Evidence that fibroblasts derive from epithelium during tissue fibrosis

Iwano, Masayuki; Plieth, David; Danoff, Theodore M.; Xue, Chengsen; Okada, Hirokazu; Neilson, Eric G.

doi:10.1172/jci0215518

Cited by 1,525 publications

(616 citation statements)

References 59 publications

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“…To characterise further immune cells expressing S100A4 that could be responsible for inducing mAIP, we conducted FACS experiments on splenocytes from FSP1·GFP (green fluoresent protein) transgenic mice 13. FSP1·GFP mice express GFP under control of the S100A4 promoter,13 and characterisation of GFP-positive splenocytes would allow for identification of candidate immune cells.…”

Section: Resultsmentioning

confidence: 99%

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Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells

Chamberlain

Kendall

et al. 2009

Gut

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Background and aims:Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model.Methods:A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor β (TGFβ) type II receptor, termed Tgfbr2fspKO, was used to determine the direct role of TGFβ in S100A4+ cells. Immunohistochemical studies suggested that Tgfbr2fspKO mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination.Results:The Tgfbr2fspKO mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2fspKO mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2fspKO DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2fspKO DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells.Conclusion:The development of mAIP in the Tgfbr2fspKO mouse model illustrates the role of TGFβ in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4+ DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis.

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Section: Resultsmentioning

confidence: 99%

“…FSP1·GFP mice express GFP under control of the S100A4 promoter,13 and characterisation of GFP-positive splenocytes would allow for identification of candidate immune cells. A population of GFP-positive cells was found to co-express the myeloid DC markers CD11b and CD11c (fig 6A).…”

Section: Resultsmentioning

confidence: 99%

Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells

Chamberlain

Kendall

et al. 2009

Gut

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“…2,20 It has been proposed that around 30% of accumulating fibroblasts during experimental kidney fibrosis in mice originate from epithelial cells that have undergone EMT. 21 EMT, and loss of E-cadherin, is associated with increased tumor cell invasion and metastasis. 17,18,22,23 Expression of other EMT markers is also associated with invasion.…”

Section: Emt In Cancer Cell Invasion and Metastasismentioning

confidence: 99%

Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes

Fuxe

Vincent²,

Herreros³

2010

Cell Cycle

291

240

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Tumor cells undergoing the epithelial-mesenchymal transition (EMT) acquire the capacity to migrate, invade the stroma and metastasize. EMT cells also acquire stem cell characteristics suggesting crosstalk between EMT and stem cell pathways and contribution of the EMT process to the generation of cancer stem cells. Indeed, transforming growth factor-beta (TGF-β), a major inducer of EMT, cooperates with stem cell pathways like Wnt, Ras, Hedgehog and Notch to induce EMT. A molecular basis for this cooperative signaling is indicated by recent data showing that many EMT associated transcription factors like Snail1, Zeb1/2, Twist, β-catenin, Lef/TCF, Foxc2 and AP-1 interact with Smads and form EMT promoting Smad complexes (EPSC) engaged in both repressing epithelial genes and activating mesenchymal genes. Thus, formation and activation of EPSC seems to represent a point of convergence between EMT and stem cell pathways. Here, we review our current understanding of the mechanisms involved in the transcriptional crosstalk between TGF-β and stem cell pathways and discuss how a fundament for the activation of these mechanisms may lead to the induction of EMT in tumors.

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“…19 A huge variety of cell types such as epithelial cells, mesenchymal stem cells, resident fibroblasts or endothelial cells have been reported to be able to transdifferentiate into CAFs through epithelial-mesenchymal transition (EMT), mesothelial-to-mesenchymal transition (MMT), or endothelial-mesenchymal transition (EndMT). [20][21][22][23][24] All these models for CAF development assume exogenous stimuli that initiate transformation and, in most cases, are thought to be sent from adjacent cancer cells in form of growth factors, such as TGF-ß and CXCL12. 23 There is experimental evidence that the CAF phenotype can also be initiated by intrinsic factors.…”

Section: Discussionmentioning

confidence: 99%

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

et al. 2016

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Constitutive epimutations of tumor suppressor genes are increasingly considered as cancer predisposing factors equally to sequence mutations. In light of the emerging role of the microenvironment for cancer predisposition, initiation, and progression, we aimed to characterize the consequences of a BRCA1 epimutation in cells of mesenchymal origin. We performed a comprehensive molecular and cellular comparison of primary dermal fibroblasts taken from a monozygous twin pair discordant for recurrent cancers and BRCA1 epimutation, whose exceptional clinical case we previously reported in this journal. Comparative transcriptome analysis identified differential expression of extracellular matrix-related genes and pro-tumorigenic growth factors, such as collagens and CXC chemokines. Moreover, genes known to be key markers of so called cancer-associated fibroblasts (CAFs), such as ACTA2, FAP, PDPN, and TNC, were upregulated in fibroblasts of the affected twin (BRCA1 mosMe ) in comparison to those of the healthy twin (BRCA1 wt ). Further analyses detected CAF-typical cellular features, including an elevated growth rate, enhanced migration, altered actin architecture and increased production of ketone bodies in BRCA1 mosMe fibroblasts compared to BRCA1 wt fibroblasts. In addition, conditioned medium of BRCA1 mosMe fibroblasts was more potent than conditioned medium of BRCA1 wt fibroblasts to promote cell proliferation in an epithelial and a cancer cell line. Our data demonstrate, that a CAF-like state is not an exclusive feature of tumor-associated tissue but also exists in healthy tissue with tumor suppressor deficiency. The naturally occurring phenomenon of twin fibroblasts differing in their BRCA1 methylation status revealed to be a unique powerful tool for exploring tumor suppressor deficiency-related changes in healthy tissue, reinforcing their significance for cancer predisposition.

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Evidence that fibroblasts derive from epithelium during tissue fibrosis

Cited by 1,525 publications

References 59 publications

Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells

Autoimmune pancreatitis results from loss of TGF signalling in S100A4-positive dendritic cells

Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion: Role of EMT promoting Smad complexes

CAF-like state in primary skin fibroblasts with constitutional BRCA1 epimutation sheds new light on tumor suppressor deficiency-related changes in healthy tissue

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