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Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases.

Piera-Velazquez S, Jimenez SA - Fibrogenesis Tissue Repair (2012)

Bottom Line: Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions.Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases.Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram showing the putative TGF-β signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in the pathogenesis of human fibrotic disorders. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the cAbl non-receptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 results in marked stimulation of Snail1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail1 targeting it for proteosomal degradation and thus, effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as the ET-1, Wnt, hypoxia and cellular stress pathways may also participate although the molecular events have not been fully elucidated. Modified from Li and Jimenez [37].
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Figure 2: Schematic diagram showing the putative TGF-β signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in the pathogenesis of human fibrotic disorders. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the cAbl non-receptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 results in marked stimulation of Snail1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail1 targeting it for proteosomal degradation and thus, effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as the ET-1, Wnt, hypoxia and cellular stress pathways may also participate although the molecular events have not been fully elucidated. Modified from Li and Jimenez [37].

Mentions: Several studies explored the underlying molecular pathways that may cause the significant loss of endothelial-specific markers while inducing strong de novo mesenchymal phenotypes. These studies identified the c-Abl protein kinase (c-Abl), protein kinase Cδ (PKC-δ), and glycogen synthase kinase 3β (GSK-3β) as important participants and that GSK-3β kinase phosphorylation was a crucial event in this process [41,42]. It is well known that phosphorylation of specific serine residues in GSK-3β results in inactivation of the kinase which in turn induces the nuclear accumulation of Snail1 followed by a profound increase in the expression of its corresponding gene. The transcriptional effects of Snail1 induce the expression of a mesenchymal cell-specific phenotype although the precise mechanisms involved remain obscure. In contrast, in the absence of GSK-3β phosphorylation the GSK-3β kinase is active and induces the proteosomal degradation of Snail1, thus abrogating the acquisition by endothelial cells of a mesenchymal cell phenotype. Other studies have shown that several important regulatory pathways including the canonical Wnt pathway, the HIF-1α hypoxia induced pathway, and the response to cellular stress may also participate in the regulation of EndoMT [43,44] as illustrated in Figure 2.


Molecular mechanisms of endothelial to mesenchymal cell transition (EndoMT) in experimentally induced fibrotic diseases.

Piera-Velazquez S, Jimenez SA - Fibrogenesis Tissue Repair (2012)

Schematic diagram showing the putative TGF-β signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in the pathogenesis of human fibrotic disorders. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the cAbl non-receptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 results in marked stimulation of Snail1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail1 targeting it for proteosomal degradation and thus, effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as the ET-1, Wnt, hypoxia and cellular stress pathways may also participate although the molecular events have not been fully elucidated. Modified from Li and Jimenez [37].
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368755&req=5

Figure 2: Schematic diagram showing the putative TGF-β signaling pathways involved in EndoMT. The diagram shows the numerous putative pathways that may participate in the EndoMT process and may be involved in the pathogenesis of human fibrotic disorders. One central pathway initiated following ligand-binding activation of the Smad-independent TGF-β pathway causes phosphorylation of GSK-3β mediated by PKC-δ and the cAbl non-receptor kinase. Phosphorylation of GSK-3β at serine 9 (ser9) causes its inhibition which then allows Snail1 to enter the nucleus. Nuclear accumulation of Snail1 results in marked stimulation of Snail1 expression which then leads to acquisition of the myofibroblast phenotype with stimulation of α-SMA. The inhibition of GSK-3β ser9 phosphorylation by specific inhibition of PKC-δ or c-Abl activity allows GSK-3β to phosphorylate Snail1 targeting it for proteosomal degradation and thus, effectively abolishes the acquisition of the myofibroblastic phenotype and the fibrotic response. Other pathways such as the ET-1, Wnt, hypoxia and cellular stress pathways may also participate although the molecular events have not been fully elucidated. Modified from Li and Jimenez [37].
Mentions: Several studies explored the underlying molecular pathways that may cause the significant loss of endothelial-specific markers while inducing strong de novo mesenchymal phenotypes. These studies identified the c-Abl protein kinase (c-Abl), protein kinase Cδ (PKC-δ), and glycogen synthase kinase 3β (GSK-3β) as important participants and that GSK-3β kinase phosphorylation was a crucial event in this process [41,42]. It is well known that phosphorylation of specific serine residues in GSK-3β results in inactivation of the kinase which in turn induces the nuclear accumulation of Snail1 followed by a profound increase in the expression of its corresponding gene. The transcriptional effects of Snail1 induce the expression of a mesenchymal cell-specific phenotype although the precise mechanisms involved remain obscure. In contrast, in the absence of GSK-3β phosphorylation the GSK-3β kinase is active and induces the proteosomal degradation of Snail1, thus abrogating the acquisition by endothelial cells of a mesenchymal cell phenotype. Other studies have shown that several important regulatory pathways including the canonical Wnt pathway, the HIF-1α hypoxia induced pathway, and the response to cellular stress may also participate in the regulation of EndoMT [43,44] as illustrated in Figure 2.

Bottom Line: Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions.Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases.Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.

View Article: PubMed Central - HTML - PubMed

Affiliation: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA 19107, USA.

ABSTRACT
Several recent studies have demonstrated that endothelial to mesenchymal transition (EndoMT), a newly recognized type of cellular transdifferentiation may be an important source of myofibroblasts during the development of experimentally induced pulmonary, cardiac and kidney fibrosis. EndoMT is a complex biological process induced by members of the transforming growth factor (TGF-β) family of regulatory polypeptides in which endothelial cells adopt a mesenchymal or myofibroblastic phenotype acquiring motile and contractile properties and initiating expression of mesenchymal cell products such as α smooth muscle actin (α-SMA) and type I collagen. Although these experimental studies provide compelling evidence for the participation of EndoMT in the development of experimentally-induced fibrotic processes the precise role of EndoMT in the pathogenesis of human fibrotic disorders requires confirmation and validation from studies of human clinical pathologic conditions. Such confirmation should lead to a change in the paradigm of the origin of profibrogenic myofibroblasts involved in human fibrotic diseases. Further understanding of the molecular mechanisms and the regulatory pathways involved in EndoMT may lead to the development of novel therapeutic approaches for the incurable and often devastating fibrotic disorders.

No MeSH data available.


Related in: MedlinePlus