NDLI: TAZ activation drives fibroblast spheroid growth, expression of pro-fibrotic paracrine signals, and context dependent ECM gene expression.

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TAZ activation drives fibroblast spheroid growth, expression of pro-fibrotic paracrine signals, and context dependent ECM gene expression.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Jorgenson, Amy J. Choi, Kyoung Moo Sicard, Delphine Smith, Karry M. J. Hiemer, Samantha E. Varelas, Xaralabos Tschumperlin, Daniel J.
Description	Author Affiliation: Jorgenson AJ ( Mayo Clinic.); Choi KM ( Mayo Clinic.); Sicard D ( Mayo Clinic.); Smith KM ( Mayo Clinic.); Hiemer SE ( Boston University.); Varelas X ( Boston University School of Medicine.); Tschumperlin DJ ( Mayo Clinic tschumperlin.daniel@mayo.edu.)
Abstract	Recent studies have implicated the Hippo pathway and its transcriptional effectors YAP and TAZ as necessary for fibroblast activation and tissue fibrosis. To test the specific and sufficient roles for TAZ in driving autonomous fibroblast activation, we cultured NIH3T3 fibroblasts expressing a doxycycline-inducible nuclear-localized mutant of TAZ (TAZ4SA) in scaffold-free 3D hanging drop spheroids, or on matrices of specified mechanical rigidity. Control NIH3T3 fibroblasts formed spheroids in hanging drop culture that remained stable and neither increased nor decreased in size significantly over 15 days. In contrast, TAZ4SA-transduced fibroblasts grew robustly in spheroid culture, and expressed enhanced levels of genes encoding pro-fibrotic soluble factors CTGF, Et-1 and PAI-1. However, TAZ4SA expression was unable to enhance expression of ECM-encoding genes Col1a1, Col1a2, Col3a1 or Fn1 in spheroid culture. Micromechanical testing indicated that spheroids composed of either control or TAZ4SA expressing cells were highly compliant and indistinguishable in mechanical properties. In fibroblasts cultured on 2D matrices of compliance similar to spheroids, TAZ4SA expression was able to enhance contractile force generation, but was unable to enhance ECM gene expression. In contrast, culture on stiff hydrogels potentiated TAZ4SA enhancement of ECM expression. TAZ4SA enhancement of Col1a1 expression on soft matrices was potentiated by TGF-ß1 while on stiff matrices it was abrogated by inhibition of MRTF, demonstrating context dependent crosstalk of TAZ with these pathways. These findings demonstrate sufficiency of TAZ activation for driving fibroblast proliferation, contraction, and soluble pro-fibrotic factor expression, and mechanical context-dependent crosstalk of TAZ with other pathways in regulating Col1a1 expression.
File Format	HTM / HTML
ISSN	03636143
e-ISSN	15221563
Journal	American Journal of Physiology - Cell Physiology
Language	English
Publisher	American Physiological Society
Publisher Date	2016-11-23
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Cell Biology
Content Type	Text
Resource Type	Article
Subject	Cell Biology Physiology

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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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