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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

Demonstration of endothelial cell-derived fibroblasts in fibroblast cultures established from lung parenchyma of mice with bleomycin induced pulmonary fibrosis. Fibroblast cultures were established from lungs from mice injected intratrachealy with either normal saline or bleomycin. When the cultures reached confluency they were stained with x-gal to identify the cells from endothelial lineage. Note the absence of x-gal staining cells in the cultures from saline injected control mice (A) in contrast with the marked abundance of x-gal staining fibroblasts in the cultures from bleomycin injected mice (B). The inset in A shows the percentage of x-gal positive cells in four separate samples of cultured fibroblasts from saline injected mice (SLF) compared to eight separate samples of fibroblasts cultured from bleomycin injected mice (BLF). Figures C and D show sequential staining of a fibroblast culture from bleomycin injected mice with x-gal (C) followed by immunocytochemistry for the mesenchymal cell markers type I collagen (red) and α- SMA (green). The arrows indicate cells positive for x-gal, type I collagen, and α- SMA, whereas the arrowheads indicate cells positive for x-gal and type I collagen. Reproduced from reference 26 with permission.
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Figure 1: Demonstration of endothelial cell-derived fibroblasts in fibroblast cultures established from lung parenchyma of mice with bleomycin induced pulmonary fibrosis. Fibroblast cultures were established from lungs from mice injected intratrachealy with either normal saline or bleomycin. When the cultures reached confluency they were stained with x-gal to identify the cells from endothelial lineage. Note the absence of x-gal staining cells in the cultures from saline injected control mice (A) in contrast with the marked abundance of x-gal staining fibroblasts in the cultures from bleomycin injected mice (B). The inset in A shows the percentage of x-gal positive cells in four separate samples of cultured fibroblasts from saline injected mice (SLF) compared to eight separate samples of fibroblasts cultured from bleomycin injected mice (BLF). Figures C and D show sequential staining of a fibroblast culture from bleomycin injected mice with x-gal (C) followed by immunocytochemistry for the mesenchymal cell markers type I collagen (red) and α- SMA (green). The arrows indicate cells positive for x-gal, type I collagen, and α- SMA, whereas the arrowheads indicate cells positive for x-gal and type I collagen. Reproduced from reference 26 with permission.

Mentions: The occurrence of EndoMT in experimentally induced cardiac fibrosis was originally described by Zeisberg et al. [21] employing endothelial cell lineage analysis in transgenic mice. In these studies, analyses of the proportion of fibroblasts present in the fibrotic myocardium of mice with aortic banding induced myocardial fibrosis showed that from 27 to 35% of fibroblasts originated from endothelial cells. Several other studies have confirmed the emergence of activated fibroblasts originating from endothelial cells in various experimentally induced models of cardiac fibrosis [22,23] and collectively have suggested that in these experimental conditions EndoMT represents an important contributor to the generation of fibrotic tissue and, therefore, this pathway may represent a novel therapeutic target. EndoMT has also emerged as a potentially important mechanism in the development and progression of experimentally induced pathological kidney and pulmonary fibrosis. Numerous studies have shown that EndoMT is a novel pathway leading to fibrotic development in diabetic nephropathy and other models of kidney fibrosis. An extensive study by Zeisberg et al. [24] examined the role of EndoMT in three murine models of chronic kidney disease: unilateral ureteral obstructive nephropathy, streptozotocin-induced diabetic nephropathy and a model of Alport renal disease. The results of these studies indicated that 30-50% of myofibroblasts in the fibrotic kidneys, identified by their expression of a fibroblast phenotype and α-SMA, display the endothelial cell specific CD31 surface marker indicating their endothelial cell origin. These studies were validated by endothelial cell lineage tracing and were also confirmed by studies from other laboratories [18,25]. The possible role of EndoMT in experimentally induced pulmonary fibrosis was examined by Hashimoto et al. [26]. These authors evaluated EndoMT as a source of interstitial fibroblasts in bleomycin-induced lung fibrosis using double-transgenic mice in which LacZ was stably expressed in endothelial cells and therefore allowed the histological identification of any cells originated from an endothelial cell lineage. Following endotracheal injection of bleomycin the areas of fibrotic involvement were shown to contain large numbers of fibroblasts of endothelial origin. To directly demonstrate the presence of endothelial cell-derived lung fibroblasts in affected lung fibrotic tissues, lung fibroblasts were isolated and cultured from either saline injected control mice or from mice that received bleomycin injections. These studies revealed that approximately 16% of lung fibroblasts in the cultures from bleomycin-treated mice were derived from endothelial cells as illustrated in Figure 1.


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

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

Demonstration of endothelial cell-derived fibroblasts in fibroblast cultures established from lung parenchyma of mice with bleomycin induced pulmonary fibrosis. Fibroblast cultures were established from lungs from mice injected intratrachealy with either normal saline or bleomycin. When the cultures reached confluency they were stained with x-gal to identify the cells from endothelial lineage. Note the absence of x-gal staining cells in the cultures from saline injected control mice (A) in contrast with the marked abundance of x-gal staining fibroblasts in the cultures from bleomycin injected mice (B). The inset in A shows the percentage of x-gal positive cells in four separate samples of cultured fibroblasts from saline injected mice (SLF) compared to eight separate samples of fibroblasts cultured from bleomycin injected mice (BLF). Figures C and D show sequential staining of a fibroblast culture from bleomycin injected mice with x-gal (C) followed by immunocytochemistry for the mesenchymal cell markers type I collagen (red) and α- SMA (green). The arrows indicate cells positive for x-gal, type I collagen, and α- SMA, whereas the arrowheads indicate cells positive for x-gal and type I collagen. Reproduced from reference 26 with permission.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Demonstration of endothelial cell-derived fibroblasts in fibroblast cultures established from lung parenchyma of mice with bleomycin induced pulmonary fibrosis. Fibroblast cultures were established from lungs from mice injected intratrachealy with either normal saline or bleomycin. When the cultures reached confluency they were stained with x-gal to identify the cells from endothelial lineage. Note the absence of x-gal staining cells in the cultures from saline injected control mice (A) in contrast with the marked abundance of x-gal staining fibroblasts in the cultures from bleomycin injected mice (B). The inset in A shows the percentage of x-gal positive cells in four separate samples of cultured fibroblasts from saline injected mice (SLF) compared to eight separate samples of fibroblasts cultured from bleomycin injected mice (BLF). Figures C and D show sequential staining of a fibroblast culture from bleomycin injected mice with x-gal (C) followed by immunocytochemistry for the mesenchymal cell markers type I collagen (red) and α- SMA (green). The arrows indicate cells positive for x-gal, type I collagen, and α- SMA, whereas the arrowheads indicate cells positive for x-gal and type I collagen. Reproduced from reference 26 with permission.
Mentions: The occurrence of EndoMT in experimentally induced cardiac fibrosis was originally described by Zeisberg et al. [21] employing endothelial cell lineage analysis in transgenic mice. In these studies, analyses of the proportion of fibroblasts present in the fibrotic myocardium of mice with aortic banding induced myocardial fibrosis showed that from 27 to 35% of fibroblasts originated from endothelial cells. Several other studies have confirmed the emergence of activated fibroblasts originating from endothelial cells in various experimentally induced models of cardiac fibrosis [22,23] and collectively have suggested that in these experimental conditions EndoMT represents an important contributor to the generation of fibrotic tissue and, therefore, this pathway may represent a novel therapeutic target. EndoMT has also emerged as a potentially important mechanism in the development and progression of experimentally induced pathological kidney and pulmonary fibrosis. Numerous studies have shown that EndoMT is a novel pathway leading to fibrotic development in diabetic nephropathy and other models of kidney fibrosis. An extensive study by Zeisberg et al. [24] examined the role of EndoMT in three murine models of chronic kidney disease: unilateral ureteral obstructive nephropathy, streptozotocin-induced diabetic nephropathy and a model of Alport renal disease. The results of these studies indicated that 30-50% of myofibroblasts in the fibrotic kidneys, identified by their expression of a fibroblast phenotype and α-SMA, display the endothelial cell specific CD31 surface marker indicating their endothelial cell origin. These studies were validated by endothelial cell lineage tracing and were also confirmed by studies from other laboratories [18,25]. The possible role of EndoMT in experimentally induced pulmonary fibrosis was examined by Hashimoto et al. [26]. These authors evaluated EndoMT as a source of interstitial fibroblasts in bleomycin-induced lung fibrosis using double-transgenic mice in which LacZ was stably expressed in endothelial cells and therefore allowed the histological identification of any cells originated from an endothelial cell lineage. Following endotracheal injection of bleomycin the areas of fibrotic involvement were shown to contain large numbers of fibroblasts of endothelial origin. To directly demonstrate the presence of endothelial cell-derived lung fibroblasts in affected lung fibrotic tissues, lung fibroblasts were isolated and cultured from either saline injected control mice or from mice that received bleomycin injections. These studies revealed that approximately 16% of lung fibroblasts in the cultures from bleomycin-treated mice were derived from endothelial cells as illustrated in Figure 1.

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