Organ‐Dependent Expression of Differentiated States in Fibroblasts Cultured <i>in Vitro</i>

Shimizu, Katsuhiko; Yoshizato, Katsutoshi

doi:10.1111/j.1440-169x.1992.00043.x

Cited by 8 publications

(3 citation statements)

References 36 publications

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“…These differences indicate that the concomitant FAK deficiency and Pyk2 upregulation likely have unique effects in differentiated fibroblasts derived from adult tissue, as we studied here, vs. an immature embryonic source. Furthermore, these data are in line with other studies that showed that fibroblasts from different organs display distinct and characteristic transcriptional patterns and should be analyzed as distinct cell types, despite all being of a "fibroblast" lineage (8,50). Furthermore, the ex- pression and subcellular localization of Pyk2 appear distinct in CFs in contrast to MEFs.…”

Section: Discussionsupporting

confidence: 90%

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration

Manso¹,

Kang²,

Plotnikov

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Migration and proliferation of cardiac fibroblasts (CFs) play an important role in the myocardial remodeling process. While many factors have been identified that regulate CF growth and migration, less is known about the signaling mechanisms involved in these processes. Here, we utilized Cre-LoxP technology to obtain focal adhesion kinase (FAK)-deficient adult mouse CFs and studied how FAK functioned in modulating cell adhesion, proliferation, and migration of these cells. Treatment of FAK(flox/flox) CFs with Ad/Cre virus caused over 70% reduction of FAK protein levels within a cell population. FAK-deficient CFs showed no changes in focal adhesions, cell morphology, or protein expression levels of vinculin, talin, or paxillin; proline-rich tyrosine kinase 2 (Pyk2) expression and activity were increased. Knockdown of FAK protein in CFs increased PDGF-BB-induced proliferation, while it reduced PDGF-BB-induced migration. Adhesion to fibronectin was not altered. To distinguish between the function of FAK and Pyk2, FAK function was inhibited via adenoviral-mediated overexpression of the natural FAK inhibitor FAK-related nonkinase (FRNK). Ad/FRNK had no effect on Pyk2 expression, inhibited the PDGF-BB-induced migration, but did not change the PDGF-BB-induced proliferation. FAK deficiency had only modest effects on increasing PDGF-BB activation of p38 and JNK MAPKs, with no alteration in the ERK response vs. control cells. These results demonstrate that FAK is required for the PDGF-BB-induced migratory response of adult mouse CFs and suggest that FAK could play an essential role in the wound-healing response that occurs in numerous cardiac pathologies.

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Section: Discussionsupporting

confidence: 90%

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration

Manso¹,

Kang²,

Plotnikov

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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“…Microenvironmental factors probably play an important role in the development of specific fibroblastic features. It has been suggested that each organ contains fibroblasts with specific features [220,231]. Moreover, Fabra et al [81] have shown that certain fibroblasts influence the invasive and metastatic potential of human colon carcinoma cells.…”

Section: Myofibroblasts In Normal Tissuesmentioning

confidence: 99%

Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity

Schmitt‐Gräff

Desmoulière

Gabbiani³

1994

Vichows Archiv A Pathol Anat

376

260

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Granulation tissue fibroblasts (myofibroblasts) develop several ultrastructural and biochemical features of smooth muscle (SM) cells, including the presence of microfilament bundles and the expression of alpha-SM actin, the actin isoform present in SM cells and myoepithelial cells and particularly abundant in vascular SM cells. Myofibroblasts have been suggested to play a role in wound contraction and in retractile phenomena observed during fibrotic diseases. When contraction stops and the wound is fully epithelialized, myofibroblasts containing alpha-SM actin disappear, probably as a result of apoptosis, and the scar classically becomes less cellular and composed of typical fibroblasts with well-developed rough endoplasmic reticulum but with no more microfilaments. In contrast, alpha-SM actin expressing myofibroblasts persist in hypertrophic scars and in fibrotic lesions of many organs, including stroma reaction to epithelial tumours, where they are allegedly involved in retractile phenomena as well as in extracellular matrix accumulation. The mechanisms leading to the development of myofibroblastic features remain to be investigated. In vivo and in vitro investigations have shown that gamma-interferon exerts an antifibrotic activity at least in part by decreasing alpha-SM actin expression whereas heparin increases the proportion of alpha-SM actin positive cells. Recently, we have observed that the subcutaneous administration of transforming growth factor-beta 1 to rats results in the formation of a granulation tissue in which alpha-SM actin expressing myofibroblasts are particularly abundant. Other cytokines and growth factors, such as platelet-derived growth factor, basic fibroblast growth factor and tumour necrosis factor-alpha, despite their profibrotic activity, do not induce alpha-SM actin in myofibroblasts. In conclusion, fibroblastic cells are relatively undifferentiated and can assume a particular phenotype according to the physiological needs and/or the microenvironmental stimuli. Further studies on fibroblast adaptation phenomena appear to be useful for the understanding of the mechanisms of development and regression of pathological processes such as wound healing and fibrocontractive diseases.

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“… 1 Research conducted over the past few decades has highlighted the role of resident and migratory fibroblasts in initiating and sustaining chronic fibrosis in key organ systems, such as the kidney, liver, lung and skin. 2 – 7 This body of work has shown that fibroblast phenotype varies as a function of both host organ 8 and the physiologic (or pathophysiologic) state of the organ. 4 Consequently, while all fibroblasts share certain defining features, the phenotype of one fibroblast subtype is not necessarily predictive of another.…”

Section: Introductionmentioning

confidence: 99%

Modeling fibrosis using fibroblasts isolated from scarred rat vocal folds

Kishimoto

et al. 2016

Laboratory Investigation

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Following injury, pathologically activated vocal fold fibroblasts (VFFs) can engage in disordered extracellular matrix (ECM) remodeling, leading to VF fibrosis and impaired voice function. Given the importance of scar VFFs to phenotypically appropriate in vitro modeling of VF fibrosis, we pursued detailed characterization of scar VFFs obtained from surgically injured rat VF mucosae, compared to those obtained from experimentally naïve, age-matched tissue. Scar VFFs initially exhibited a myofibroblast phenotype characterized by increased proliferation, increased Col1a1 transcription and collagen, type I synthesis, increased Acta2 transcription and α-smooth muscle actin synthesis, and enhanced contractile function. These features were most distinct at passage 1 (P1); we observed a coalescence of the scar and naïve VFF phenotypes at later passages. An empirical Bayes statistical analysis of the P1 cell transcriptome identified 421 genes that were differentially expressed by scar, compared to naïve, VFFs. These genes were primarily associated with the wound response, ECM regulation, and cell proliferation. Follow-up comparison of P1 scar VFFs and their in vivo tissue source showed substantial transcriptomic differences. Finally, P1 scar VFFs responded to treatment with hepatocyte growth factor and transforming growth factor-β3, two biologics with reported therapeutic value. Despite the practical limitations inherent to working with early passage cells, this experimental model is easily implemented in any suitably equipped laboratory and has the potential to improve the applicability of preclinical VF fibrosis research.

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Organ‐Dependent Expression of Differentiated States in Fibroblasts Cultured in Vitro

Cited by 8 publications

References 36 publications

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration

Cardiac fibroblasts require focal adhesion kinase for normal proliferation and migration

Heterogeneity of myofibroblast phenotypic features: an example of fibroblastic cell plasticity

Modeling fibrosis using fibroblasts isolated from scarred rat vocal folds

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