Evidence of Fibroblast Heterogeneity and the Role of Fibroblast Subpopulations in Fibrosis

Fries, Kristin M.; Blieden, Timothy M.; Looney, R. John; Sempowski, Gregory D.; Silvera, Maria; Willis, Richard A.; Phipps, Richard P.

doi:10.1006/clin.1994.1144

Cited by 315 publications

(234 citation statements)

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“…This protein is involved in T-cell activation (23) and has widespread nonimmunologic functions, including inhibition of neurite outgrowth (24), apoptotic signaling (25), leukocyte and melanoma cell adhesion and migration (26,27), tumor suppression (28,29), and fibroblast proliferation and migration (30)(31)(32). It is an important marker of mesenchymal stem cells being associated with development, cancer, and CSC.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines

et al. 2012

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The recently emerged concept of cancer stem cell (CSC) has led to a new hypothesis on the basis for tumor progression. Basically, the CSC theory hypothesizes the presence of a hierarchically organized and relatively rare cell population, which is responsible for tumor initiation, self-renewal, and maintenance, in addition to accumulation of mutation and resistance to chemotherapy. CSCs have recently been described in breast cancer. Different genetic markers have been used to isolate breast CSCs, none of which have been correlated with the tumorigenicity or metastatic potential of the cells, limiting their precise characterization and clinical application in the development of therapeutic protocols. Here, we sought for subpopulations of CSCs by analyzing 10 judiciously chosen stem cell markers in a normal breast cell line (MCF10-A) and in four human breast cancer cell lines (MCF-7, MDA-MB-231, MDA-MB-435, and Hs578-T) displaying different degrees of metastatic and invasiveness potential. We were able to identify two markers, which are differentially expressed in nontumorigenic versus tumor cells. The CD90 marker was highly expressed in the malignant cell lines. Interestingly, the CD14 molecule displayed higher expression levels in the nontumorigenic cell line. Therefore, we demonstrated that these two markers, which are more commonly used to isolate and characterize stem cells, are differentially expressed in breast tumor cells, when compared with nontumorigenic breast cells. ' 2012 International Society for Advancement of Cytometry Key terms CD90; Thy-1; breast cancer; cancer stem cell; CD14; breast cancer stem cell

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Section: Discussionmentioning

confidence: 99%

Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines

et al. 2012

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“…However, our laboratory and others have shown that fibroblasts from different human tissues are truly heterogeneous, and have different biosynthetic repertoires and responses to provocation with activating agents. 38 Therefore, we wondered whether the inhibitory effects of ITE on TGF␤1 signaling would prove to be specific to orbital fibroblasts or would generalize to fibroblasts derived from a variety of human tissues. As shown above, we were able to demonstrate that ITE exerts an effect on Tenon's capsule fibroblast cultures that is similar to that observed in cultures of orbital fibroblasts ( Figure 2D).…”

Section: Ite Inhibits Tgf␤1-induced Myofibroblast Differentiation In mentioning

confidence: 99%

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Lehmann

Xia

Kulkarni

et al. 2011

The American Journal of Pathology

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Fibrosis can occur in any human tissue when the normal wound healing response is amplified. Such amplification results in fibroblast proliferation, myofibroblast differentiation, and excessive extracellular matrix deposition. Occurrence of these sequelae in organs such as the eye or lung can result in severe consequences to health. Unfortunately, medical treatment of fibrosis is limited by a lack of safe and effective therapies. These therapies may be developed by identifying agents that inhibit critical steps in fibrotic progression; one such step is myofibroblast differentiation triggered by transforming growth factor-␤1 (TGF␤1). In this study, we demonstrate that TGF␤1-induced myofibroblast differentiation is blocked in human fibroblasts by a candidate endogenous aryl hydrocarbon receptor (AhR) ligand 2-(1=H-indole-3=-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE). Our data show that ITE disrupts TGF␤1 signaling by inhibiting the nuclear translocation of Smad2/3/4. Although ITE functions as an AhR agonist, and biologically persistent AhR agonists, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin, cause severe toxic effects, ITE exhibits no toxicity. Interestingly, ITE effectively inhibits TGF␤1-driven myofibroblast differentiation in AhR ؊/؊ fibroblasts: Its ability to inhibit TGF␤1 signaling is AhR independent. As supported by the results of this study, the small molecule ITE inhibits myofibroblast differentiation and may be useful clinically as an antiscarring agent.

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“…It is known that the embryologic development of the connective tissue in the head region is different from that in the trunk region (Larsen, 1993;Kaufman and Bard, 1999). It is also known that fibroblasts from the skin and oral tissues are not homogeneous, they differ in morphology and function between tissue types (Fries et al, 1994) and they are derived from different embryologic origins. It has been thought that all of the oral fibroblasts are of neural crest origin, while the skin fibroblasts are from the mesodermal somites (Larsen, 1993;Kaufman and Bard, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…homogeneous population, and can differ in morphology and function between tissue types (Fries et al, 1994). Thus the choice of fibroblast to engineer the connective tissue component is likely to be very important.…”

Section: Discussionmentioning

confidence: 99%

Recapitulation of oral mucosal tissues in long‐term organotypic culture

et al. 2003

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To test the influence of fibroblasts on epithelial morphology and expression of keratinocyte proteins and barrier lipids, we bioengineered homotypic and heterotypic oral mucosae and skin using cultured adult human cells. Fibroblasts were allowed to modify collagen type I gels for 2 weeks before keratinocytes were added. The organotypic cultures were then grown at the air-liquid interface for 4 weeks. In homotypic combinations, epithelial morphology and protein expression closely mimicked those in vivo. In heterotypic combinations, the morphology resembled that in vivo and keratinocytes expressed their typical markers, except when skin keratinocytes were recombined with alveolar fibroblasts; they expressed K19, K4, and K13, which is similar to oral mucosal epithelia rather than to the epidermis. Morphologically, the stratum corneum layers were typical for the epithelial tissues. Grafting the bioengineered cultures to the backs of Nude mice did not change the results, suggesting that our findings are not merely a culture phenomenon. Lipid profiles of the homotypic combinations mimicked the profiles found in the normal epithelial tissues, except that the engineered alveolar epithelium expressed more ceramide 2 than that in vivo. In the heterotypic combinations, keratinocytes appeared to control the lipid profile, except in the combination of skin keratinocytes with alveolar fibroblasts, wherein the ceramide profile appeared to be partly that of alveolar epithelium and partly that of epidermis. These results suggest that cultured adult fibroblasts and keratinocytes are sufficient to recapitulate graftable oral tissues, and, except for alveolar fibroblasts, the type of fibroblast had little influence on keratinocyte differentiation. Anat Rec Part A 270A: 162-174, 2003.

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Evidence of Fibroblast Heterogeneity and the Role of Fibroblast Subpopulations in Fibrosis

Cited by 315 publications

References 0 publications

Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines

Differential expression of CD90 and CD14 stem cell markers in malignant breast cancer cell lines

The Aryl Hydrocarbon Receptor Ligand ITE Inhibits TGFβ1-Induced Human Myofibroblast Differentiation

Recapitulation of oral mucosal tissues in long‐term organotypic culture

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