Treatment Of Systemic Sclerosis Research Articles

Systemic Sclerosis: A Case Report and Review of Current Advances in Treatment

Systemic sclerosis (SSc) is a chronic multisystem disease characterized by excess deposition of connective tissue in skin and internal organs, associated with microvasculature changes and immunologic abnormalities.
 We hereby report a case of scleroderma in a 52 year old female with classical clinical and histopathological findings. The latter part of this article discusses and reviews existing and novel emerging therapies for the treatment of SSc, with an emphasis on recent trials targeting the cutaneous and pulmonary manifestations of this disease.

Hematopoietic Cell Transplantation for Systemic Sclerosis-A Review.

Systemic sclerosis (SSc) is an autoimmune, multi-organ, connective tissue disease associated with significant morbidity and mortality. Conventional immunosuppressive therapies demonstrate limited efficacy. Autologous hematopoietic stem cell transplantation (HCT) is more efficacious but carries associated risks, including treatment-related mortality. Here, we review HCT as a treatment for SSc, its efficacy and toxicity in comparison to conventional therapies, and the proposed mechanisms of action. Furthermore, we discuss the importance of and recent developments in patient selection. Finally, we highlight the knowledge gaps and future work required to further improve patient outcomes.

Is heart-type fatty acid binding protein (H-FABP) a valid marker of arterial stiffness in patients with systemic sclerosis?

Background/Aim: Both micro- and macro-vascular involvement has been researched in systemic sclerosis (SSc) for many years. In this study, the relationship of arterial stiffness with heart-type fatty acid binding protein (h-FABP), which is well-accepted as a cardiac marker, was investigated for the first time.
 Methods: In this case-control study, 40 patients diagnosed with SSc between the ages of 18 and 65 were included. Thirty healthy individuals of similar age and gender were included as the control group. Patients were excluded from the study if they had cardiovascular risk factors, active infections, and/or malignancies. Along with detecting biochemical markers in the blood, results from methods, such as 24-h blood pressure Holter recordings, pulse-wave velocities (PWV), and echocardiograms (ECHO) were obtained from patients.
 Results: The homocysteine mean level was higher in the patient group than in the control group (P < 0.001). H-FABP and asymmetric dimethylarginine (ADMA) means were similar between the two groups (P = 0.286 and P = 0.340, respectively). Vascular parameters, including mean arterial pressure (MAP), augmentation index normalized to the 75 /min heart rate (AIx @ 75), and PWV were also similar between the two groups (P = 0.498, P = 0.382 and P = 0.180, respectively).
 Conclusion: It can be concluded that no ongoing myocardial damage occurs based on normotensive Holter findings, normal h-FABP levels, and ECHO findings in our patients. It is suggested that vasodilatory treatments, such as pentoxifylline and calcium channel blockers, which the patients receive for SSc treatment due to Raynaud Syndrome, may protect them from hypertension and therefore offer protection from myocardial damage.

MiR-27a as a diagnostic biomarker and potential therapeutic target in systemic sclerosis

Systemic sclerosis (SSc) or scleroderma is a multiorgan rheumatoid disease characterized by skin tightening or organ dysfunction due to fibrosis, vascular damage, and autoimmunity. No specific cause has been discovered for this illness, and hence no effective treatment exists for it. On the other hand, due to the lack of diagnostic biomarkers capable of effectively and specifically differentiating the patients, early diagnosis has not been possible. Due to their potent regulatory roles in molecular pathways, microRNAs are among the novel candidates for the diagnosis and treatment of diseases like SSc. MiR-27a is a microRNA known for its role in the pathogenesis of fibrosis and cancer, both of which employ similar signaling pathways; hence we hypothesized that Mir-27a could be dysregulated in the blood of individuals affected by SSc and it might be useful in the diagnosis or treatment of this disease. Blood was collected from 60 SSc patients (30 limited and 30 diffuse) diagnosed by a rheumatologist according to ACR/AULAR criteria; following RNA isolation and cDNA synthesis; real-time qPCR was performed on the samples using Taq-Man probes and data were analyzed by the ΔΔCT method. Also, potential targets of miR-27a were evaluated using bioinformatics. It was revealed that miR-27a was significantly down-regulated in SSc patients in comparison to healthy individuals, but there was no difference in miR-27 expression between limited and diffused SSc patients. Besides, miR-27a was found to target several contributing factors to SSc. It seems that miR-27a has a protective role in SSc, and its downregulation could result in the disease's onset. Based on bioinformatics analyses, it is speculated that miR-27a likely targets factors contributing to the pathogenesis of SSc, which are elevated upon the downregulation of miR-27a; hence, miR-27a mimics could be considered as potential therapeutic agents for the treatment of SSc in future studies. Since no difference was observed between limited and diffuse patient groups, it is unlikely that this microRNA has a role in disease progression. According to ROC analysis of qPCR data, miR-27a could be employed as a valuable diagnostic biomarker for SSc.

Presence of autoantibodies and epidemiological characteristics of systemic sclerosis patients in western Paraná

Systemic sclerosis (SSc) is a systemic autoimmune disease of the connective tissue with unknown etiology, characterized by abnormal collagen deposition in the skin. The changes in patients result in the obliteration of microvessels and fibrosis, leading to damage to the skin, gastrointestinal tract, kidneys, lungs, heart, and oral cavity. Brazil has insufficient data about the epidemiological and laboratory aspects of SSc. This study aimed to identify and characterize the patients in treatment for SSc in Cascavel/PR, a city in the south of Brazil. Data were collected from March 2019 to September 2020 from all health services of Cascavel that provide care in rheumatology: a university-affiliated hospital, two public outpatient clinics, and six private clinics. Data about age, sex, residence, time to diagnosis, the form of the disease, and the results of tests for antinuclear (ANA) and anti-extractable nuclear antigens (ENA) antibodies were obtained. The study identified 57 patients; 82.5% were female with a mean age of 50.4 years, and the predominant disease form was diffuse (52.6%). The ANA test was positive in 87.7% of the patients, of which 49.2% showed high titers and a predominance of the centromeric pattern. Anti-Scl-70, anti-centromere (ACA), and anti-RNA polymerase III antibodies were positive in 28.1%, 25%, and 5% of the patients. The characteristics of the patients diagnosed with SSc in Cascavel/PR are similar to those reported in the literature. This study contributed to the scarce Brazilian data about the disease.

A BENEFICIAL EFFECT OF LONG-TERM TREATMENT OF RITUXIMAB IN INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS

A BENEFICIAL EFFECT OF LONG-TERM TREATMENT OF RITUXIMAB IN INTERSTITIAL LUNG DISEASE ASSOCIATED WITH SYSTEMIC SCLEROSIS

New Era in Systemic Sclerosis Treatment: Recently Approved Therapeutics.

Systemic sclerosis (SSc) is a chronic autoimmune disease with a poor prognosis. Among the various complications of SSc, treatment options for the fibrotic lesions, skin sclerosis, and SSc-associated interstitial lung disease (SSc-ILD) have been limited. However, since 2019, the efficacy and safety of nintedanib, tocilizumab, and rituximab for SSc or SSc-ILD have been demonstrated in double-blind, randomized, placebo-controlled trials, respectively. The antifibrotic agent nintedanib was approved for SSc-ILD in all regions of the United States, Europe, and Japan after the SENSCIS study confirmed that it suppressed the reduction in forced vital capacity (FVC), a measure of SSc-ILD. Tocilizumab, an anti-interleukin-6 receptor antibody, was approved for the treatment of SSc-ILD in the United States after the FocuSSced study showed that it inhibited the decrease in FVC. Rituximab, an anti-CD20 antibody, showed improvement in both modified Rodnan skin score, a measure of skin sclerosis, and FVC in the DESIRES study, and was approved in Japan for the treatment of SSc itself. With the development of these three drugs, SSc treatment is entering a new era. This paper outlines the latest advances in SSc therapeutics, focusing on nintedanib, tocilizumab, and rituximab.

Recommendations for diagnosis and treatment of systemic sclerosis in China

Systemic sclerosis (SSc) is an autoimmune rheumatic disease that is characterized by skin fibrosis with multi-organ involvement. In China, the standardized diagnosis and treatment for SSc is still lacking. Based on the diagnosis criteria and guidelines from China and abroad, Chinese Rheumatology Association developed the current standardization of diagnosis and treatment for SSc. The purposes of this guideline are to standardize clinical management for SSc in China, to interpret the key evaluation tools for SSc, and to recommend therapeutic principle and strategies.

Single-cell sequencing reveals the antifibrotic effects of YAP/TAZ in systemic sclerosis

Systemic sclerosis (SSc) is a heterogeneous disease with skin fibrosis. Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is associated with fibrotic response. This work attempted to determine the precise mechanism of YAP/TAZ in SSc. Single-cell sequencing (scRNA-seq) was used to analyse the differential gene expression between SSc patients and healthy volunteers, showing that the YAP/TAZ signalling pathway was enriched in the fibroblasts of SSc patients. Subsequently, enzyme-linked immunosorbent assay and immunohistochemical analyses were conducted to examine the levels of YAP and TAZ in mild and severe SSc patients. YAP and TAZ were highly expressed in the serum and skin tissues of mild and severe SSc patients, especially severe SSc patients. Additionally, an SSc mouse model was induced by bleomycin, and the impacts of YAP/TAZ knockdown on the pathological changes in skin and lung tissues were detected by haematoxylin and eosin staining and Masson staining. Knockdown of YAP and TAZ inhibited α-SMA mRNA and protein expression in skin and lung tissues of SSc mice. Inhibition of YAP and TAZ reduced skin inflammation and thickness and repressed lung inflammation and fibrosis in SSc mice. Importantly, knockdown of YAP and TAZ synergistically inhibited inflammation and fibrosis in skin and lung tissues in SSc mice. In conclusion, this work demonstrated that knockdown of YAP and TAZ exerted a synergistic effect on alleviating SSc in mice. Thus, this work suggests that YAP/TAZ is a potential target for SSc treatment.

Stem cell transplantation for systemic sclerosis.

Stem cell transplantation for systemic sclerosis.

Wenyang Huazhuo Tongluo formula alleviates pulmonary vascular injury and downregulates HIF-1α in bleomycin-induced systemic sclerosis mouse model

BackgroundVascular damage, autoimmune abnormalities, and fibrosis are the three pathological features of systemic sclerosis (SSc).However, pulmonary vascular damage is the main factor affecting the progression and prognosis of SSc. The main purpose of this study was to explore the molecular mechanism of Wenyang Huazhuo Tongluo Formula in alleviating pulmonary vascular injury in bleomycin-induced SSc mouse model.MethodsMasson staining and H&E staining were used to analyze the degree of pulmonary vascular fibrosis and the infiltration of leukocyte cells in lung tissue ofbleomycin-induced SSc mouse models treated with saline (BLM group), Wenyang Huazhuo Tongluo Formula (WYHZTL group) and HIF-1α inhibitor KC7F2 (KC7F2 group). Blood vessel exudation was determined by analyzing the cell number and albumin concentration in bronchoalveolar lavage fluid using a cell counter and ELISA assay, respectively. The degree of vascular injury was assessed by measuring the expression levels of vWF, E-selectin, ICAM-1, VCAM-1, VE-cadherin and claudin-5 in serum and pulmonary vascular endothelial cells using ELISA and immunofluorescence staining. Finally, the effect of Wenyang Huazhuo Tongluo Formula on the expression of HIF-1α was detected using immunofluorescence staining.ResultsWenyang Huazhuo Tongluo Formula and KC7F2 significantly inhibited bleomycin-induced pulmonary vascular fibrosis and the level of perivascular inflammatory cell infiltration. The number of cells and the concentration of albumin were significantly reduced in the bronchoalveolar lavage fluid of the WYHZTL group and KC7F2 group compared with the BLM group. In addition, treatment with Wenyang Huazhuo Tongluo Formula and KC7F2 significantly downregulated the expression levels of vWF, E-selectin, ICAM-1, VCAM-1 and HIF-1α, but upregulated the expression of VE-cadherin and claudin-5 in serum and pulmonary vascular endothelial cells, compared with treatment with saline.ConclusionsThis study reveals that Wenyang Huazhuo Tongluo Formula plays a new role in the treatment of SSc by alleviating pulmonary vascular damage. Furthermore, we found that Wenyang Huazhuo Tongluo Formula alleviates pulmonary vascular injury and inhibits HIF-1α expression.

Sphingosine 1-phosphate receptor-targeted therapeutics in rheumatic diseases.

Sphingosine 1-phosphate (S1P), which acts via G protein-coupled S1P receptors (S1PRs), is a bioactive lipid essential for vascular integrity and lymphocyte trafficking. The S1P-S1PR signalling axis is a key component of the inflammatory response in autoimmune rheumatic diseases. Several drugs that target S1PRs have been approved for the treatment of multiple sclerosis and inflammatory bowel disease and are under clinical testing for patients with systemic lupus erythematosus (SLE). Preclinical studies support the hypothesis that targeting the S1P-S1PR axis would be beneficial to patients with SLE, rheumatoid arthritis (RA) and systemic sclerosis (SSc) by reducing pathological inflammation. Whereas most preclinical research and development efforts are focused on reducing lymphocyte trafficking, protective effects of circulating S1P on endothelial S1PRs, which maintain the vascular barrier and enable blood circulation while dampening leukocyte extravasation, have been largely overlooked. In this Review, we take a holistic view of S1P-S1PR signalling in lymphocyte and vascular pathobiology. We focus on the potential of S1PR modulators for the treatment of SLE, RA and SSc and summarize the rationale, pathobiology and evidence from preclinical models and clinical studies. Improved understanding of S1P pathobiology in autoimmune rheumatic diseases and S1PR therapeutic modulation is anticipated to lead to efficacious and safer management of these diseases.

Involvement of Multiple Variants of Soluble CD146 in Systemic Sclerosis: Identification of a Novel Profibrotic Factor.

Systemic sclerosis (SSc) is an autoimmune disorder characterized by excessive fibrosis, immune dysfunction, and vascular damage, in which the expression of many growth factors is deregulated. CD146 was recently described as a major actor in SSc. Since CD146 also exists as a circulating soluble form (sCD146) that acts as a growth factor in numerous angiogenic- and inflammation-related pathologies, we sought to identify the mechanisms underlying the generation of sCD146 and to characterize the regulation and functions of the different variants identified in SSc. We performed in vitro experiments, including RNA-Seq and antibody arrays, and in vivo experiments using animal models of bleomycin-induced SSc and hind limb ischemia. Multiple forms of sCD146, generated by both shedding and alternative splicing of the primary transcript, were discovered. The shed form of sCD146 was generated from the cleavage of both long and short membrane isoforms of CD146 through ADAM-10 and TACE metalloproteinases, respectively. In addition, 2 novel sCD146 splice variants, I5-13-sCD146 and I10-sCD146, were identified. Of interest, I5-13-sCD146 was significantly increased in the sera of SSc patients (P < 0.001; n = 117), in particular in patients with pulmonary fibrosis (P < 0.01; n = 112), whereas I10-sCD146 was decreased (P < 0.05; n = 117). Further experiments revealed that shed sCD146 and I10-sCD146 displayed proangiogenic activity through the focal adhesion kinase and protein kinase Cε signaling pathways, respectively, whereas I5-13-sCD146 displayed profibrotic effects through the Wnt-1/β-catenin/WISP-1 pathway. Variants of sCD146, and in particular the novel I5-13-sCD146 splice variant, could constitute novel biomarkers and/or molecular targets for the diagnosis and treatment of SSc and other angiogenesis- or fibrosis-related disorders.

The Roles of Noncoding RNAs in Systemic Sclerosis.

Noncoding RNAs (ncRNAs) constitute more than 90% of the RNAs in the human genome. In the past decades, studies have changed our perception of ncRNAs from “junk” transcriptional products to functional regulatory molecules that mediate critical processes, including chromosomal modifications, mRNA splicing and stability, and translation, as well as key signaling pathways. Emerging evidence suggests that ncRNAs are abnormally expressed in not only cancer but also autoimmune diseases, such as systemic sclerosis (SSc), and may serve as novel biomarkers and therapeutic targets for the diagnosis and treatment of SSc. However, the functions and underlying mechanisms of ncRNAs in SSc remain incompletely understood. In this review, we discuss the current findings on the biogenetic processes and functions of ncRNAs, including microRNAs and long noncoding RNAs, as well as explore emerging ncRNA-based diagnostics and therapies for SSc.

Therapeutic Effect of Cyclin-Dependent Kinase 4/6 Inhibitor on Dermal Fibrosis in Murine Models of Systemic Sclerosis.

One of the histologic characteristics of systemic sclerosis (SSc) is an increased number of dermal myofibroblasts, and transforming growth factor β (TGFβ) plays a crucial role in the promotion of myofibroblast differentiation from fibroblasts, leading to dermal fibrosis. This study was undertaken to 1) examine whether inhibition of the cell cycle with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor suppresses the proliferation of fibroblasts and their differentiation into myofibroblasts, and 2) assess the therapeutic effects of a CDK4/6 inhibitor, administered as monotherapy or in combination with a TGFβ receptor (TGFβR) inhibitor, on dermal fibrosis in murine models of SSc. Fibroblasts obtained from the skin of patients with SSc were cultured in the presence or absence of TGFβ. The effects of palbociclib, a CDK4/6 inhibitor, on fibroblast proliferation and TGFβ-induced differentiation into myofibroblasts were examined using bromodeoxyuridine uptake assays as well as immunofluorescence and immunoblotting analyses. Murine models of HOCl- and bleomycin-induced dermal fibrosis were used to study the effect of a CDK4/6 inhibitor on dermal fibrosis, with the CDK4/6 inhibitor treatment administered as monotherapy or in combination with galunisertib, a TGFβR inhibitor. Addition of a CDK4/6 inhibitor to the cell cultures suppressed the proliferation of human dermal SSc fibroblasts and their TGFβ-induced differentiation into myofibroblasts, without inhibiting canonical and noncanonical TGFβ signals. In murine models of dermal fibrosis, treatment of mice with a CDK4/6 inhibitor decreased dermal thickness and collagen content, as well as dermal fibroblast proliferation and the numbers of myofibroblasts. Combination therapy with the CDK4/6 inhibitor and TGFβR inhibitor resulted in additive antifibrotic effects. Mechanistically, the CDK4/6 inhibitor suppressed the expression of cellular communication network 2 and cadherin-11, which are proteins that have important roles in the development and progression of fibrosis. Results of this study demonstrate the therapeutic effect of a CDK4/6 inhibitor on dermal fibrosis when administered as monotherapy or in combination with a TGFβR inhibitor. CDK4/6 inhibitors, including palbociclib used in the present study, may represent novel agents for the treatment of SSc, which, if used in combination with a TGFβR inhibitor, might result in increased efficacy.

Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review.

Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.

MSCs-laden injectable self-healing hydrogel for systemic sclerosis treatment.

As a novel cellular therapy, the anti-inflammatory and immunomodulatory virtues of mesenchymal stem cells (MSCs) make them promising candidates for systemic sclerosis (SSc) treatment. However, the clinical efficacy of this stratagem is limited because of the short persistence time, poor survival, and engraftment of MSCs after injection in vivo. Herein, we develop a novel MSCs-laden injectable self-healing hydrogel for SSc treatment. The hydrogel is prepared using N, O-carboxymethyl chitosan (CS-CM) and 4-armed benzaldehyde-terminated polyethylene glycol (PEG-BA) as the main components, imparting with self-healing capacity via the reversible Schiff-base connection between the amino and benzaldehyde groups. We demonstrate that the hydrogel laden with MSCs not only promoted the proliferation of MSCs and increased the cellular half-life in vivo, but also improve their immune-modulating functions. The tube formation assay indicates that the MSCs could significantly promote angiopoiesis. Moreover, the MSCs-laden hydrogel could inhibit fibrosis by modulating the synthesis of collagen and ameliorate disease progression in SSc disease model mice after subcutaneous injection of bleomycin. All these results highlight this novel MSCs-laden hydrogel and its distinctive functions in treatment of chronic SSc, indicating the additional potential to be used widely in the clinic.

Mesenchymal Stem Cell-Based Therapy as a New Approach for the Treatment of Systemic Sclerosis.

Systemic sclerosis (SSc) is an intractable autoimmune disease with unmet medical needs. Conventional immunosuppressive therapies have modest efficacy and obvious side effects. Targeted therapies with small molecules and antibodies remain under investigation in small pilot studies. The major breakthrough was the development of autologous haematopoietic stem cell transplantation (AHSCT) to treat refractory SSc with rapidly progressive internal organ involvement. However, AHSCT is contraindicated in patients with advanced visceral involvement. Mesenchymal stem cells (MSCs) which are characterized by immunosuppressive, antifibrotic and proangiogenic capabilities may be a promising alternative option for the treatment of SSc. Multiple preclinical and clinical studies on the use of MSCs to treat SSc are underway. However, there are several unresolved limitations and safety concerns of MSC transplantation, such as immune rejections and risks of tumour formation, respectively. Since the major therapeutic potential of MSCs has been ascribed to their paracrine signalling, the use of MSC-derived extracellular vesicles (EVs)/secretomes/exosomes as a "cell-free" therapy might be an alternative option to circumvent the limitations of MSC-based therapies. In the present review, we overview the current knowledge regarding the therapeutic efficacy of MSCs in SSc, focusing on progresses reported in preclinical and clinical studies using MSCs, as well as challenges and future directions of MSC transplantation as a treatment option for patients with SSc.

Problems to Consider Before Determining the Regimen of the Treatment for Juvenile Systemic Sclerosis Treatment: A Case Report Where Tocilizumab Monotherapy Succeeded Efficiently and Safely.

Juvenile systemic sclerosis (SSc) is a rare condition that results in various disorders, including growth retardation and learning disabilities in addition to impaired quality of life due to fibrosis and microvascular disorders in multiple organs. Recently, efficacies of immunosuppressants such as cyclophosphamide and mycophenolate mofetil, as well as biological agents, have been reported in adult patients with SSc. However, there has been no consensus in the treatment of juvenile SSc due to its rarity and the fact that skin sclerosis may be self-limiting in some patients. Here, we present a case of 13-year-onset SSc with growth retardation and learning disabilities, in addition to skin sclerosis, interstitial lung disease, and possible myocardial fibrosis that was successfully treated with tocilizumab monotherapy without remarkable adverse reactions. As careful case-by-case management of patient’s growth and education along with standard treatment is needed, the documentation of such case is important for the evaluation of the efficient and safe therapy for juvenile SSc.

Therapeutic effects of adipose-derived mesenchymal stem/stromal cells with enhanced migration ability and hepatocyte growth factor secretion by low-molecular-weight heparin treatment in bleomycin-induced mouse models of systemic sclerosis

BackgroundAdipose-derived mesenchymal stem cells (ASCs) have gained attention as a new treatment for systemic sclerosis (SSc). Low-molecular-weight heparin (LMWH) enhances cell function and stimulates the production of hepatocyte growth factor (HGF) in a variety of cells. This study investigated the effects of LMWH on the functions of mouse ASCs (mASCs), and the therapeutic effects of mASCs activated with LMWH (hep-mASCs) in mouse models of SSc.MethodsThe cellular functions of mASCs cultured with different concentrations of LMWH were determined. Mice were divided into four groups: bleomycin (BLM)-induced SSc (BLM-alone), BLM-induced SSc administered with mASCs (BLM-mASC), and BLM-induced SSc administered with mASCs activated with 10 or 100 μg/mL LMWH (BLM-hep-mASC); there were 9 mice per group (n = 9). Skin inflammation and fibrosis were evaluated using histological and biochemical examinations and gene expression levels.ResultsIn vitro assays showed that migration ability and HGF production were significantly higher in hep-mASCs than in mASCs alone. The mRNA expression levels of cell migration factors were significantly upregulated in hep-mASCs compared to those in mASCs alone. The hep-mASCs accumulated in the skin tissues more than mASCs alone. The thickness of skin and hydroxyproline content in BLM-hep-mASC groups were significantly decreased, and the skin mRNA expression levels of interleukin-2, α-smooth muscle actin, transforming growth factor β1, collagen type 1 alpha 1, and tissue inhibitor of metalloproteinase 2 were significantly downregulated compared to those in the BLM-alone group.Conclusionshep-mASCs showed higher anti-inflammatory and anti-fibrotic effects than mASCs alone and may be a promising candidate for SSc treatment.