Related Experiment Video
Updated: Apr 6, 2026
Suppression of Pro-fibrotic Signaling Potentiates Factor-mediated Reprogramming of Mouse Embryonic Fibroblasts into Induced Cardiomyocytes
Published on: June 3, 2018
Transcription Factor EB Drives Thrombospondin-1 Expression to Dampen Focal-adhesion Signaling and Limit
Cong Liu1, Qiang Zhang2, Dawang Zhou3
1Department of Emergency Medicine, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Insights
Transcription factor EB (TFEB) suppresses cardiac fibroblast activation by targeting Thrombospondin-1 (Thbs1). This TFEB-Thbs1 axis offers a new therapeutic target for mitigating cardiac fibrosis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Fibrosis Research
Background:
- Cardiac fibroblasts (CFs) are crucial for heart development and function.
- Understanding the regulation of CF activation is key to treating cardiac diseases.
- Transcription factor EB (TFEB) is investigated for its role in suppressing CF activation.
Purpose of the Study:
- To determine if TFEB directly suppresses cardiac fibroblast activation.
- To elucidate the molecular mechanisms underlying TFEB's action in CFs.
- To explore TFEB's potential in gene and cell therapy for cardiac fibrosis.
Main Methods:
- Transcriptome sequencing of CFs from TFEB-overexpressing and control mice post-myocardial infarction (MI).
- Differential gene expression and pathway analyses using R software.
- Chromatin immunoprecipitation (ChIP-qPCR) to validate TFEB binding to the Thrombospondin-1 (Thbs1) promoter.
- Western blot and cell assays (wound healing, Transwell) to assess protein expression and cell migration.
Main Results:
- TFEB overexpression modulated RNA expression linked to CF transformation and extracellular matrix (ECM) pathways.
- Thrombospondin-1 (Thbs1) mRNA and protein levels were significantly increased in TFEB-overexpressing CFs.
- TFEB directly binds to the Thbs1 promoter, reducing focal adhesion (FA) complex activation and modulating ECM receptor interactions.
Conclusions:
- TFEB exerts anti-fibrotic effects on CFs by modulating Thbs1 and focal adhesion signaling.
- The TFEB-Thbs1 axis represents a novel therapeutic target for reducing cardiac fibrosis.
- TFEB's protective role against MI injury is linked to the Thbs1/FA signaling pathway.
Background:
Cardiac fibroblasts (CFs) are essential for cardiac morphogenesis and homeostasis. We investigated whether transcription factor EB (TFEB) directly targeted and suppressed the activation of CFs, aiming to elucidate its underlying pathological mechanism from the perspectives of gene and cell therapy.
Methods:
Following myocardial infarction (MI) induction, we performed transcriptome sequencing of CFs isolated from R26-LSL-TFEB+/+; Acta2-cre (n = 3) and R26-LSL-TFEB+/+ (n = 3) mice. Differential gene expression and functional enrichment analyses were conducted using R software. The binding between TFEB and Thrombospondin-1 (Thbs1) was validated by ChIP-qPCR assay. CFs were extracted from adult mice in the R26-LSL-TFEB+/+; Acta2-cre and R26-LSL-TFEB+/+ groups. Protein expressions of integrin, CD47, CD36, Thbs1, p-paxillin, vinculin, P-FAK, and α- SMA were detected by Western blot. Cell migration was assessed by the wound healing and Transwell assays.
Results:
TFEB modulated the expression of a broad spectrum of RNAs associated with the transformation of CFs. Pathway analysis revealed significant enrichment in pathways related to extracellular matrix (ECM) receptor interaction and focal adhesion (FA). Notably, both mRNA and protein levels of Thbs1 were markedly elevated in TFEB-overexpressing CFs. Integrated computational prediction and chromatin immunoprecipitation assays identified that TFEB directly bound to the promoter region of Thbs1. This binding was associated with downstream modulation of its receptor network and a concomitant reduction in FA complex activation at the protein level. These findings positioned Thbs1 as a key transcriptional target through which TFEB regulated ECM-related signaling and cellular adhesion dynamics in CFs.
Discussion:
The current findings showed that the modulation of Thbs1 and associated FA signaling was a mechanism through which TFEB overexpression exerted its anti-fibrotic effects on CFs. This highlighted the TFEB-Thbs1 axis as a potential novel target for developing therapeutic strategies to mitigate cardiac fibrosis.
Conclusions:
This study suggested that the protective effect of TFEB against MI injury was associated with the Thbs1/FA signaling pathway, providing a novel potential therapeutic target for cardiac fibrosis.
Related Concept Videos
01:17Intracellular Signaling Affects Focal Adhesions
Some...
01:24Regulation of Angiogenesis and Blood Supply
01:16TGF - β Signaling Pathway
01:30General Transcription Factors
02:16Transcription Factors
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal