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The myofibroblast, multiple origins for major roles in normal and pathological tissue repair.

Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A - Fibrogenesis Tissue Repair (2012)

Bottom Line: Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts.However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair.These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Facultés de Médecine et de Pharmacie, Université de Limoges, EA 6309 "Maintenance Myélinique et Neuropathies Périphériques", FR 3503, Limoges F-87025, France.

ABSTRACT
Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

No MeSH data available.


Related in: MedlinePlus

Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.
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Figure 2: Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.

Mentions: Myofibroblasts can originate from various cell types as illustrated in Figure 2. The major contribution of the cells originates from local recruitment of connective tissue fibroblasts. For example in the skin, dermal fibroblasts located at the edges of the wound can acquire a myofibroblastic phenotype and participate in tissue repair. In the liver, the role of perisinusoidal hepatic stellate cells has been widely studied and their key role during fibrogenesis has been clearly demonstrated. However, in the connective tissue, important heterogeneity in fibroblastic cell subpopulations has been observed. These subpopulations reside in different locations within the organ and have specific activation and deactivation properties. At least three subpopulations have been identified in the dermis: superficial dermal fibroblasts, reticular fibroblasts, which reside in the deep dermis, and fibroblasts associated with hair follicles. These cell subpopulations can be isolated and exhibit distinctive differences when cultured separately [20]. In the liver, in the main two subpopulations of fibrogenic cells have been described: i) the hepatic stellate cells located in the space of Disse between the hepatocytes and the sinusoidal endothelial cells and ii) the portal fibroblasts located in the connective tissue surrounding portal tracts [21]. We recently applied the precision cut-liver slice (PCLS) model which preserves the normal lobular architecture and allows the maintenance of cell-cell interactions within their original extracellular matrix to study hepatic stellate cell and portal fibroblast behaviour in rat PCLS derived from fibrotic tissue [22,23]. In pathological situations, myofibroblastic cells expressing α-smooth muscle actin are derived either from hepatic stellate cells (e.g. in alcoholic cirrhosis where myofibroblasts are present in the parenchyma and in septa) or from portal fibroblasts (e.g. in cholestatic fibrosis where myofibroblasts are present in enlarged portal areas). Thus, in the liver, fibrogenic cells mainly include hepatic stellate cells and portal fibroblasts, even if, in some cases, second layer cells located around centrilobular veins can be involved in parenchymal fibrosis [24]. Moreover, today, the involvement in tissue repair of local mesenchymal stem cells is discussed more and more. These progenitor cells have been described in the dermal sheath that surrounds the outside of the hair follicle facing the epithelial stem cells. They are involved in the regeneration of the dermal papilla and they can also became wound healing (myo)fibroblasts after a lesion [25]. Mesenchymal stem cells have not yet been described in the liver, but at the periphery of portal tracts, in Hering's canals, epithelial stem cells have been described. Hering's canal represents the junction between hepatocytes and bile duct epithelial cells, and in this area, numerous proliferative cells are observed after a hepatic lesion. This area may constitute a niche containing not only epithelial stem cells but also mesenchymal stem cells and these two cell types may cooperate depending on the tissue need. This concept of a cell association, able to reconstitute the different organ cell populations and constituting a niche of stem cells is currently discussed in diverse organs notably in the liver [26]. Recent data have also implicated circulating cells, called fibrocytes, in the tissue repair process. Fibrocytes enter into injured skin together with inflammatory cells and acquire a myofibroblastic phenotype [27]. In post-burn scars, fibrocytes are recruited to the site of the lesion where they stimulate local inflammatory response and produce extracellular matrix proteins thus contributing to hypertrophic scar formation [28]. Fibrocytes are also implicated in the lung in subepithelial fibrosis observed in asthma [29], and in renal fibrosis [30]. Another type of circulating cell originating from bone marrow has been suggested to participate in tissue repair. These mesenchymal stem cells are bone marrow-derived non-hematopoietic precursor cells [31] that contribute to the maintenance and regeneration of connective tissues through engraftment. Indeed, they have the capacity to engraft into several organs and to differentiate into wound healing myofibroblasts. The engraftment in injured organs is regulated by the severity of the damage [32]. Interestingly, very poor engraftment of intravenously administered mesenchymal stem cells in healthy organs was observed. In hepatic fibrosis, a significant proportion of myofibroblasts may originate from the bone marrow [33]. Finally, epithelial- and endothelial-to-mesenchymal transition (EMT), a process by which differentiated or malignant epithelial and endothelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury, particularly in the kidney [34]. However, the degree to which this process contributes to fibrosis remains a matter of intense debate and is likely to be context-dependent. All together, mesenchymal stem cells, fibrocytes, bone marrow-derived cells and cells derived from an EMT process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the tissue's requirement for these cells.


The myofibroblast, multiple origins for major roles in normal and pathological tissue repair.

Micallef L, Vedrenne N, Billet F, Coulomb B, Darby IA, Desmoulière A - Fibrogenesis Tissue Repair (2012)

Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368789&req=5

Figure 2: Myofibroblast origins. The main myofibroblast progenitor after injury of different tissues appears to be locally residing fibroblasts. Indeed, various cell types can acquire a myofibroblastic phenotype; these diverse origins lead to distinct myofibroblast sub-populations. EMT: epithelial- and endothelial-to-mesenchymal transition.
Mentions: Myofibroblasts can originate from various cell types as illustrated in Figure 2. The major contribution of the cells originates from local recruitment of connective tissue fibroblasts. For example in the skin, dermal fibroblasts located at the edges of the wound can acquire a myofibroblastic phenotype and participate in tissue repair. In the liver, the role of perisinusoidal hepatic stellate cells has been widely studied and their key role during fibrogenesis has been clearly demonstrated. However, in the connective tissue, important heterogeneity in fibroblastic cell subpopulations has been observed. These subpopulations reside in different locations within the organ and have specific activation and deactivation properties. At least three subpopulations have been identified in the dermis: superficial dermal fibroblasts, reticular fibroblasts, which reside in the deep dermis, and fibroblasts associated with hair follicles. These cell subpopulations can be isolated and exhibit distinctive differences when cultured separately [20]. In the liver, in the main two subpopulations of fibrogenic cells have been described: i) the hepatic stellate cells located in the space of Disse between the hepatocytes and the sinusoidal endothelial cells and ii) the portal fibroblasts located in the connective tissue surrounding portal tracts [21]. We recently applied the precision cut-liver slice (PCLS) model which preserves the normal lobular architecture and allows the maintenance of cell-cell interactions within their original extracellular matrix to study hepatic stellate cell and portal fibroblast behaviour in rat PCLS derived from fibrotic tissue [22,23]. In pathological situations, myofibroblastic cells expressing α-smooth muscle actin are derived either from hepatic stellate cells (e.g. in alcoholic cirrhosis where myofibroblasts are present in the parenchyma and in septa) or from portal fibroblasts (e.g. in cholestatic fibrosis where myofibroblasts are present in enlarged portal areas). Thus, in the liver, fibrogenic cells mainly include hepatic stellate cells and portal fibroblasts, even if, in some cases, second layer cells located around centrilobular veins can be involved in parenchymal fibrosis [24]. Moreover, today, the involvement in tissue repair of local mesenchymal stem cells is discussed more and more. These progenitor cells have been described in the dermal sheath that surrounds the outside of the hair follicle facing the epithelial stem cells. They are involved in the regeneration of the dermal papilla and they can also became wound healing (myo)fibroblasts after a lesion [25]. Mesenchymal stem cells have not yet been described in the liver, but at the periphery of portal tracts, in Hering's canals, epithelial stem cells have been described. Hering's canal represents the junction between hepatocytes and bile duct epithelial cells, and in this area, numerous proliferative cells are observed after a hepatic lesion. This area may constitute a niche containing not only epithelial stem cells but also mesenchymal stem cells and these two cell types may cooperate depending on the tissue need. This concept of a cell association, able to reconstitute the different organ cell populations and constituting a niche of stem cells is currently discussed in diverse organs notably in the liver [26]. Recent data have also implicated circulating cells, called fibrocytes, in the tissue repair process. Fibrocytes enter into injured skin together with inflammatory cells and acquire a myofibroblastic phenotype [27]. In post-burn scars, fibrocytes are recruited to the site of the lesion where they stimulate local inflammatory response and produce extracellular matrix proteins thus contributing to hypertrophic scar formation [28]. Fibrocytes are also implicated in the lung in subepithelial fibrosis observed in asthma [29], and in renal fibrosis [30]. Another type of circulating cell originating from bone marrow has been suggested to participate in tissue repair. These mesenchymal stem cells are bone marrow-derived non-hematopoietic precursor cells [31] that contribute to the maintenance and regeneration of connective tissues through engraftment. Indeed, they have the capacity to engraft into several organs and to differentiate into wound healing myofibroblasts. The engraftment in injured organs is regulated by the severity of the damage [32]. Interestingly, very poor engraftment of intravenously administered mesenchymal stem cells in healthy organs was observed. In hepatic fibrosis, a significant proportion of myofibroblasts may originate from the bone marrow [33]. Finally, epithelial- and endothelial-to-mesenchymal transition (EMT), a process by which differentiated or malignant epithelial and endothelial cells undergo a phenotypic conversion that gives rise to the matrix-producing fibroblasts and myofibroblasts, is increasingly recognized as an integral part of tissue fibrogenesis after injury, particularly in the kidney [34]. However, the degree to which this process contributes to fibrosis remains a matter of intense debate and is likely to be context-dependent. All together, mesenchymal stem cells, fibrocytes, bone marrow-derived cells and cells derived from an EMT process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the tissue's requirement for these cells.

Bottom Line: Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts.However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair.These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

View Article: PubMed Central - HTML - PubMed

Affiliation: Facultés de Médecine et de Pharmacie, Université de Limoges, EA 6309 "Maintenance Myélinique et Neuropathies Périphériques", FR 3503, Limoges F-87025, France.

ABSTRACT
Myofibroblasts differentiate, invade and repair injured tissues by secreting and organizing the extracellular matrix and by developing contractile forces. When tissues are damaged, tissue homeostasis must be re-established, and repair mechanisms have to rapidly provide harmonious mechanical tissue organization, a process essentially supported by (myo)fibroblasts. Under physiological conditions, the secretory and contractile activities of myofibroblasts are terminated when the repair is complete (scar formation) but the functionality of the tissue is only rarely perfectly restored. At the end of the normal repair process, myofibroblasts disappear by apoptosis but in pathological situations, myofibroblasts likely remain leading to excessive scarring. Myofibroblasts originate from different precursor cells, the major contribution being from local recruitment of connective tissue fibroblasts. However, local mesenchymal stem cells, bone marrow-derived mesenchymal stem cells and cells derived from an epithelial-mesenchymal transition process, may represent alternative sources of myofibroblasts when local fibroblasts are not able to satisfy the requirement for these cells during repair. These diverse cell types probably contribute to the appearance of myofibroblast subpopulations which show specific biological properties and which are important to understand in order to develop new therapeutic strategies for treatment of fibrotic and scarring diseases.

No MeSH data available.


Related in: MedlinePlus