23 results on '"Ranade, Sanjeev S."'
Search Results
2. Single-cell multimodal analyses reveal epigenomic and transcriptomic basis for birth defects in maternal diabetes
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Nishino, Tomohiro, Ranade, Sanjeev S., Pelonero, Angelo, van Soldt, Benjamin J., Ye, Lin, Alexanian, Michael, Koback, Frances, Huang, Yu, Wallace, Langley Grace, Sadagopan, Nandhini, Lam, Adrienne, Zholudeva, Lyandysha V., Li, Feiya, Padmanabhan, Arun, Thomas, Reuben, van Bemmel, Joke G., Gifford, Casey A., Costa, Mauro W., and Srivastava, Deepak
- Published
- 2023
- Full Text
- View/download PDF
3. A transcriptional switch governs fibroblast activation in heart disease
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Alexanian, Michael, Przytycki, Pawel F, Micheletti, Rudi, Padmanabhan, Arun, Ye, Lin, Travers, Joshua G, Gonzalez-Teran, Barbara, Silva, Ana Catarina, Duan, Qiming, Ranade, Sanjeev S, Felix, Franco, Linares-Saldana, Ricardo, Li, Li, Lee, Clara Youngna, Sadagopan, Nandhini, Pelonero, Angelo, Huang, Yu, Andreoletti, Gaia, Jain, Rajan, McKinsey, Timothy A, Rosenfeld, Michael G, Gifford, Casey A, Pollard, Katherine S, Haldar, Saptarsi M, and Srivastava, Deepak
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Heart Disease ,Cardiovascular ,Lung ,Genetics ,Underpinning research ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Animals ,Chromatin ,Enhancer Elements ,Genetic ,Epigenomics ,Fibroblasts ,Gene Expression Regulation ,Heart Diseases ,Homeodomain Proteins ,Humans ,Mice ,Proteins ,Single-Cell Analysis ,Transcription Factors ,Transcriptome ,Transforming Growth Factor beta ,General Science & Technology - Abstract
In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.
- Published
- 2021
4. Network-based screen in iPSC-derived cells reveals therapeutic candidate for heart valve disease
- Author
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Theodoris, Christina V, Zhou, Ping, Liu, Lei, Zhang, Yu, Nishino, Tomohiro, Huang, Yu, Kostina, Aleksandra, Ranade, Sanjeev S, Gifford, Casey A, Uspenskiy, Vladimir, Malashicheva, Anna, Ding, Sheng, and Srivastava, Deepak
- Subjects
Heart Disease ,Biotechnology ,Stem Cell Research ,Rare Diseases ,Stem Cell Research - Induced Pluripotent Stem Cell ,Cardiovascular ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Orphan Drug ,Genetics ,Regenerative Medicine ,Aetiology ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Good Health and Well Being ,Algorithms ,Animals ,Aortic Valve ,Aortic Valve Disease ,Aortic Valve Stenosis ,Calcinosis ,Disease Models ,Animal ,Drug Discovery ,Drug Evaluation ,Preclinical ,Gene Expression Regulation ,Gene Regulatory Networks ,Haploinsufficiency ,Humans ,Induced Pluripotent Stem Cells ,Machine Learning ,Mice ,Inbred C57BL ,Nitriles ,RNA-Seq ,Receptor ,Notch1 ,Small Molecule Libraries ,Thiazoles ,General Science & Technology - Abstract
Mapping the gene-regulatory networks dysregulated in human disease would allow the design of network-correcting therapies that treat the core disease mechanism. However, small molecules are traditionally screened for their effects on one to several outputs at most, biasing discovery and limiting the likelihood of true disease-modifying drug candidates. Here, we developed a machine-learning approach to identify small molecules that broadly correct gene networks dysregulated in a human induced pluripotent stem cell (iPSC) disease model of a common form of heart disease involving the aortic valve (AV). Gene network correction by the most efficacious therapeutic candidate, XCT790, generalized to patient-derived primary AV cells and was sufficient to prevent and treat AV disease in vivo in a mouse model. This strategy, made feasible by human iPSC technology, network analysis, and machine learning, may represent an effective path for drug discovery.
- Published
- 2021
5. Single-cell analysis of cardiogenesis reveals basis for organ-level developmental defects
- Author
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de Soysa, T Yvanka, Ranade, Sanjeev S, Okawa, Satoshi, Ravichandran, Srikanth, Huang, Yu, Salunga, Hazel T, Schricker, Amelia, del Sol, Antonio, Gifford, Casey A, and Srivastava, Deepak
- Subjects
Pediatric ,Stem Cell Research ,Heart Disease ,Stem Cell Research - Nonembryonic - Non-Human ,Congenital Structural Anomalies ,Cardiovascular ,Genetics ,1.1 Normal biological development and functioning ,Aetiology ,Underpinning research ,2.1 Biological and endogenous factors ,Animals ,Basic Helix-Loop-Helix Transcription Factors ,Cell Differentiation ,Cell Movement ,Cluster Analysis ,Female ,Heart ,Heart Defects ,Congenital ,Male ,Mice ,Sequence Analysis ,RNA ,Single-Cell Analysis ,Tretinoin ,General Science & Technology - Abstract
Organogenesis involves integration of diverse cell types; dysregulation of cell-type-specific gene networks results in birth defects, which affect 5% of live births. Congenital heart defects are the most common malformations, and result from disruption of discrete subsets of cardiac progenitor cells1, but the transcriptional changes in individual progenitors that lead to organ-level defects remain unknown. Here we used single-cell RNA sequencing to interrogate early cardiac progenitor cells as they become specified during normal and abnormal cardiogenesis, revealing how dysregulation of specific cellular subpopulations has catastrophic consequences. A network-based computational method for single-cell RNA-sequencing analysis that predicts lineage-specifying transcription factors2,3 identified Hand2 as a specifier of outflow tract cells but not right ventricular cells, despite the failure of right ventricular formation in Hand2-null mice4. Temporal single-cell-transcriptome analysis of Hand2-null embryos revealed failure of outflow tract myocardium specification, whereas right ventricular myocardium was specified but failed to properly differentiate and migrate. Loss of Hand2 also led to dysregulation of retinoic acid signalling and disruption of anterior-posterior patterning of cardiac progenitors. This work reveals transcriptional determinants that specify fate and differentiation in individual cardiac progenitor cells, and exposes mechanisms of disrupted cardiac development at single-cell resolution, providing a framework for investigating congenital heart defects.
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- 2019
6. Oligogenic inheritance of a human heart disease involving a genetic modifier
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Gifford, Casey A, Ranade, Sanjeev S, Samarakoon, Ryan, Salunga, Hazel T, de Soysa, T Yvanka, Huang, Yu, Zhou, Ping, Elfenbein, Aryé, Wyman, Stacia K, Bui, Yen Kim, Cordes Metzler, Kimberly R, Ursell, Philip, Ivey, Kathryn N, and Srivastava, Deepak
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Rare Diseases ,Cardiovascular ,Pediatric ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Stem Cell Research ,Heart Disease ,Human Genome ,Stem Cell Research - Induced Pluripotent Stem Cell ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,CRISPR-Associated Protein 9 ,Cardiac Myosins ,Cardiomyopathies ,Clustered Regularly Interspaced Short Palindromic Repeats ,Exome ,Gene Frequency ,Heterozygote ,Homeobox Protein Nkx-2.5 ,Humans ,Induced Pluripotent Stem Cells ,Mice ,Mice ,Mutant Strains ,Multifactorial Inheritance ,Mutation ,Missense ,Myocytes ,Cardiac ,Myosin Heavy Chains ,Paternal Inheritance ,Thyroid Nuclear Factor 1 ,Transcription Factors ,General Science & Technology - Abstract
Complex genetic mechanisms are thought to underlie many human diseases, yet experimental proof of this model has been elusive. Here, we show that a human cardiac anomaly can be caused by a combination of rare, inherited heterozygous mutations. Whole-exome sequencing of a nuclear family revealed that three offspring with childhood-onset cardiomyopathy had inherited three missense single-nucleotide variants in the MKL2, MYH7, and NKX2-5 genes. The MYH7 and MKL2 variants were inherited from the affected, asymptomatic father and the rare NKX2-5 variant (minor allele frequency, 0.0012) from the unaffected mother. We used CRISPR-Cas9 to generate mice encoding the orthologous variants and found that compound heterozygosity for all three variants recapitulated the human disease phenotype. Analysis of murine hearts and human induced pluripotent stem cell-derived cardiomyocytes provided histologic and molecular evidence for the NKX2-5 variant's contribution as a genetic modifier.
- Published
- 2019
7. Long telomeres protect against age-dependent cardiac disease caused by NOTCH1 haploinsufficiency
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Theodoris, Christina V, Mourkioti, Foteini, Huang, Yu, Ranade, Sanjeev S, Liu, Lei, Blau, Helen M, and Srivastava, Deepak
- Subjects
Biological Sciences ,Bioinformatics and Computational Biology ,Biomedical and Clinical Sciences ,Genetics ,Pediatric ,Heart Disease ,Cardiovascular ,Rare Diseases ,Biotechnology ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Aging ,Animals ,Haploinsufficiency ,Heart Septal Defects ,Heart Valve Diseases ,Humans ,Mice ,Mice ,Mutant Strains ,Promoter Regions ,Genetic ,Receptor ,Notch1 ,Telomere ,Telomere Homeostasis ,Medical and Health Sciences ,Immunology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Diseases caused by gene haploinsufficiency in humans commonly lack a phenotype in mice that are heterozygous for the orthologous factor, impeding the study of complex phenotypes and critically limiting the discovery of therapeutics. Laboratory mice have longer telomeres relative to humans, potentially protecting against age-related disease caused by haploinsufficiency. Here, we demonstrate that telomere shortening in NOTCH1-haploinsufficient mice is sufficient to elicit age-dependent cardiovascular disease involving premature calcification of the aortic valve, a phenotype that closely mimics human disease caused by NOTCH1 haploinsufficiency. Furthermore, progressive telomere shortening correlated with severity of disease, causing cardiac valve and septal disease in the neonate that was similar to the range of valve disease observed within human families. Genes that were dysregulated due to NOTCH1 haploinsufficiency in mice with shortened telomeres were concordant with proosteoblast and proinflammatory gene network alterations in human NOTCH1 heterozygous endothelial cells. These dysregulated genes were enriched for telomere-contacting promoters, suggesting a potential mechanism for telomere-dependent regulation of homeostatic gene expression. These findings reveal a critical role for telomere length in a mouse model of age-dependent human disease and provide an in vivo model in which to test therapeutic candidates targeting the progression of aortic valve disease.
- Published
- 2017
8. Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation
- Author
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Nonomura, Keiko, Lukacs, Viktor, Sweet, Daniel T., Goddard, Lauren M., Kanie, Akemi, Whitwam, Tess, Ranade, Sanjeev S., Fujimori, Toshihiko, Kahn, Mark L., and Patapoutian, Ardem
- Published
- 2018
9. Piezo1 links mechanical forces to red blood cell volume.
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Cahalan, Stuart M, Lukacs, Viktor, Ranade, Sanjeev S, Chien, Shu, Bandell, Michael, and Patapoutian, Ardem
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Erythrocytes ,Animals ,Mice ,Knockout ,Mice ,Calcium ,Ion Channels ,DNA Primers ,Microscopy ,Electron ,Scanning ,Erythrocyte Count ,Blotting ,Western ,Enzyme-Linked Immunosorbent Assay ,Flow Cytometry ,Analysis of Variance ,Mechanotransduction ,Cellular ,Mutation ,Fluorescence ,Small Molecule Libraries ,Biomechanical Phenomena ,cell biology ,cell volume regulation ,knockout animals ,mechanotransduction ,mouse ,neuroscience ,physiology ,red blood cells ,Knockout ,Microscopy ,Electron ,Scanning ,Blotting ,Western ,Mechanotransduction ,Cellular ,Clinical Research ,Hematology ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Biochemistry and Cell Biology - Abstract
Red blood cells (RBCs) experience significant mechanical forces while recirculating, but the consequences of these forces are not fully understood. Recent work has shown that gain-of-function mutations in mechanically activated Piezo1 cation channels are associated with the dehydrating RBC disease xerocytosis, implicating a role of mechanotransduction in RBC volume regulation. However, the mechanisms by which these mutations result in RBC dehydration are unknown. In this study, we show that RBCs exhibit robust calcium entry in response to mechanical stretch and that this entry is dependent on Piezo1 expression. Furthermore, RBCs from blood-cell-specific Piezo1 conditional knockout mice are overhydrated and exhibit increased fragility both in vitro and in vivo. Finally, we show that Yoda1, a chemical activator of Piezo1, causes calcium influx and subsequent dehydration of RBCs via downstream activation of the KCa3.1 Gardos channel, directly implicating Piezo1 signaling in RBC volume control. Therefore, mechanically activated Piezo1 plays an essential role in RBC volume homeostasis.
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- 2015
10. Piezo1, a mechanically activated ion channel, is required for vascular development in mice
- Author
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Ranade, Sanjeev S, Qiu, Zhaozhu, Woo, Seung-Hyun, Hur, Sung Sik, Murthy, Swetha E, Cahalan, Stuart M, Xu, Jie, Mathur, Jayanti, Bandell, Michael, Coste, Bertrand, Li, Yi-Shuan J, Chien, Shu, and Patapoutian, Ardem
- Subjects
Neurosciences ,Pain Research ,Bioengineering ,Cardiovascular ,Chronic Pain ,2.1 Biological and endogenous factors ,1.1 Normal biological development and functioning ,Underpinning research ,Aetiology ,Animals ,Cardiovascular System ,Embryonic Development ,Endothelial Cells ,Ion Channels ,Mechanotransduction ,Cellular ,Mice ,Mice ,Transgenic - Abstract
Mechanosensation is perhaps the last sensory modality not understood at the molecular level. Ion channels that sense mechanical force are postulated to play critical roles in a variety of biological processes including sensing touch/pain (somatosensation), sound (hearing), and shear stress (cardiovascular physiology); however, the identity of these ion channels has remained elusive. We previously identified Piezo1 and Piezo2 as mechanically activated cation channels that are expressed in many mechanosensitive cell types. Here, we show that Piezo1 is expressed in endothelial cells of developing blood vessels in mice. Piezo1-deficient embryos die at midgestation with defects in vascular remodeling, a process critically influenced by blood flow. We demonstrate that Piezo1 is activated by shear stress, the major type of mechanical force experienced by endothelial cells in response to blood flow. Furthermore, loss of Piezo1 in endothelial cells leads to deficits in stress fiber and cellular orientation in response to shear stress, linking Piezo1 mechanotransduction to regulation of cell morphology. These findings highlight an essential role of mammalian Piezo1 in vascular development during embryonic development.
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- 2014
11. A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors
- Author
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Krup, Alexis Leigh, primary, Winchester, Sarah A. B., additional, Ranade, Sanjeev S., additional, Agrawal, Ayushi, additional, Devine, W. Patrick, additional, Sinha, Tanvi, additional, Choudhary, Krishna, additional, Dominguez, Martin H., additional, Thomas, Reuben, additional, Black, Brian L., additional, Srivastava, Deepak, additional, and Bruneau, Benoit G., additional
- Published
- 2023
- Full Text
- View/download PDF
12. A Mesp1-dependent developmental breakpoint in transcriptional and epigenomic specification of early cardiac precursors
- Author
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Krup, Alexis Leigh, primary, Winchester, Sarah A.B., additional, Ranade, Sanjeev S., additional, Agrawal, Ayushi, additional, Devine, W. Patrick, additional, Sinha, Tanvi, additional, Choudhary, Krishna, additional, Dominguez, Martin H., additional, Thomas, Reuben, additional, Black, Brian L., additional, Srivastava, Deepak, additional, and Bruneau, Benoit G., additional
- Published
- 2022
- Full Text
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13. Single Cell Multimodal Analyses Reveal Epigenomic and Transcriptomic Basis for Birth Defects in Maternal Diabetes
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Nishino, Tomohiro, primary, Ranade, Sanjeev S., additional, Pelonero, Angelo, additional, van Soldt, Benjamin J., additional, Ye, Lin, additional, Alexanian, Michael, additional, Koback, Frances, additional, Huang, Yu, additional, Sadagopan, Nandhini, additional, Padmanabhan, Arun, additional, Thomas, Reuben, additional, van Bemmel, Joke G., additional, Gifford, Casey A., additional, Costa, Mauro W., additional, and Srivastava, Deepak, additional
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- 2022
- Full Text
- View/download PDF
14. Single Cell Epigenetics Reveal Cell-Cell Communication Networks in Normal and Abnormal Cardiac Morphogenesis
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Ranade, Sanjeev S., primary, Whalen, Sean, additional, Zlatanova, Ivana, additional, Nishino, Tomohiro, additional, van Soldt, Benjamin, additional, Ye, Lin, additional, Pelonero, Angelo, additional, Wallace, Langley Grace, additional, Huang, Yu, additional, Alexanian, Michael, additional, Padmanabhan, Arun, additional, Gonzalez-Teran, Barbara, additional, Przytycki, Pawel, additional, Costa, Mauro W., additional, Gifford, Casey A., additional, Black, Brian L., additional, Pollard, Katherine S., additional, and Srivastava, Deepak, additional
- Published
- 2022
- Full Text
- View/download PDF
15. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea
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Nonomura, Keiko, Woo, Seung-Hyun, Chang, Rui B., Gillich, Astrid, Qiu, Zhaozhu, Francisco, Allain G., Ranade, Sanjeev S., Liberles, Stephen D., and Patapoutian, Ardem
- Published
- 2017
- Full Text
- View/download PDF
16. Piezo2 is the major transducer of mechanical forces for touch sensation in mice
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Ranade, Sanjeev S., Woo, Seung-Hyun, Dubin, Adrienne E., Moshourab, Rabih A., Wetzel, Christiane, Petrus, Matt, Mathur, Jayanti, Begay, Valerie, Coste, Bertrand, Mainquist, James, Wilson, A.J., Francisco, Allain G., Reddy, Kritika, Qiu, Zhaozhu, Wood, John N., Lewin, Gary R., and Patapoutian, Ardem
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Ion channels -- Physiological aspects ,Mechanoreceptors -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals (1). It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive (2). Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes (3,4). It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron (4-6); however, major aspects of touch sensation remain intact without Merkel cell activity (4,7). Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation., Dorsal root ganglion (DRG) neurons have pseudounipolar axons that terminate in the skin where they form specialized mechanoreceptors that are tuned to detect mechanical forces such as stretch, indentation and [...]
- Published
- 2014
17. A Transcriptional Switch Governing Fibroblast Plasticity Underlies Reversibility of Chronic Heart Disease
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Alexanian, Michael, primary, Przytycki, Pawel F., additional, Micheletti, Rudi, additional, Padmanabhan, Arun, additional, Ye, Lin, additional, Travers, Joshua G., additional, Teran, Barbara Gonzalez, additional, Duan, Qiming, additional, Ranade, Sanjeev S., additional, Felix, Franco, additional, Linares-Saldana, Ricardo, additional, Huang, Yu, additional, Andreoletti, Gaia, additional, Yang, Jin, additional, Ivey, Kathryn N., additional, Jain, Rajan, additional, McKinsey, Timothy A., additional, Rosenfeld, Michael G., additional, Gifford, Casey, additional, Pollard, Katherine S., additional, Haldar, Saptarsi M., additional, and Srivastava, Deepak, additional
- Published
- 2020
- Full Text
- View/download PDF
18. Single-cell transcriptome analysis during cardiogenesis reveals basis for organ level developmental anomalies
- Author
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de Soysa, T. Yvanka, primary, Ranade, Sanjeev S., additional, Okawa, Satoshi, additional, Ravichandran, Srikanth, additional, Huang, Yu, additional, Salunga, Hazel T., additional, Schricker, Amelia, additional, Del Sol, Antonio, additional, Gifford, Casey A., additional, and Srivastava, Deepak, additional
- Published
- 2018
- Full Text
- View/download PDF
19. Oligogenic inheritance of congenital heart disease involving a NKX2-5 modifier
- Author
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Gifford, Casey A., primary, Ranade, Sanjeev S., additional, Samarakoon, Ryan, additional, Salunga, Hazel T., additional, de Soysa, T. Yvanka, additional, Huang, Yu, additional, Zhou, Ping, additional, Elfenbein, Aryé, additional, Wyman, Stacia K., additional, Bui, Yen Kim, additional, Cordes Metzler, Kimberly R., additional, Ursell, Philip, additional, Ivey, Kathryn N., additional, and Srivastava, Deepak, additional
- Published
- 2018
- Full Text
- View/download PDF
20. Piezo2 senses airway stretch and mediates lung inflation-induced apnoea
- Author
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Nonomura, Keiko, primary, Woo, Seung-Hyun, additional, Chang, Rui B., additional, Gillich, Astrid, additional, Qiu, Zhaozhu, additional, Francisco, Allain G., additional, Ranade, Sanjeev S., additional, Liberles, Stephen D., additional, and Patapoutian, Ardem, additional
- Published
- 2016
- Full Text
- View/download PDF
21. Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
- Author
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Keiko Nonomura, Lukacs, Viktor, Sweet, Daniel T., Goddard, Lauren M., Akemi Kanie, Whitwam, Tess, Ranade, Sanjeev S., Toshihiko Fujimori, Kahn, Mark L., and Patapoutian, Ardem
- Subjects
LYMPHATICS ,MECHANOTRANSDUCTION (Cytology) ,ION channels ,ENDOTHELIAL cells ,PLEURAL effusions ,BLOOD vessels - Abstract
PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1
cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell-cell junctions, was impaired in Tie2Cre;Piezo1cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell-cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation. [ABSTRACT FROM AUTHOR]- Published
- 2018
- Full Text
- View/download PDF
22. Mechanically Activated Ion Channels
- Author
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Ranade, Sanjeev S., primary, Syeda, Ruhma, additional, and Patapoutian, Ardem, additional
- Published
- 2015
- Full Text
- View/download PDF
23. Author response: Piezo1 links mechanical forces to red blood cell volume
- Author
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Cahalan, Stuart M, primary, Lukacs, Viktor, additional, Ranade, Sanjeev S, additional, Chien, Shu, additional, Bandell, Michael, additional, and Patapoutian, Ardem, additional
- Published
- 2015
- Full Text
- View/download PDF
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