Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts

Mah, Wesley; Jiang, Guoqiao; Olver, Dylan; Gallant‐Behm, Corrie L.; Wiebe, Colin; Hart, David A.; Koivisto, Leeni; Larjava, Hannu; Häkkinen, Lari

doi:10.1016/j.ajpath.2017.04.017

Cited by 39 publications

(44 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the present study, we demonstrate by genome wide gene expression profiling that lobular-like and interlobular-like fibroblasts differ by entire lineage programs with characteristics and functions in common with previously reported papillary and reticular fibroblasts, respectively, in mice and humans [1,14,39]. In this regard, it is interesting that CD26 − fibroblasts in mice segregate into mature CD26 + papillary fibroblasts [1] and that in both mice and humans such fibroblasts are responsible for ECM production and in turn fibrosis [57][58][59]. We propose that the CD26 + interlobular-like Fig.…”

Section: Discussionsupporting

confidence: 85%

Fibroblasts direct differentiation of human breast epithelial progenitors

et al. 2020

View full text Add to dashboard Cite

Background Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics. Methods Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells’ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells. Results hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling. Conclusions The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.

show abstract

Section: Discussionsupporting

confidence: 85%

Fibroblasts direct differentiation of human breast epithelial progenitors

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In the present study, we demonstrate by genome wide gene expression pro ling that lobular-like and interlobular-like broblasts differ by entire lineage programs with characteristics and functions in common with previously reported papillary and reticular broblasts, respectively, in mice and humans [1,14,39]. In this regard, it is interesting that CD26broblasts in mice segregate into mature CD26 + papillary broblasts [1] and that in both mice and humans such broblasts are responsible for ECM production and in turn brosis [57][58][59].…”

Section: Discussionsupporting

confidence: 83%

Fibroblasts direct differentiation of human breast epithelial progenitors

Morsing¹,

Kim

Villadsen

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics. Methods Primary lobular- and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular- and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells´ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal- or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-b)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-b inhibitor, SB431542, prior to heterotypic co-culture with luminal cells.Results hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-b signaling. Conclusions The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.

show abstract

“…At present, many studies believe that TGF-β1 is the key cytokine regulating the pathological progress of keloid. Though the mechanism remains unclear, the upregulated expression of TGF-β1 may be closely related to the excessive collagen synthesis in keloid [ 13 , 21, 22 ]. However, in our study, IGF-1-induced noncanonical TGF-β signalling was crucial to CD26 + KF activation.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, cell heterogeneity has been considered to be closely related to scar formation [ 12 , 13 ]; however, because of the lack of a specific marker it is difficult to identify subsets in keloid tissue, which is a significant barrier in keloid research [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

CD26 upregulates proliferation and invasion in keloid fibroblasts through an IGF-1-induced PI3K/AKT/mTOR pathway

Min

et al. 2020

Burns &Amp; Trauma

View full text Add to dashboard Cite

Background Keloid is a fibrotic dermal disease characterized by an abnormal increase in fibroblast proliferation and invasion. These pathological behaviours may be related to the heterogeneity of keloid fibroblasts (KFs); however, because of a lack of effective biomarkers for KFs it is difficult to study the underlying mechanism. Our previous studies revealed that the expansion of CD26+ KFs was responsible for increased keloid proliferation and invasion capabilities; the intrinsic relationship and mechanism between CD26 and keloid is therefore worthy of further investigation. The aim of this study was to explore molecular mechanisms in the process of CD26 upregulated KFs proliferation and invasion abilities, and provide more evidence for CD26 as an effective biomarker of keloid and a new clinical therapeutic target. Methods Flow cytometry was performed to isolate CD26+/CD26− fibroblasts from KFs and normal fibroblasts. To generate stably silenced KFs for CD26 and insulin-like growth factor-1 receptor (IGF-1R), lentiviral particles encoding shRNA targeting CD26 and IGF-1R were used for transfection. Cell proliferations were analysed by cell counting kit-8 assay and 5-ethynyl-2′-deoxyuridine (EdU) incorporation assay. Scratching assay and transwell assay were used to assess cell migration and invasion abilities. To further quantify the regulatory role of CD26 expression in the relevant signalling pathway, RT-qPCR, western blot, ELISA, PI3K activity assay and immunofluorescence were used. Results Aberrant expression of CD26 in KFs was proven to be associated with increased proliferation and invasion of KFs. Furthermore, the role of the IGF-1/IGF-1 receptor axis was also studied in CD26 and was found to upregulate KF proliferation and invasion. The PI3K/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway was shown to affect CD26-regulated KF proliferation and invasion by increasing phosphorylation levels of S6 kinase and 4E-binding protein. Conclusions CD26 can be the effective biomarker for KFs, and its expression is closely related to proliferation and invasion in keloids through the IGF-1-induced PI3K/AKT/mTOR pathway. This work provides a novel perspective on the pathological mechanisms affecting KFs and therapeutic strategies against keloids.

show abstract

Elevated CD26 Expression by Skin Fibroblasts Distinguishes a Profibrotic Phenotype Involved in Scar Formation Compared to Gingival Fibroblasts

Cited by 39 publications

References 77 publications

Fibroblasts direct differentiation of human breast epithelial progenitors

Fibroblasts direct differentiation of human breast epithelial progenitors

Fibroblasts direct differentiation of human breast epithelial progenitors

CD26 upregulates proliferation and invasion in keloid fibroblasts through an IGF-1-induced PI3K/AKT/mTOR pathway

Contact Info

Product

Resources

About