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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

-↑hydroxyproline

-↑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

SU5416:

-↑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

-PAH

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

-↑macrophages

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