threshold of GATA4 and GATA6 expression is required for cardiovascular development. Proc Natl Acad Sci U S A. 2006 Jul 25; 103(30):11189-94. PMID: 16847256.
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    41. Schebesta M, Lien CL, Engel FB, Keating MT. Transcriptional profiling of caudal fin regeneration in zebrafish. ScientificWorldJournal. 2006 Jun 02; 6 Suppl 1:38-54. PMID: 17205186.
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    42. Whitehead GG, Makino S, Lien CL, Keating MT. fgf20 is essential for initiating zebrafish fin regeneration. Science. 2005 Dec 23; 310(5756):1957-60. PMID: 16373575.
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    43. Makino S, Whitehead GG, Lien CL, Kim S, Jhawar P, Kono A, Kawata Y, Keating MT. Heat-shock protein 60 is required for blastema formation and maintenance during regeneration. Proc Natl Acad Sci U S A. 2005 Oct 11; 102(41):14599-604. PMID: 16204379.
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    44. Oh J, Wang Z, Wang DZ, Lien CL, Xing W, Olson EN. Target gene-specific modulation of myocardin activity by GATA transcription factors. Mol Cell Biol. 2004 Oct; 24(19):8519-28. PMID: 15367672.
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    45. Lien CL, McAnally J, Richardson JA, Olson EN. Cardiac-specific activity of an Nkx2-5 enhancer requires an evolutionarily conserved Smad binding site. Dev Biol. 2002 Apr 15; 244(2):257-66. PMID: 11944935.
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    46. Lazakovitch EM, She BR, Lien CL, Woo WM, Ju YT, Lin-Chao S. The Gas7 gene encodes two protein isoforms differentially expressed within the brain. Genomics. 1999 Nov 01; 61(3):298-306. PMID: 10552931.
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    47. Lien CL, Wu C, Mercer B, Webb R, Richardson JA, Olson EN. Control of early cardiac-specific transcription of Nkx2-5 by a GATA-dependent enhancer. Development. 1999 Jan; 126(1):75-84. PMID: 9834187.
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    48. Cripps RM, Black BL, Zhao B, Lien CL, Schulz RA, Olson EN. The myogenic regulatory gene Mef2 is a direct target for transcriptional activation by Twist during Drosophila myogenesis. Genes Dev. 1998 Feb 01; 12(3):422-34. PMID: 9450935.
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