Papers by Maria Trojanowska
Frontiers in Immunology, 2020
Scleroderma (SSc) is an autoimmune connective tissue disease characterized by immune dysregulatio... more Scleroderma (SSc) is an autoimmune connective tissue disease characterized by immune dysregulation, vasculopathy, and fibrosis. We have previously demonstrated that low Fli1 expression in SSc fibroblasts and endothelial cells plays an important role in SSc pathogenesis. Cells of myeloid and lymphoid origin also express Fli1 and are dysregulated in patients with SSc, playing key roles in disease pathogenesis. However, the role for immune Fli1 in SSc is not yet clear. Our aim was to elucidate whether Fli1 contributes to the immune dysregulation seen in SSc. Comparison of the expression of Fli1 in monocytes, Band T-cell fractions of PBMCs isolated from SSc patients and healthy controls (HC), showed an increase in Fli1 levels in monocytes. We used siRNA transfected human myeloid cells and mouse peritoneal macrophages obtained from Fli1 flox/flox LysMCre +/+ mice, and found that markers of alternative macrophage activation were increased with Fli1 deletion. Coculture of Fli1-deficient myeloid cells and primary human or mouse fibroblasts resulted in a potent induction of collagen type I, independent of TGFβ upregulation. We next analyzed global gene expression profile in response to Fli1 downregulation, to gain further insight into the molecular mechanisms of this process and to identify differentially expressed genes in myeloid cells. Of relevance to SSc, the top most upregulated pathways were hallmark IFN-γ and IFN-α response. Additionally, several genes previously linked to SSc pathogenesis and fibrosis in general were also induced, including CCL2, CCL7, MMP12, and CXCL10. ANKRD1, a profibrotic transcription co-regulator was the top upregulated gene in our array. Our results show that Fli1-deficient myeloid cells share key features with cells from SSc patients, with higher expression of profibrotic markers and activation of interferon responsive genes, thus suggesting that dysregulation of Fli1 in myeloid cells may contribute to SSc pathogenesis.
Journal of Dermatological Science, 2016
Journal of Investigative Dermatology, 2014
Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized b... more Scleroderma (SSc) is a complex and heterogeneous connective tissue disease mainly characterized by autoimmunity, vascular damage, and fibrosis that mostly involve the skin and lungs. Epstein-Barr virus (EBV) is a lymphotropic g-herpesvirus that has co-evolved with human species, infecting 495% of the adult population worldwide, and has been a leading candidate in triggering several autoimmune diseases. Here we show that EBV establishes infection in the majority of fibroblasts and endothelial cells in the skin of SSc patients, characterized by the expression of the EBV noncoding small RNAs (EBERs) and the increased expression of immediate-early lytic and latency mRNAs and proteins. We report that EBV is able to persistently infect human SSc fibroblasts in vitro, inducing an aberrant innate immune response in infected cells. EBV-Toll-like receptor (TLR) aberrant activation induces the expression of selected IFN-regulatory factors (IRFs), IFN-stimulated genes (ISGs), transforming growth factor-b1 (TGFb1), and several markers of fibroblast activation, such as smooth muscle actin and Endothelin-1, and all of these genes play a key role in determining the profibrotic phenotype in SSc fibroblasts. These findings imply that EBV infection occurring in mesenchymal, endothelial, and immune cells of SSc patients may underlie the main pathological features of SSc including autoimmunity, vasculopathy, and fibrosis, and provide a unified disease mechanism represented by EBV reactivation.
Arthritis Research & Therapy, 2015
Introduction: HLA-B*35 is associated with increased risk of developing pulmonary hypertension in ... more Introduction: HLA-B*35 is associated with increased risk of developing pulmonary hypertension in SSc patients. We previously reported that HLA-B*35 induces endothelial cell dysfunction via activation of ER stress/UPR and upregulation of the inflammatory response. Because PBMCs from lcSSc-PAH patients are also characterized by activation of ER stress/UPR and inflammation, the goal of this study was to assess whether the presence of HLA-B*35 contributes to those characteristics. Methods: PBMCs were purified from healthy controls (n = 49 HC) and lcSSc patients, (n = 44 with PAH, n = 53 without PAH). PBMCs from each group were stratified for the presence of HLA-B*35. Global changes in gene expression in response to HLA-B*35, HLA-B*8 or empty lentivirus were investigated by microarray analysis in HC PBMCs. Total RNA was extracted and qPCR was performed to measure gene expression. Results: ER stress markers, in particular the chaperones BiP and DNAJB1 were significantly elevated in PBMC samples carrying the HLA-B*35 allele. IL-6 expression was also significantly increased in HLA-B*35 lcSSc PBMCs and positively correlated with ER stress markers. Likewise, HMGB1 was increased in HLA-B*35-positive lcSSc PBMCs. Global gene expression analysis was used to further probe the role of HLA-B*35. Among genes downregulated by HLA-B*35 lentivirus were genes related to complement (C1QB, C1QC), cell cycle (CDNK1A) and apoptosis (Bax, Gadd45). Interestingly, complement genes (C1QC and C1QB) showed elevated expression in lcSSc without PAH, but were expressed at the low levels in lcSSc-PAH. The presence of HLA-B*35 correlated with the decreased expression of the complement genes. Furthermore, HLA-B*35 correlated with decreased expression of cyclin inhibitors (p21, p57) and pro-apoptotic genes (Bax, Gadd45) in lcSSc B35 subjects. FYN, a tyrosine kinase involved in proliferation of immune cells, was among the genes that were positively regulated by HLA-B*35. HLA-B*35 correlated with increased levels of FYN in lcSSc PBMCs. Conclusions: Our study demonstrates that HLA-B*35 contributes to the dysregulated expression of selected ER stress, inflammation and proliferation related genes in lcSSc patient PBMCs, as well as healthy individuals, thus supporting a pathogenic role of HLA-B*35 in the development of PAH in SSc patients.
Nature Reviews Disease Primers, 2015
Journal of the American Society of Nephrology
ABSTRACT. Smad7, a protein induced by transforming growth factor–β1 (TGF-β1) in many target cells... more ABSTRACT. Smad7, a protein induced by transforming growth factor–β1 (TGF-β1) in many target cells, inhibits TGF-β1 signal transduction and is thought to mediate an intracellular negative feedback response that limits TGF-β1 effects. It is possible that overexpression of Smad7 could block specified effects of TGF-β1 on mesangial cells, a TGF-β target in glomerular disease. Smad7 mRNA was induced by TGF-β1 within 1 h in a concentration-dependent manner in a transformed mouse mesangial cell (MMC) line. Uptake of 14C-spermidine from the medium by MMC and the transcriptional activity of a segment of the human collagen pro-α2 type 1 chain (COL1A2) promoter fused to a luciferase reporter gene were used as indices of TGF-β1. Treatment with TGF-β1 increased 14C-spermidine uptake rate in a time-, concentration-, and temperature-dependent manner. For example, exposure to 1 ng/ml TGF-β1 for 15 h increased uptake approximately twofold, a response that was attenuated by cycloheximide. Transfectio...
American Journal of Physiology-Gastrointestinal and Liver Physiology
Clinical studies and in vitro data from isolated parietal cells suggest that acute Helicobacter p... more Clinical studies and in vitro data from isolated parietal cells suggest that acute Helicobacter pylori infection inhibits acid secretion. Gastric acidification is mediated by H+-K+-ATPase, an integral protein of parietal cell apical membranes. To test the hypothesis that H. pyloridownregulates H+-K+-ATPase α-subunit (HKα) gene expression and to identify potential intracellular signaling pathways mediating such regulation, we transfected human gastric adenocarcinoma (AGS) cells with human and rat HKα 5′-flanking DNA fused to a luciferase reporter plasmid. Histamine caused dose-dependent, cimetidine-sensitive (10−4M) increases in cAMP, free intracellular Ca2+, and HKα promoter activation in AGS cells. H. pylori infection of transfected AGS cells dose dependently inhibited basal and histamine-stimulated HKα promoter activity by 80% and 66%, respectively. H. pylori dose dependently inhibited phorbol myristate acetate-induced (10−7 M) and staurosporine- (10−7 M) and calphostin C-sensitiv...
Arthritis research & therapy, Jan 7, 2018
Friend leukemia virus integration 1 (Fli1) deficiency, a predisposing factor of systemic sclerosi... more Friend leukemia virus integration 1 (Fli1) deficiency, a predisposing factor of systemic sclerosis (SSc), induces SSc-like phenotypes in various cell types. A recent study demonstrated the transdifferentiation of T helper type 2 cell (Th2)-like regulatory T cells (Tregs) in SSc lesional skin through interleukin (IL)-33 produced by fibroblasts. Therefore, we investigated the role of Fli1 deficiency in dermal fibroblast-mediated transdifferentiation of Tregs. Cytokine expression was assessed in Tregs by flow cytometry and in skin samples and cultivated cells by immunostaining, immunoblotting, and/or qRT-PCR. Fli1 binding to the target gene promoters was examined by chromatin immunoprecipitation. Murine dermal fibroblasts and Tregs were cocultured with or without blocking antibodies against target cytokines. Th2- and Th17-like cell proportions in skin-homing Tregs were increased in bleomycin-treated Fli1 mice compared with bleomycin-treated wild-type mice, whereas Th1-, Th2-, and Th17-...
The Journal of investigative dermatology, 2017
Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment option... more Systemic sclerosis (scleroderma, SSc) is a devastating fibrotic disease with few treatment options. Fumaric acid esters, including dimethyl fumarate (DMF, Tecfidera®) have shown therapeutic effects in several disease models, prompting us to determine whether DMF is effective as a treatment for SSc dermal fibrosis. We found that DMF blocks the pro-fibrotic effects of TGFβ in SSc skin fibroblasts. Mechanistically, we found that DMF treatment reduced nuclear localization of TAZ and YAP proteins via inhibition of PI3-K/Akt1 pathway. In addition, DMF abrogated TGFβ/Akt1-mediated inhibitory phosphorylation of GSK3β and a subsequent βTRCP-mediated proteasomal degradation of TAZ, as well as a corresponding decrease of TAZ/YAP transcriptional targets. Depletion of TAZ/YAP recapitulated the anti-fibrotic effects of DMF. We also confirmed the increase of TAZ/YAP in skin biopsies from patients with diffuse SSc. We further showed that DMF significantly diminished nuclear TAZ/YAP localization in ...
The Journal of experimental medicine, Jan 3, 2017
Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disorder characterized by v... more Systemic sclerosis (SSc), or scleroderma, is a multisystem autoimmune disorder characterized by vasculopathy and fibrosis in the skin and internal organs, most frequently in the esophagus and lungs. Hitherto, studies on SSc pathogenesis centered on immune cells, vascular cells, and fibroblasts. Although dysregulated keratinocytes in SSc have been recently reported, the contribution of epithelial cells to pathogenesis remains unexplored. In this study, we demonstrated the induction of SSc-like molecular phenotype in keratinocytes by gene silencing of transcription factor Friend leukemia virus integration 1 (Fli1), the deficiency of which is implicated in SSc pathogenesis. Keratin 14-expressing epithelial cell-specific Fli1 knockout mice spontaneously developed dermal and esophageal fibrosis with epithelial activation. Furthermore, they developed remarkable autoimmunity with interstitial lung disease derived from thymic defects with down-regulation of autoimmune regulator (Aire). Impo...
Journal of Investigative Dermatology, 2017
Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensiv... more Systemic sclerosis (SSc) is a multisystem inflammatory and vascular disease resulting in extensive tissue fibrosis. Glycyrrhizin, clinically used for chronic hepatic diseases and itching dermatitis, modulates the pathological processes of inflammation, vasculopathy, and fibrosis in human diseases and their animal models. Therefore, we investigated a potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis, with bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-β signaling in dermal fibroblasts through the down-regulation of thrombospondin 1, a latent transforming growth factor-β receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. These results indicate that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition and improves endothelial Fli1 deficiency-dependent vascular disintegrity, implying its potential as a disease-modifying drug for SSc.
PloS one, 2016
Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an im... more Carcinoma associated fibroblasts (CAFs) form the main constituents of tumor stroma and play an important role in tumor growth and invasion. The presence of CAFs is a strong predictor of poor prognosis of head and neck squamous cell carcinoma. Despite significant progress in determining the role of CAFs in tumor progression, the mechanisms contributing to their activation remain poorly characterized, in part due to fibroblast heterogeneity and the scarcity of reliable fibroblast surface markers. To search for such markers in oral squamous cell carcinoma (OSCC), we applied a novel approach that uses RNA-sequencing data derived from the cancer genome atlas (TCGA). Specifically, our strategy allowed for an unbiased identification of genes whose expression was closely associated with a set of bona fide stroma-specific transcripts, namely the interstitial collagens COL1A1, COL1A2, and COL3A1. Among the top hits were genes involved in cellular matrix remodeling and tumor invasion and migra...
American Journal of Respiratory Cell and Molecular Biology, 2017
Endothelial cell (EC) activation underlies many vascular diseases, including pulmonary arterial h... more Endothelial cell (EC) activation underlies many vascular diseases, including pulmonary arterial hypertension (PAH). Several members of the E-twenty six (ETS) family of transcription factors are important regulators of the gene network governing endothelial homeostasis, and their aberrant expression is associated with pathological angiogenesis. The goal of this study was to determine whether deficiencies of the ETS family member FLI1 and its closest homolog ERG are associated with PAH. We found that endothelial ERG was significantly reduced in the lung samples from patients with PAH, as well as in chronically hypoxic mice. Functional studies revealed that depletion of ERG or FLI1 in human pulmonary ECs led to increased expression of inflammatory genes, including interferon genes, whereas genes regulating endothelial homeostasis and cell-cell adhesion were downregulated. Simultaneous knockdown of both ERG and FLI1 had synergistic or additive effects on the expression of these genes, suggesting that ERG and FLI1 co-regulate at least a subset of their target genes. Functionally, both ERG and FLI1 induced cell monolayer permeability with a potency similar to that of VEGF. Notably, stimulation of ECs with Toll-like receptor 3 (TLR3) ligand Poly(I:C) suppressed ERG expression and induced ERG dissociation from the IFNB1 promoter, while promoting STAT1 recruitment. Consistent with the upregulation of inflammatory genes seen in vitro, Erg and Fli1 double heterozygote mice showed increased immune cell infiltration and expression of cytokines in the lung. In conclusion, loss of ERG and FLI1 might contribute to the pathogenesis of vascular lung complications through the induction of inflammation.
Scientific Reports, 2017
Pulmonary arterial hypertension (PAH) is a fatal condition for which there is no cure. Dimethyl F... more Pulmonary arterial hypertension (PAH) is a fatal condition for which there is no cure. Dimethyl Fumarate (DMF) is an FDA approved anti-oxidative and anti-inflammatory agent with a favorable safety record. The goal of this study was to assess the effectiveness of DMF as a therapy for PAH using patient-derived cells and murine models. We show that DMF treatment is effective in reversing hemodynamic changes, reducing inflammation, oxidative damage, and fibrosis in the experimental models of PAH and lung fibrosis. Our findings indicate that effects of DMF are facilitated by inhibiting pro-inflammatory NFκB, STAT3 and cJUN signaling, as well as βTRCP-dependent degradation of the pro-fibrogenic mediators Sp1, TAZ and β-catenin. These results provide a novel insight into the mechanism of its action. Collectively, preclinical results demonstrate beneficial effects of DMF on key molecular pathways contributing to PAH, and support its testing in PAH treatment in patients. Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by vasoconstriction and vascular remodeling of pre-capillary pulmonary arterioles, leading to vascular rarefaction and remodeling, restriction of blood flow, increases in pulmonary arterial pressure (PAP) and pulmonary vascular resistance, and eventually right ventricular failure and death 1. One of the known PAH risk factors is a pre-existing connective tissue disease, e.g. systemic sclerosis (SSc). SSc is characterized by autoimmunity, vasculopathy and fibrosis causing damage in multiple organ systems. Patients with SSc and PAH (SSc-PAH) have a poorer response to treatment and a worse prognosis (greater mortality) than other subgroups of PAH. Systemic vasculopathy and chronic inflammation are likely factors contributing to the more severe PAH disease manifestation in those patients 2. The pathological processes underpinning vascular remodeling in PAH are complex and involve interactions between different cell types within the vascular wall with further contributions from the immune and circulating progenitor cells. In response to injury, pulmonary endothelial cells (ECs) undergo phenotypic alterations resulting in secretion of excessive amounts of numerous mediators, including growth factors mitogenic for smooth muscle cells (SMCs) and fibroblasts, as well as chemokines that attract inflammatory cells. Due to the altered paracrine signaling proliferation of SMCs in PAH is enhanced, while apoptosis is depressed resulting in muscularization of peripheral small pulmonary arteries (PAs) and increased vasoconstriction 3,4. It has also been recognized that adventitial fibroblasts play an important role in PAH not only as principal contributors to the pathological extracellular matrix (ECM) remodeling resulting in fibrosis and increased vascular stiffness, but also as mediators of vascular inflammation through the recruitment and activation of macrophages 5. The role of reactive oxygen species (ROS)-driven oxidative stress in the pathological process of vasculopathy and hypertension is well established. Excessive ROS diminishes nitric oxide (NO) bioavailability leading to increased vasoconstriction and damages the vasculature by inducing inflammation and fibrosis 6. Altered redox
J Cell Physiol, 2000
Transcription of the alpha2(I) collagen gene (COL1A2) in fibroblasts is potently induced by trans... more Transcription of the alpha2(I) collagen gene (COL1A2) in fibroblasts is potently induced by transforming growth factor-beta (TGF-beta). Smad family proteins function as intracellular signal transducers for TGF-beta that convey information from the cell membrane to the nucleus. In the present study, we establish the functional requirement for endogenous Smad3 and Smad4 in TGF-beta-stimulated COL1A2 transcription in human skin fibroblasts in vitro. Furthermore, using transfections with a series of 5' deletions of the human COL1A2 promoter, we identify a proximal region between -353 and -148 bp, which is required for full stimulation of transcription by a constitutively active TGF-beta type I receptor. This region of the COL1A2 promoter contains a CAGA motif also found in the promoter of the plasminogen activator inhibitor-1. Substitutions disrupting this sequence decreased the binding of nuclear extracts or recombinant Smad3 to the CAGACA oligonucleotide, and markedly reduced the transcriptional response to TGF-beta or overexpressed Smad3 in transient transfection assays. The insertion of tandem repeats of CAGACA conferred TGF-beta stimulation to a heterologous minimal promoter-reporter construct. Inhibition of endogenous Smad expression in fibroblasts by antisense oligonucleotides or cDNA against Smad3 or Smad4, and transfection of COL1A2 promoter constructs into Smad4-deficient breast adenocarcinoma cells, indicated the critical role of Smads for the full TGF-beta response. The importance of Smad binding to the CAGACA box of COL1A2 was further established by transcriptional decoy oligonucleotide competition. Taken together, the results identify a functional Smad-binding element of the COL1A2 promoter harboring a CAGACA consensus sequence that is both necessary and sufficient for stimulation by TGF-beta, and demonstrate that interaction of this Smad-binding element with endogenous Smads is required for the full TGF-beta response in fibroblasts.
Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective ... more Transforming growth factor-beta (TGF-beta) is an important regulator of physiological connective tissue biosynthesis and plays a central role in pathological tissue fibrosis. Previous studies have established that a biologically active lipid mediator, sphingosine 1-phosphate (S1P), mimics some of the profibrotic functions of TGF-beta through cross-activation of Smad signaling. Here we report that another product of sphingosine kinase, dihydrosphingosine 1-phosphate (dhS1P), has an opposite role in the regulation of TGF-beta signaling. In contrast to S1P, dhS1P inhibits TGF-beta-induced Smad2/3 phosphorylation and up-regulation of collagen synthesis. The effects of dhS1P require a lipid phosphatase, PTEN, a key modulator of cell growth and survival. dhS1P stimulates phosphorylation of the C-terminal domain of PTEN and its subsequent translocation into the nucleus. We demonstrate a novel function of nuclear PTEN as a co-factor of the Smad2/3 phosphatase, PPM1A. Complex formation of PTEN with PPM1A does not require the lipid phosphatase activity but depends on phosphorylation of the serine/threonine residues located in the C-terminal domain of PTEN. Upon complex formation with PTEN, PPM1A is protected from degradation induced by the TGF-beta signaling. Consequently, overexpression of PTEN abrogates TGF-beta-induced Smad2/3 phosphorylation. This study establishes a novel role for nuclear PTEN in the stabilization of PPM1A. PTEN-mediated cross-talk between the sphingolipid and TGF-beta signaling pathways may play an important role in physiological and pathological TGF-beta signaling.
Molecular and Cellular Biology, 2009
J Cell Physiol, 1990
Platelet-derived growth factor (PDGF) and transforming growth factor P (TGF-P), potent modulators... more Platelet-derived growth factor (PDGF) and transforming growth factor P (TGF-P), potent modulators of mesenchymal cell growth and differentiation, are often colocalizable in vivo. Previous in vitro studies in fibroblastic cell lines have shown variable, even antagonistic effects of TGF-P on the mitogenic action of PDGF. This study demonstrates that in diploid human dermal fibroblasts, TGF-PI i s weakly mitogenic in the absence of serum or purified growth factors, and that TGF-P, potentiates DNA synthesis in PDGF-stimulated fibroblasts with delayed kinetics when compared to stimulation with PDGF alone. TGF-P1 enhances mitogenic potency of all three PDGF isoforms and increases receptor binding of both 1251 PDGF-AA and 1251 PDGF-BB, consistent with the increased expression of the a type PDGF receptor. The induction of PDGF a receptor subunits by TGF-P may play a role in enhancing the proliferative potential of human fibroblasts in certain physiologic and pathologic conditions.
J Dermatological Sci, 1995
Current Opinion in Rheumatology, Nov 1, 2004
Systemic sclerosis is a complex disease manifesting itself by fibrosis of skin and other internal... more Systemic sclerosis is a complex disease manifesting itself by fibrosis of skin and other internal organs. Fibroblasts isolated from scleroderma lesions and cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix proteins, consistent with the disease phenotype. Cultured systemic sclerosis fibroblasts therefore serve as a principal experimental model for studying the molecular and cellular mechanisms involved in collagen overproduction in this disease. This review will discuss recent findings related to intracellular signal transduction pathways implicated in deregulated extracellular matrix deposition by systemic sclerosis fibroblasts. Recent findings suggest that constitutively elevated synthesis of extracellular matrix by cultured systemic sclerosis fibroblasts is, at least in part, due to the aberrant activation of the autocrine transforming growth factor-beta signaling. Enhanced constitutive transforming growth factor-beta signaling may result from the elevated levels of transforming growth factor-beta receptor type I and/or inappropriate activation of Smad3. These alterations of the transforming growth factor-beta signaling in systemic sclerosis fibroblasts may facilitate increased collagen production in vivo even under conditions of low ligand availability. However, there exist many inconsistencies among published reports regarding the detailed mechanisms of this pathway in systemic sclerosis fibroblasts, and additional studies in this area are needed. Other signaling molecules implicated in fibrotic phenotype include several members of the protein kinase C family, mammalian target of rapamycin, mitogen-activated protein kinase, necdin, reactive oxygen species, and sphingolipids. These signaling pathways may work in conjunction with transforming growth factor-beta signaling to regulate the behavior of systemic sclerosis fibroblasts. Alterations in multiple signaling pathways contribute to elevated extracellular matrix synthesis by systemic sclerosis fibroblasts. Improved understanding of the key signaling molecules may provide a novel avenue for therapeutic interventions.
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Papers by Maria Trojanowska