positive regulation of myofibroblast differentiation

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of myofibroblast differentiation. [GO_REF:0000058, GOC:BHF, GOC:BHF_miRNA, GOC:rph, GOC:TermGenie, PMID:20533548]

Positive regulation of myofibroblast differentiation is a complex and tightly controlled process that involves the coordinated activation of multiple signaling pathways and transcription factors. It plays a crucial role in tissue repair and fibrosis, but dysregulation can lead to pathological conditions. Here's a detailed breakdown:

**1. Initiation and Induction:**
* **Stimuli:** The process is triggered by various stimuli, including tissue injury, inflammation, and growth factors such as transforming growth factor beta (TGF-β). These signals activate intracellular signaling cascades.
* **Signaling Pathways:**
* **TGF-β Pathway:** TGF-β is a key player in myofibroblast differentiation. It binds to its receptor, leading to phosphorylation of SMAD2/3 proteins. These activated SMADs form complexes with SMAD4 and translocate to the nucleus, where they activate target genes involved in myofibroblast differentiation.
* **Wnt Pathway:** Wnt signaling also contributes to myofibroblast differentiation by activating β-catenin, a key transcription factor.
* **MAPK Pathway:** Mitogen-activated protein kinases (MAPKs) are also involved in myofibroblast activation, primarily through the ERK1/2 pathway.

**2. Transcriptional Regulation:**
* **Transcription Factors:** The activated signaling pathways converge on specific transcription factors that regulate the expression of genes crucial for myofibroblast differentiation. Some important factors include:
* **SMAD3:** A direct target of TGF-β signaling, it activates the transcription of genes like α-smooth muscle actin (α-SMA).
* **β-catenin:** Activated by Wnt signaling, it contributes to the expression of myofibroblast-specific genes.
* **MYC:** A proto-oncogene, MYC can be upregulated during myofibroblast differentiation and enhances the expression of genes involved in proliferation and extracellular matrix production.

**3. Phenotypic Changes:**
* **Expression of Myofibroblast Markers:** The activated transcription factors lead to the expression of myofibroblast-specific markers:
* **α-SMA:** A contractile protein that gives myofibroblasts their characteristic contractile properties.
* **Collagen I:** A major component of the extracellular matrix, its production increases during myofibroblast differentiation, contributing to fibrosis.
* **Fibronectin:** Another extracellular matrix protein, it promotes cell adhesion and migration.
* **Contractility:** Myofibroblasts acquire contractility due to the expression of α-SMA, allowing them to exert mechanical force on the surrounding tissues.

**4. Resolution and Regulation:**
* **Negative Regulation:** The process of myofibroblast differentiation is tightly regulated to ensure appropriate wound healing and prevent excessive fibrosis. Mechanisms of negative regulation include:
* **TGF-β Inhibitors:** Some molecules can block the TGF-β pathway, reducing myofibroblast activation.
* **MicroRNAs:** Small non-coding RNAs called microRNAs can target specific mRNAs involved in myofibroblast differentiation, inhibiting their translation and limiting myofibroblast function.
* **Apoptosis:** Myofibroblasts undergo programmed cell death (apoptosis) once their function in tissue repair is complete.

**5. Implications:**
* **Wound Healing:** Myofibroblast differentiation is essential for normal wound healing, as these cells contribute to tissue repair and contraction.
* **Fibrosis:** Uncontrolled myofibroblast differentiation can lead to excessive fibrosis, a process characterized by the excessive accumulation of extracellular matrix in tissues, which can impair organ function. This can occur in various organs, including the lungs, liver, kidneys, and heart.
* **Cancer:** Myofibroblasts can also play a role in cancer progression, promoting tumor growth and metastasis.

**Overall, positive regulation of myofibroblast differentiation is a complex and tightly regulated process involving multiple signaling pathways, transcription factors, and phenotypic changes. It plays a critical role in normal tissue repair but can contribute to pathological conditions when dysregulated.**'
"

Proteins (1)

Compounds (53)