The DOI matches its Crossref record; 40 of the 41 references it cites were found in a registry or an index.
Generation of Quiescent Cardiac Fibroblasts From Human Induced Pluripotent Stem Cells for In Vitro Modeling of Cardiac Fibrosis
Open accessAbstract
Rationale: Activated fibroblasts are the major cell type that secretes excessive extracellular matrix in response to injury, contributing to pathological fibrosis and leading to organ failure. Effective anti-fibrotic therapeutic solutions, however, are not available due to the poorly defined characteristics and unavailability of tissue-specific fibroblasts. Recent advances in single-cell RNA-sequencing fill such gaps of knowledge by enabling delineation of the developmental trajectories and identification of regulatory pathways of tissue-specific fibroblasts among different organs. Objective: This study aims to define the transcriptome profiles of tissue-specific fibroblasts using recently reported mouse single-cell RNA-sequencing atlas and to develop a robust chemically defined protocol to derive cardiac fibroblasts (CFs) from human induced pluripotent stem cells for in vitro modeling of cardiac fibrosis and drug screening. Methods and Results: By analyzing the single-cell transcriptome profiles of fibroblasts from 10 selected mouse tissues, we identified distinct tissue-specific signature genes, including transcription factors that define the identities of fibroblasts in the heart, lungs, trachea, and bladder. We also determined that CFs in large are of the epicardial lineage. We thus developed a robust chemically defined protocol that generates CFs from human induced pluripotent stem cells. Functional studies confirmed that iPSC-derived CFs preserved a quiescent phenotype and highly resembled primary CFs at the transcriptional, cellular, and functional levels. We demonstrated that this cell-based platform is sensitive to both pro- and anti-fibrosis drugs. Finally, we showed that crosstalk between human induced pluripotent stem cell-derived cardiomyocytes and CFs via the atrial/brain natriuretic peptide-natriuretic peptide receptor-1 pathway is implicated in suppressing fibrogenesis. Conclusions: This study uncovers unique gene signatures that define tissue-specific identities of fibroblasts. The bona fide quiescent CFs derived from human induced pluripotent stem cells can serve as a faithful in vitro platform to better understand the underlying mechanisms of cardiac fibrosis and to screen anti-fibrotic drugs.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“These models are proficient in generating force and exhibit predictable responses to pharmacological agents.[ 23 , 24 ]”
From Engineered in vitro multi-cell type ventricle model generates long-term pulsatile flow and modulates cardiac output in response to cardioactive drugs (2025) · cites this paper as [23]
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Myofibroblasts and mechano-regulation of connective tissue remodelling
Tomasek, J. J., Gabbiani, G., Hinz, B., Chaponnier, C., & Brown, R. A. (2002) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm809 · Cited by 4,290
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes
Whyte, W. A., Orlando, D. A., Hnisz, D., Abraham, B. J., Lin, C. Y., Kagey, M. H., Rahl, P. B., Lee, T. I., & Young, R. A. (2013) · Cell · doi:10.1016/j.cell.2013.03.035 · Cited by 4,143
Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris
The Tabula Muris Consortium, coordination, O., coordination, L., processing, O. C. A., sequencing, L. P. A., analysis, C. D., annotation, C. T., Writing group, Supplemental text writing group, & Principal investigators (2018) · Nature · doi:10.1038/s41586-018-0590-4 · Cited by 2,842
Pericytes: Developmental, Physiological, and Pathological Perspectives, Problems, and Promises
Armulik, A., Genové, G., & Betsholtz, C. (2011) · Developmental Cell · doi:10.1016/j.devcel.2011.07.001 · Cited by 2,653
Induced pluripotent stem cell technology: a decade of progress.
Shi, Y., Inoue, H., Wu, J. C., & Yamanaka, S. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.245 · Cited by 1,525
Self-citationRequirement of the transcription factor GATA4 for heart tube formation and ventral morphogenesis.Preprint
Molkentin, J. D., Lin, Q., Duncan, S. A., & Olson, E. N. (1997) · Genes & Development · doi:10.1101/gad.11.8.1061 · Cited by 1,137
Pirfenidone in idiopathic pulmonary fibrosis
Taniguchi, H., Ebina, M., Kondoh, Y., Ogura, T., Azuma, A., Suga, M., Taguchi, Y., Takahashi, H., Nakata, K., Sato, A., et al. (2009) · European Respiratory Journal · doi:10.1183/09031936.00005209 · Cited by 980
Forcing cells to change lineages
Graf, T., & Enver, T. (2009) · Nature · doi:10.1038/nature08533 · Cited by 899
Cardiac fibroblasts, fibrosis and extracellular matrix remodeling in heart disease
Fan, D., Takawale, A., Lee, J., & Kassiri, Z. (2012) · Fibrogenesis & Tissue Repair · doi:10.1186/1755-1536-5-15 · Cited by 814
Pirfenidone in idiopathic pulmonary fibrosis: Figure 1–
Swigris, J., & Fairclough, D. (2010) · European Respiratory Journal · doi:10.1183/09031936.00071710 · Cited by 802
Karlmark, K. R., Weiskirchen, R., Zimmermann, H. W., Gassler, N., Ginhoux, F., Weber, C., Merad, M., Luedde, T., Trautwein, C., & Tacke, F. (2009) · Hepatology · doi:10.1002/hep.22950 · Cited by 782
IL-11 is a crucial determinant of cardiovascular fibrosis
Schafer, S., Viswanathan, S., Widjaja, A. A., Lim, W.-W., Moreno-Moral, A., DeLaughter, D. M., Ng, B., Patone, G., Chow, K., Khin, E., et al. (2017) · Nature · doi:10.1038/nature24676 · Cited by 639
Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications
Weiskirchen, R., Weiskirchen, S., & Tacke, F. (2018) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2018.06.003 · Cited by 567
Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression
Wang, Z., Wang, D.-Z., Hockemeyer, D. F., McAnally, J., Nordheim, A., & Olson, E. N. (2004) · Nature · doi:10.1038/nature02382 · Cited by 562
Acharya, A., Baek, S. T., Huang, G., Eskiocak, B., Goetsch, S., Sung, C. Y., Banfi, S., Sauer, M. F., Olsen, G. S., Duffield, J. S., et al. (2012) · Development · doi:10.1242/dev.079970 · Cited by 498
Zeisberg, M., & Kalluri, R. (2012) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00328.2012 · Cited by 474
Direct Lineage Reprogramming: Strategies, Mechanisms, and Applications
Xu, J., Du, Y., & Deng, H. (2015) · Cell stem cell · doi:10.1016/j.stem.2015.01.013 · Cited by 434
TIMP-2 Is Required for Efficient Activation of proMMP-2 in Vivo
Wang, Z., Jüttermann, R., & Soloway, P. D. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001270200 · Cited by 388
Kruppel-like Factor 4 Abrogates Myocardin-induced Activation of Smooth Muscle Gene Expression
Liu, Y., Sinha, S., McDonald, O. G., Shang, Y., Hoofnagle, M. H., & Owens, G. K. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m412862200 · Cited by 364
Natriuretic peptide metabolism, clearance and degradation
Potter, L. R. (2011) · FEBS Journal · doi:10.1111/j.1742-4658.2011.08082.x · Cited by 359
GATA4 is essential for formation of the proepicardium and regulates cardiogenesis
Watt, A. J., Battle, M. A., Li, J., & Duncan, S. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400752101 · Cited by 354
Zile, M. R., O’Meara, E., Claggett, B. L., PRESCOTT, M. F., Solomon, S. D., Swedberg, K. B., Packer, M., McMurray, J. J. V., Shi, V. C., Lefkowitz, M. P., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.042 · Cited by 259
Swaney, J. S., Roth, D. M., Olson, E. R., Naugle, J. E., Meszaros, J. G., & Insel, P. A. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408704102 · Cited by 224
Cardiogenic Genes Expressed in Cardiac Fibroblasts Contribute to Heart Development and Repair
Furtado, M. B., Costa, M. W., Pranoto, E. A., Salimova, E., Pinto, A. R., Lam, N. T., Park, A. J., Snider, P. L., Chandran, A., Harvey, R. P., et al. (2014) · Circulation Research · doi:10.1161/circresaha.114.302530 · Cited by 214
Tbx20is essential for cardiac chamber differentiation and repression ofTbx2
Singh, M. K., Christoffels, V. M., Dias, J. M. M., Trowe, M., Petry, M., Schuster-Gossler, K., Bürger, A., Ericson, J., & Kispert, A. (2005) · Development · doi:10.1242/dev.01854 · Cited by 203
Natriuretic Peptides in the Regulation of Cardiovascular Physiology and Metabolic Events
Kerkelä, R., Ulvila, J., & Magga, J. M. (2015) · Journal of the American Heart Association · doi:10.1161/jaha.115.002423 · Cited by 172
Paik, D. T., Tian, L., Lee, J., Sayed, N., Chen, I. Y., Rhee, S., Rhee, J., Kim, Y., Wirka, R. C., Buikema, J. W., et al. (2018) · Circulation Research · doi:10.1161/circresaha.118.312913 · Cited by 147
Self-citationIyer, D., Gambardella, L., Bernard, W. G., Serrano, F., Mascetti, V. L., Pedersen, R. A., Talasila, A., & Sinha, S. (2015) · Development · doi:10.1242/dev.119271 · Cited by 137
Pandya, K., Kim, H., & Smithies, O. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0607700103 · Cited by 120
Role of inflammatory cells in fibroblast activation
Hartupee, J. C., & Mann, D. L. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.11.016 · Cited by 110
Bao, X., Lian, X. L., Hacker, T. A., Schmuck, E. G., Qian, T., Bhute, V. J., Han, T., Shi, M., Drowley, L., Plowright, A. T., et al. (2016) · Nature Biomedical Engineering · doi:10.1038/s41551-016-0003 · Cited by 106
Dynamic cell–cell and cell–ECM interactions in the heart
Howard, C. M., & Baudino, T. A. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.10.006 · Cited by 105
Sacubitril/valsartan: beyond natriuretic peptides
Singh, J. S., Burrell, L. M., Cherif, M., Squire, I. B., Clark, A. L., & Lang, C. C. (2017) · Heart · doi:10.1136/heartjnl-2017-311295 · Cited by 99
Yan, X., Zhang, H., Fan, Q., Hu, J., Tao, R., Chen, Q., Iwakura, Y., Shen, W., Lu, L., Zhang, Q., et al. (2017) · Circulation Research · doi:10.1161/circresaha.116.310260 · Cited by 91
Self-citationTcf21 regulates the specification and maturation of proepicardial cells
Tandon, P., Miteva, Y., Kuchenbrod, L. M., Cristea, I. M., & Conlon, F. L. (2013) · Development · doi:10.1242/dev.093385 · Cited by 90
Levick, S. P., Soto‐Pantoja, D. R., Bi, J., Hundley, W. G., Widiapradja, A., Manteufel, E. J., Bradshaw, T. W., & Meléndez, G. C. (2018) · Heart Lung and Circulation · doi:10.1016/j.hlc.2018.08.003 · Cited by 85
Iyer, D., Gambardella, L., Bernard, W. G., Serrano, F., Mascetti, V. L., Pedersen, R. A., Sinha, S., & Talasila, A. (2016) · Development · doi:10.1242/dev.136143 · Cited by 57
Horie, M., Miyashita, N., Mikami, Y., Noguchi, S. F., Yamauchi, Y., Suzukawa, M., Fukami, T., Ohta, K., Asano, Y., Sato, S., et al. (2017) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00193.2017 · Cited by 55
Miyoshi, T., Nakamura, K., Miura, D., Yoshida, M., Saito, Y., Akagi, S., Ohno, Y., Kondo, M., & Ito, H. (2018) · Cardiology Journal · doi:10.5603/cj.a2018.0048 · Cited by 25
Stem cell culture: Simply derived epicardial cells
Paik, D. T., & Wu, J. C. (2017) · Nature Biomedical Engineering · doi:10.1038/s41551-016-0015 · Cited by 3
Self-citation
Cited by
Sorted by citations
Cardiac fibrosis: Myofibroblast-mediated pathological regulation and drug delivery strategies
Liu, M., Abad, B. L. D. J., & Cheng, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.03.021 · Cited by 370
Li, Y., Ren, P., Dawson, A., Vasquez, H. G., Ageedi, W., Zhang, C., Luo, W., Chen, R., Li, Y., Kim, S., et al. (2020) · Circulation · doi:10.1161/circulationaha.120.046528 · Cited by 344
Zile, M. R., O’Meara, E., Claggett, B. L., PRESCOTT, M. F., Solomon, S. D., Swedberg, K. B., Packer, M., McMurray, J. J. V., Shi, V. C., Lefkowitz, M. P., et al. (2019) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2018.11.042 · Cited by 259
Paik, D. T., Chandy, M., & Wu, J. C. (2019) · Pharmacological Reviews · doi:10.1124/pr.116.013003 · Cited by 219
Self-citationZhang, W., Chen, S., Zhou, S., Wu, S., & Wang, H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.643149 · Cited by 210
Metadata
- Authors
- Zhang, H., Tian, L., Shen, M., Tu, C., Wu, H., Gu, M., Paik, D. T., & Wu, J. C.
- Affiliations
- Stanford Cardiovascular Institute (US)
- Stanford Medicine (US)
- Corresponding author
- Zhang, Hao
- Tian, Lei
- Shen, Mengcheng
- Venue
- Circulation Research
- Published
- 2019-08-16
- Volume
- 125
- Issue
- 5
- Pages
- 552-566
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC6768436
- OpenAlex
- W2957473759
- Cited by
- 187
- References
- 41
- Citations by year
- 2026: 22 · 2025: 25 · 2024: 36 · 2023: 20 · 2022: 31 · 2021: 30 · 2020: 17 · 2019: 5
- FWCI
- 6.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (UG3TR002588, UH3TR002588)
- National Heart, Lung, and Blood Institute (K99HL133473, R00HL133473, K99HL135258, R01HL141371, R01HL145676, R01HL146690)
- National Institute of Biomedical Imaging and Bioengineering (T32EB009035)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- cardiac fibroblasts, myocardial fibrosis, induced pluripotent stem cells, quiescent fibroblasts, single-cell transcriptome, atrial natriuretic peptide, fibrogenesis
- MeSH terms
- Animals, Antifibrinolytic Agents, Cells, Cultured, Fibroblasts, Fibrosis, Humans, Myocytes, Cardiac, Mice, Induced Pluripotent Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
