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Table 2 Preclinical Inducible Models in Studies of Systemic Sclerosis

From: Mesenchymal stem cell as a novel approach to systemic sclerosis; current status and future perspectives

Target preclinical feature Animal Models Observed Characteristics The Underlying Mechanisms of Model Designing Advantages Disadvantages References
Systemic phenotype of the disease HOCl-injected mice -skin, lung and kidney implication
-vascular abnormalities
-autoantibodies production
-↑CD4 + T-cell and B-cell in the spleen
HOCl injection→↑ROS:
-↑collagen and α-SMA production in skin
- anti-DNA topoisomerase-1 autoantibodies production→ systemic symptoms
HOCl injection→↑AOPP→ systemic fibrosis
-presenting the key features of the human disease (in three main aspects of fibrosis, inflammation and vasculopathy)
- Presenting the role of ROS and AOPPs in the pathogenesis of SSc
ND (Rozier et al. 2018; Asano and Sato 2013; Morin et al. 2015)
Skin fibrosis Vinyl Chloride Injected mice -skin and spleen fibrosis and cell infiltration
-↑IL-4 and IL-13 during a Th2 immune response
vinyl chloride injection→ activation of micro chimeric fetal cells→ cell division→ symptoms presentation -showing the role of micro chimeric fetal circulating cells and chemical exposure in the pathogenesis of SSc
-an easily reproducible model
ND (Morin et al. 2015; Storkanova and Tomcik 2017; Christner et al. 2000)
Lung fibrosis Silica-induced lung fibrosis mice - pulmonary tissue fibrosis instillation of silica→ macrophage activation→ phagocytosis of silica particles→ pro-fibrotic cytokines(PDGF, TGFβ) production→ lung fibrosis -mimicking the pulmonary phenotype of long-term exposure to silica dust(as a permanent fibrotic stimuli) -an expensive animal model
-a time consuming process
-specialized equipment requirement
-lacking the characteristics of UIP
(Storkanova and Tomcik 2017)
FITC induced lung fibrosis mice -pulmonary edema, inflammation and fibrosis FITC usage:
- binding to the protein in the lungs→ formation of a new antigen→ antibody formation
-↑mononuclear cells and neutrophils infiltration→ acute lung injury
-↑CCL12 and CCL2 → ↑CCR2 expressing fibroblasts→ pulmonary fibrosis
-fibrosis detection using green fluorescence.
-the phenotype occurs rather fast (during 14–28 days) and continues for at least 6 months.
-lacking the characteristics of UIP (Storkanova and Tomcik 2017; Chung et al. 2003)
Radiation-induced lung fibrosis mice -pulmonary tissue fibrosis Radiation→ pneumocystis I and II death→ the production of pro-inflammatory and pro-fibrotic cytokines (TGFβ, TNF-α) by macrophages→ fibrosis -presenting the characteristics of UIP. -an expensive animal model
-a time consuming process
(Storkanova and Tomcik 2017)
Lung fibrosis / Immunogenic/inflammatory features Bleomycin-Injected mice -lung and skin fibrosis
-↑type-I collagen
-Antinuclear autoantibodies production (anti-Scl-70, anti-U1-RNP, and anti-histone)
Bleomycin injection→↑ROS → endothelial cell damage and ↑adhesion molecules→ leukocytes attraction and fibroblast activation→ fibrosis -presenting some of the early inflammatory symptoms of the disease.
-useful to test the efficacy of anti-fibrotic therapeutics
-useful to assess the potential of the pro-inflammatory genes of the patient
-not presenting the typical clinical features and autoantibody patterns of the disease (Rozier et al. 2018; Morin et al. 2015; Yamamoto 2010)
Immunogenic/inflammatory features Scl-GVHD mice -fibrosis formation and chronic inflammation of the skin, lung, and gastrointestinal tract
-↑CCL2, CCL5, CCL17, IFN-γ-inducible chemokines, PDGF, CTGF, FGF, EGF, NGF, VEGF and adhesion molecules in the skin
BM and spleen cells transplantation into BALB/cJ (H-2d) mice→ the donor immune cells infiltration+ auto-reactive host T cells escape from thymic negative selection -demonstrating many clinical and histological similarities to scleroderma -ND on symptoms of vasculopathy presentation in mice while vasculopathy is one the signs of patients with Scl-GVHD (Morin et al. 2015; Yamamoto 2010)
Pulmonary atrial hypertension (PAH) chronic hypoxia+ semaxanib (SU5416)-induced PAH mice -PAH hypoxia→ pro-inflammatory cytokines secretion
-↑growth factors (FGF, PDGF) → endothelial cells proliferation→ PAH
-↑shear stress in the artery wall→ angioobliterative PAH
-exhibiting the pathophysiological role of endothelial proliferation of pulmonary artery in PAH -the hypoxia-induced PAH is slight and reversible (Storkanova and Tomcik 2017; Nicolls et al. 2012)
MCTP- induced PAH rats -PAH MCTP→ endothelium and smooth
muscle cell proliferation and mononuclear inflammatory cells infiltration→ PAH
-presenting the acute process of PAH -the induced phenotype is easily treatable that is different from PAH in human SSc (Storkanova and Tomcik 2017; Stenmark et al. 2009)
SU5416-induced PAH athymic rats -severe PAH macrophage, B cell and anti-endothelial antibodies→ pulmonary artery inflammation→ lack of regulatory T cell→ severe PAH -studying the function of T reg anti-inflammatory cells in counteracting PAH in SSc patients. ND (Storkanova and Tomcik 2017; Nicolls et al. 2012)
ETAR and AT1R antibodies injected mice - obliterative vasculopathy of pulmonary vessels
anti-ETAR and anti-AT1R injection→↑α-SMA expression and lymphocyte infiltration in perivascular areas→ obliterative vasculopathy, ↑vascular reactivity and vascular remodeling -useful to assess the roles of ETAR and AT1R antibodies in the disease pathogenesis ND (Morin et al. 2015; Becker et al. 2014)
Phenotypes caused by a particular factor topoisomerase-1+ CFA injected mice -skin and lung fibrosis
-↑IL-6, TGF-β1, IL-17 and IL-10
-Th2 and Th17 in BAL
topoisomerase-1 + CFA injection→↑Th2/Th17 immune pathway→ skin sclerosis, ILD, and ↑inflammatory cytokines -mimicking diffuse SSc symptoms
-proposing the relationship between responses to topo I and the pathogenesis of the disease.
-advantageous for studying the effects of immunosuppressive and anti-inflammatory drugs on SSc.
ND (Asano and Sato 2013; Morin et al. 2015)
Angiotensin II-Induced mice -↑collagen, CTGF, TGFβ and pSmad2 expression
-↑hydroxyproline content in skin
-↑immune cell infiltration into the skin
-↑vascular injury markers(vWF, TSP-1 and MMP-12)
-exogenous angiotensin II:
-collagen I receptor stimulation→ skin fibrosis
-the dysregulation of endothelial-to-mesenchymal transition→ activated fibroblasts production
-showing the role of the renin-angiotensin pathway in the process of fibrosis formation
-advantageous for studying the effects of anti-inflammatory drugs on SSc.
-not mimicking the auto-immune process of the human disease.
-blockage of related signaling pathway has little effect on the pathophysiology of the disease
(Asano and Sato 2013; Morin et al. 2015)
Exogenous TGFβ+ CTGF injected mice -ECM-rich skin fibrosis
TGFβ→granulation and fibrotic tissue formation
CTGF and bFGF→ sustained ↑collagen I gene expression→ fibrosis maintenance
-presenting sustained fibrosis due to the use of CTGF in combination with TGFβ ND (Yamamoto 2017)
  1. HOCl Hypochlorous Acid, CCR CC chemokine receptor, FITC Fuorescein Isothiocyanate, TNF-α Tumour Necrosis Factor Alpha, UIP Usual Interstitial Pneumonia, RNP Ribonucleoprotein, ROS Reactive Oxygen Species, CCL C-C Chemokine Ligand, IFN-γ Interferon-Gamma, NGF Nerve Growth Factor, EGF Epidermal growth factor, GVHD Graft versus host disease, VEGF Vascular Endothelial Growth Factor, FGF Fibroblast Growth Factor, PDGF Platelet-Derived Growth Factor, SU5416 Semaxanib, MCTP Monocrotaline, PAH Pulmonary Atrial Hypertension, ETAR Anti-endothelin receptor Type-A, AT1R Anti-angiotensin Receptor Type − 1, ILD Interstitial Lung Disease, IL Interleukin, CFA Complete Freund’s Adjuvant, Th T helper, pSmad2 phospho-Smad2, α-SMA Alpha-Smooth Muscle Actin, vWF von Willebrand Factor, TSP-1 Thrombospondin-1, MMP Matrix Metalloproteinases, SSc Systemic Sclerosis, ECM Extracellular Matrix, bFGF Basic Fibroblast Growth Factor, CTGF Connective Tissue Growth Factor, TGFβ Transforming Growth Factor beta, ND No Data