Macrophages communicate with mesangial cells through the CXCL12/DPP4 axis in lupus nephritis pathogenesis.

Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand-receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Biochanin A: Disrupting the inflammatory vicious cycle for dry eye disease.

Dry eye disease (DED) is a complex disorder driven by several factors like reduced tear production, increased evaporation, or poor tear quality. Oxidative stress plays a key role by exacerbating the inflammatory cycle. Previous studies explored antioxidants for DED treatment due to the link between oxidative damage and inflammation. Biochanin A (BCA) is a bioisoflavone from red clover with potent anti-inflammatory effects. This study investigated BCA's therapeutic potential for DED. Human corneal epithelial cells were cultured under hyperosmotic conditions to mimic DED. BCA treatment increased cell viability and decreased apoptosis and inflammatory cytokine expression. A DED mouse model was developed using female C57BL/6 mice in a controlled low-humidity environment combined with scopolamine injections. Mice received eye drops containing phosphate-buffered saline, low-dose BCA, or high-dose BCA. The effectiveness was evaluated by measuring tear volume, fluorescein staining, eye-closing ratio, corneal sensitivity and PAS staining. The levels of inflammatory components in corneas and conjunctiva were measured to assess DED severity. Maturation of antigen-presenting cells in cervical lymph nodes was analyzed by flow cytometry. BCA eye drops effectively reduced inflammation associated with DED in mice. BCA also decreased oxidative stress levels by reducing reactive oxygen species and enhancing the nuclear translocation of nuclear factor erythroid-2-related factor 2 (Nrf2). These findings demonstrate that BCA ameliorates oxidative stress and ocular surface inflammation, indicating potential as a DED treatment by relieving oxidative damage and mitigating inflammation.

Umbilical cord mesenchymal stem cells transplantation in patients with systemic sclerosis: a 5-year follow-up study.

OBJECTIVE: To assess the long-term safety and efficacy of umbilical cord mesenchymal stem cells transplantation (UMSCT) in patients with systemic sclerosis (SSc). METHODS: Forty-one patients with moderate to severe SSc underwent UMSCT at the Affiliated Drum Tower Hospital of Nanjing University Medical School from 2009 to 2017. In this study, we conducted a longitudinal and retrospective analysis and compared the clinical and laboratory manifestations before and after UMSCT. The main outcome of the study was overall survival. We evaluated changes in the modified Rodnan Skin Score (mRSS), as well as the changes in the pulmonary examination by using high-resolution computed tomography (HRCT) and ultrasound cardiogram (UCG). Additionally, we assessed the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the severity of peripheral vascular involvement during the first year after treatment. RESULTS: The overall 5-year survival rate was 92.7% (38 out of 41 patients). Following UMSCT, the mean mRSS significantly decreased from 18.68 (SD = 7.26, n = 41) at baseline to 13.95 (SD = 8.49, n = 41), 13.29 (SD = 7.67, n = 38), and 12.39 (SD = 8.49, n = 38) at 1, 3, and 5 years, respectively. Improvement or stability in HRCT images was observed in 72.0% of interstitial lung disease (ILD) patients. Pulmonary arterial hypertension (PAH) remained stable in 5 out of 8 patients at the 5-year follow-up. No adverse events related to UMSCT were observed in any of the patients during the follow-up period. CONCLUSION: UMSCT may provide a safe and feasible treatment option for patients with moderate to severe SSc based on long-term follow-up data. The randomized controlled study will further confirm the clinical efficacy of UMSCT in SSc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00962923. Key Point • UMSCT is safe and effective for SSc patients.

Allogenic Umbilical Cord-Derived Mesenchymal Stromal Cells Sustain Long-Term Therapeutic Efficacy Compared With Low-Dose Interleukin-2 in Systemic Lupus Erythematosus.

OBJECTIVES: Mesenchymal stromal cells (MSCs) and low-dose interleukin-2 (IL-2) both have demonstrated efficacy in treating systemic lupus erythematosus (SLE). The aim of this study is to conduct a head-to-head comparison between the 2 treatments and provide insights for clinical applications. METHODS: Lupus-prone mice were treated with umbilical cord-derived MSCs (UC-MSCs), IL-2, or a combination of UC-MSCs and IL-2, respectively. The lupus-like symptoms, renal pathology, and T-cell response were assessed 1 or 4 weeks later. Modulation of IL-2 production by MSCs on immune cells was investigated by the coculture assay. Disease activity and serum IL-2 of SLE patients were determined before and after receiving UC-MSCs. RESULTS: Both UC-MSCs and IL-2 improved lupus symptoms in lupus-prone mice 1 week after treatment, while the effects of UC-MSCs lasted up to 4 weeks. Moreover, the UC-MSC-treated group showed better renal pathology improvement. Importantly, UC-MSCs combined with IL-2 did not provide better efficacy than UC-MSCs alone. Consistent with this, UC-MSCs alone and UC-MSCs + IL-2 resulted in similar levels of serum IL-2 and frequencies of Tregs. Neutralization of IL-2 partly reduced the promotion of Tregs by UC-MSCs, suggesting that IL-2 was involved in the upregulation of Tregs by UC-MSCs. Lastly, an increase in serum IL-2 positively correlated with the reduction of disease activity of SLE patients by UC-MSCs. CONCLUSION: Both the single injection of UC-MSCs and repeated IL-2 administration exerted comparable efficacy in alleviating SLE manifestations, but UC-MSCs provided sustained alleviation and showed better improvement in renal pathology.

Human SLE variant NCF1-R90H promotes kidney damage and murine lupus through enhanced Tfh2 responses induced by defective efferocytosis of macrophages.

OBJECTIVES: We previously identified a hypomorphic variant, p.Arg90His (p.R90H) of neutrophil cytosolic factor 1 (NCF1, a regulatory subunit of phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 complex), as an putative causal variant for systemic lupus erythematosus (SLE), and established a knock-in (KI) H90 variant in the C57BL/6 background to study how this variant promotes lupus development. METHODS: Wild type (WT) and KI littermates were assessed for immune profiles and lupus-like features. Disease activity and renal damage of patients with SLE were assessed by systemic lupus erythematosus disease activity index (SLEDAI) and renal items of systemic lupus international collaborating clinics (SLICC), respectively. RESULTS: Compared with WT littermates, 5-week-old homozygous KI mice had reduced oxidative burst, splenomegaly, elevated type I interferon (IFN-I) scores, increased ratios of splenic follicular T helper 2 (Tfh2) to either T follicular regulatory (Tfr) or Tfh1 cells, increased ANA+ follicular, germinal centre and plasma cells without spontaneous kidney disease up to 1 year of age. Pristane treatment exacerbated the immune dysregulation and induced IFN-I-dependent kidney disease in 36-week-old H90 KI female mice. Decreased efferocytosis of macrophages derived from KI mice and patients with homozygous H90 SLE promoted elevated ratios of Tfh2/Tfr and Tfh2/Tfh1 as well as dysregulated humoral responses due to reduced voltage-gated proton channel 1 (Hv1)-dependent acidification of phagosome pH to neutralise the decreased electrogenic effect of the H90 variant, resulting in impaired maturation and phagosome proteolysis, and increased autoantibody production and kidney damage in mice and patients with SLE of multiple ancestries. CONCLUSIONS: A lupus causal variant, NCF1-H90, reduces macrophage efferocytosis, enhances Tfh2 responses and promotes autoantibody production and kidney damage in both mice and patients with SLE.

Clinical significance of HScore and MS score comparison in the prognostic evaluation of anti-MDA5-positive patients with dermatomyositis and interstitial lung disease.

OBJECTIVES: To evaluate the clinical significance of the HScore and MS score in the prognosis of anti-melanoma differentiation-associated gene 5 (MDA5) positive patients with dermatomyositis (DM) and interstitial lung disease (ILD). METHODS: The clinical features as well as HScore and MS score were compared between the survivors (n = 61) and nonsurvivors (n = 36) among 97 anti-MDA5-positive DM-ILD patients. Potential prognostic factors were analysed. RESULTS: Compared with survivors, nonsurvivors had significantly older age, tended to be male, and had a significantly higher frequency of fever at disease onset, higher levels of aspartate transaminase, lactate dehydrogenase, and serum ferritin, as well as higher values of HScore and MS score but had a significantly lower frequency of arthritis at disease onset. Multivariate analysis revealed that age ≥50 years [hazard ratio (HR) = 2.70, p = .040, 95% confidence interval (CI) 1.05-6.97)], male gender (HR = 3.20, p = .017, 95% CI 1.23-8.28), and higher HScore (HR = 3.72, p = .003, 95% CI 1.56-8.86) were independent risk factors for mortality. Patients with more risk factors had significantly poorer survival (p < .001). CONCLUSIONS: Older age, high HScore, and male gender are risk factors for poor survival among anti-MDA5-positive DM-ILD patients, suggesting the potential role of macrophage activation in the pathogenesis.

Biomimetic Ca2+ nanogenerator based on ions interference strategy for tumour-specific therapy.

Intracellular Ca2+ ions as second messenger played key role in cell behaviour, which was often overlooked in traditional antitumor treatment. Disrupting Ca2+ ion homeostasis by Ca2+ overload might switch ions signal from 'regulating' to 'destroying'. Inspired by this, a biomimetic Ca2+ nanogenerator was constructed. Briefly, the curcumin (CUR) was loaded into mesoporous calcium carbonate nanoparticles (MCC NPs), and then coated with platelet (PLT) membrane. Upon reaching tumour cells by PLT membrane-mediated tumour targeting effect, PLT@MCC/CUR would instantaneously decompose in acidic lysosomes, concurrently accompanying with Ca2+ generation and CUR release. The CUR could further facilitate Ca2+ release from endoplasmic reticulum (ER) and inhibit Ca2+ efflux, aggravating Ca2+ overload to disrupt mitochondrial Ca2+ homeostasis for mitochondria apoptosis signalling pathway activation. Interestingly, such effect was ineffective in normal cells, realising the tumour-specific therapeutic therapy. Based on ions interference strategy, PLT@MCC/CUR herein offered synergistic combination of Ca2+ overload therapy and chemotherapy, which would pave the way towards more effective nanotherapeutics.

Reduced Let-7f in Bone Marrow-Derived Mesenchymal Stem Cells Triggers Treg/Th17 Imbalance in Patients With Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) patients exist an imbalance between regulatory T (Treg) and T helper 17 cells (Th17), which might be contributed by defective immune regulation of bone marrow derived mesenchymal stem cells (BM-MSCs) from SLE patients. Our microRNA array analysis showed markedly down-regulated expression levels of microRNA let-7f in BM-MSCs from SLE patients compared to those from normal controls (NOR). To explore the role of let-7f in the disease pathogenesis, we showed that expression levels of let-7f in SLE BM-MSCs were negatively associated with SLE disease activity, and the predicted let-7 family targeted gene expression of interlukin-6 (IL-6) was significantly higher in BM-MSCs from SLE patients compared to normal controls (NOR). Transient transfection of BM-MSCs with let-7f mimics or inhibitors showed reduced levels of let-7f impaired the proliferation rate of BM-MSCs, BM-MSC-mediated downregulation of Th17 cells and upregulation of Treg cells, increased the apoptosis rate of BM-MSCs through targeting IL-6 and activating signal transducers and activators of transcription-3 (STAT3) pathway, but had no significant effect on the differentiation of Th1 and Th2. Our findings showed a key role of let-7f in the imbalance of Treg/Th17 mediated by SLE BM-MSCs, suggesting the potential of manipulating let-7f expression in BM-MSCs for treating SLE patients.

PPy nanoneedle based nanoplatform capable of overcoming biological barriers for synergistic chemo-photothermal therapy.

The biological barriers in vivo have limited the site-specific bioavailability and impeded therapeutic efficacy. To tackle these issues, nonspherical particles with a shape effect have attracted wide attention to affect the in vivo translocation of a drug delivery system. Herein, we constructed a nanoplatform based on polypyrrole (PPy) nanoneedles by hyaluronic acid (HA) modification and doxorubicin (DOX) loading. The PPy-HA@DOX nanoneedles with high aspect ratios could enhance the extravasation through the fenestrated vasculature of tumors, transport across tumor cell membrane via an endocytosis mechanism or even penetrated the membrane directly, and ultimately enter the nucleus easily via the nuclear pore complex by passive diffusion. With the ability of overcoming biological barriers, the PPy nanoneedle based nanoplatform would deliver drugs into the organelles more effectively. Under near infrared (NIR) laser irradiation, PPy as the photothermal agent could lead to tumor cellular structure damage for photothermal therapy (PTT). Therefore, PPy-HA@DOX developed here would exploit the merits of synergistic combination of chemo-photothermal therapy, which would pave the way toward more effective nanotherapeutics.

Cancer Cell Membrane-Biomimetic Nanoplatform for Enhanced Sonodynamic Therapy on Breast Cancer via Autophagy Regulation Strategy.

Autophagy was considered as a double-edged sword that might cooperate, aggravate, or antagonize apoptosis. We found that the sonodynamic therapy (SDT) in low dosage induced autophagy and might function as a survival pathway for breast cancer and exhibit resistance to SDT-mediated apoptosis. In this sense, it was highly desired to enhance SDT via autophagy regulation strategy. Herein, we reported a biomimetic nanoplatform based on hollow mesoporous titanium dioxide nanoparticles (HMTNPs) by autophagy inhibitor (hydroxychloroquine sulphate, HCQ) loading and cancer cell membrane (CCM) coating. Owing to the biomimetic surface functionalization, the CCM-HMTNPs/HCQ could escape from macrophage phagocytosis, actively recognize and home in on the tumor by homologous targeting ability. Afterward, the released HCQ in response to the ultrasound stimulus was capable of blocking the autophagic flux and cutting off the nutrients supply derived from the damaged organelles, which was anticipated to abrogate the cells' resistance to SDT. Meanwhile, the vessel normalization effect of HCQ alleviated the tumor hypoxia, which was bound to enhance the oxygen-dependent HMTNPs-mediated SDT treatment. Based on the above findings, it was undoubtedly logical that CCM-HMTNPs/HCQ would sensitize breast cancer cells to SDT via autophagy regulation strategy, which held a great promise in cancer treatment.

MicroRNA-663 induces immune dysregulation by inhibiting TGF-ß1 production in bone marrow-derived mesenchymal stem cells in patients with systemic lupus erythematosus.

Mesenchymal stem cells (MSCs) are critical for immune regulation. Although several microRNAs (miRNAs) have been shown to participate in autoimmune pathogenesis by affecting lymphocyte development and function, the roles of miRNAs in MSC dysfunction in autoimmune diseases remain unclear. Here, we show that patients with systemic lupus erythematosus (SLE) display a unique miRNA signature in bone marrow-derived MSCs (BMSCs) compared with normal controls, among which miR-663 is closely associated with SLE disease activity. MiR-663 inhibits the proliferation and migration of BMSCs and impairs BMSC-mediated downregulation of follicular T helper (Tfh) cells and upregulation of regulatory T (Treg) cells by targeting transforming growth factor ß1 (TGF-ß1). MiR-663 overexpression weakens the therapeutic effect of BMSCs, while miR-663 inhibition improves the remission of lupus disease in MRL/lpr mice. Thus, miR-663 is a key mediator of SLE BMSC regulation and may serve as a new therapeutic target for the treatment of lupus.

Mesenchymal stem cells prevent podocyte injury in lupus-prone B6.MRL-Faslpr mice via polarizing macrophage into an anti-inflammatory phenotype.

BACKGROUND: Podocyte injury plays a pathogenic role in the development of lupus nephritis (LN). Mesenchymal stem cells (MSCs) have shown promising therapeutic potential for LN. However, whether MSCs can prevent podocyte injury in LN remains unknown. METHODS: Human umbilical cord-derived MSCs (UC-MSCs) were infused into lupus-prone B6.MRL-Faslpr (B6.lpr) mice to investigate the influences of UC-MSCs on podocyte injury in LN. Podocytes and macrophages were co-cultured with UC-MSCs in vitro to study the mechanism by which UC-MSC protect podocytes. We further explored the effects of UC-MSCs on macrophage polarization. RESULTS: We found that UC-MSCs promoted the expression of podocyte-specific markers, podocin and synaptopodin, in lupus-prone B6.lpr mice, along with the improvement of lupus renal pathology in terms of reduced IgG and C3 deposition in glomeruli and decreased anti-dsDNA antibody level. Besides, UC-MSC treatment decreased podocyte foot process effacement, as UC-MSCs-treated macrophages led to less podocyte injury in vitro. Interestingly, we further found that UC-MSCs-treated macrophages exhibited an anti-inflammatory phenotype with higher expression of CD206, and lower expression of tumor necrosis factor-α and interleukin-1ß. Additionally, UC-MSCs-treated lupus mice showed reduced renal macrophage infiltration and elevated CD206 expression in kidney. CONCLUSIONS: Our results demonstrated that UC-MSCs ameliorated LN by preventing podocyte injury possibly through reducing macrophage infiltration and polarizing macrophage into an anti-inflammatory phenotype.

Safety analysis in patients with autoimmune disease receiving allogeneic mesenchymal stem cells infusion: a long-term retrospective study.

OBJECTIVE: The aim of this study was to evaluate the safety of mesenchymal stem cell infusion in patients with autoimmune diseases. METHODS: A total of 404 patients with autoimmune diseases who received mesenchymal stem cell infusion between 2007 and 2016 were included in this study. Adverse events in these patients were collected, mainly including infections and malignancies. Sources of information included hospitalization records and data from outpatient visits and each follow-up. RESULTS: The mean follow-up period of all patients was 43.4 ± 25.9 months (range 1-109). Majority of stem cells were from the umbilical cord. The most common indications for mesenchymal stem cell infusion were systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis. The median age at infusion was 38.7 ± 15.7 years. The 5-year and 8-year survival rates were 90.4% and 88.9%, respectively. Median follow-up of survivors was 45.1 ± 25.7 months. The incidence rate of infections was 29.5% (119/404), and that of serious infections was 12.9% (52/404). Five patients (1.2%) experienced malignancies. Deaths occurred in 45 patients, and transplantation-related mortality was 0.2%. The most common causes of deaths in our study were disease relapse and complications associated with the underlying disease. CONCLUSION: Autoimmune disease is an emerging indication for mesenchymal stem cell infusion. Our data shows that mesenchymal stem cell infusion is a safe therapy for patients with autoimmune diseases. The incidences of adverse events, whether infections or malignancies, are acceptable in these patients. TRIAL REGISTRATION: ClinaicalTrials.gov, NCT00698191 . Registered 17 June 2008-Retrospectively registered.

Mesenchymal stem cells induced CD4+ T cell apoptosis in treatment of lupus mice.

Umbilical cord-derived mesenchymal stem cell transplantation (UCMSCT) has been used to treat human autoimmune diseases like lupus for example, but little is known about its effect on cell apoptosis. Here we evaluated the efficacy of UCMSCT for lupus treatment and explored the mechanism by which mesenchymal stem cells (MSCs) modulate T cell apoptosis in lupus mice. 1 × 106 human umbilical cord-derived mesenchymal stem cells (UC-MSCs) were injected into B6.MRL-Faslpr (B6.lpr) mice via tail vein. 6 h, 24 h or 4 weeks later, the mice were sacrificed and the apoptosis of lymphocytes in peripheral blood and spleen were detected by flow cytometry. The immune cell subpopulations in spleen were also measured at 6 h and 24 h, respectively. The therapeutic effects were assessed after 4 weeks. The frequency of peripheral blood CD4+ T cell apoptosis was reduced in lupus-prone B6.lpr mice. UCMSCT alleviated the disease phenotypes in B6.lpr mice, decreased the ratio of Th1 as well as Th2 cells, and increased percentages of apoptotic CD4+ T cells in vivo and vitro. Collectively, our findings unravel that UCMSCT alleviate lupus disease and reverse immune imbalance possibly by promoting T cell apoptosis in B6.lpr mice.

Severe thrombocytopenia in connective tissue diseases: a single-center review of 131 cases.

To analyze the clinical characteristics of severe thrombocytopenia in patients with various connective tissue diseases (CTDs), one hundred thirty-one consecutive CTD patients with blood platelet count less than 20 × 109/L on admission, which was ascribed to the nature of diseases, during January 2011 to June 2015 in our department were enrolled and checked for their survival status in September 2015. The patients were categorized based on background diseases or therapeutic effects, and compared with clinical features, treatment strategies, and long-term outcomes among the groups. Cumulative survival rates were estimated using Kaplan-Meier analysis. Of the patients, 88.5% were female. The most frequently seen background diseases were primary Sjögren's syndrome (pSS) (53.4%) and systemic lupus erythematosus (SLE) (40.5%). Age on admission for SLE patients (36.7 ± 14.1 years) was much younger than that for other patients (44.4 ± 15.4 years for pSS and 46 ± 16.1 years for other CTDs, p < 0.05). Ninety-six cases accompanied with various bleeding symptoms, which were more common in pSS patients than in SLE patients (80.0% vs. 64.2%, p < 0.05). Glucocorticoids and/or intravenous immunoglobulin were applied as initial therapy with an overall response rate of 36.6%. For patients failed to respond, immunosuppressive drugs were added and the other 22.8% benefited from the treatment. Compared to those ineffective to the aforementioned drugs, patients with therapeutic effects had significantly high immunoglobulin G levels. Twenty patients with refractory diseases accepted mesenchymal stem cell transplantation (MSCT) with a total effective rate of 65.0%. Eleven patients died after the follow-up for a mean time of 27.7 months, of which 7 were associated with hemorrhage. There was no difference in the survival rate among different background diseases. However, compared with those who did not gain remission, patients achieved partial or complete remission had better cumulative survival rates (p < 0.01). In conclusion, among various CTDs, severe thrombocytopenia often occurs in patients with SLE or pSS. Early response to the treatments, but not the background disease, is an important predictor of long-term prognosis. For patients with refractory thrombocytopenia, MSCT may provide an alternative therapeutic strategy.

Association between Type I interferon and depletion and dysfunction of endothelial progenitor cells in C57BL/6 mice deficient in both apolipoprotein E and Fas ligand.

Patients with systemic lupus erythematosus (SLE) have a tremendously increased risk for cardiovascular disease (CVD), which could not be accounted in entirety by traditional Framingham risk factors. To study whether the accelerated atherosclerosis in SLE patients is mediated by type I interferon (IFN-I) through the regulation of endothelial progenitor cells (EPCs), we created a line of C57BL/6 mice with deficiency in both apolipoprotein E (ApoE-/-) and fas ligand (FasL-/-, gld.). As expected, the resultant gld. ApoE-/- mice exhibited both aggravated lupus-like disease and atherosclerosis under normal diet. Increased expression of IFN-I-stimulated genes (ISGs) was closely associated with depletion and dysfunction of EPCs, as well as with accelerated atherosclerotic lesion in gld. ApoE-/- mice. While only IFN-α instead of other interventions, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IRS423 and IRS661, impaired EPC function in vitro. Mechanistically, activation or inhibition of the TLR7/9 signaling could modulate EPC number and function in vivo. Decreased proliferation rate and increased apoptotic rate of EPCs induced by IFN-α might contribute to the results to a certain extent. Thus, our data suggest that excessive expression of IFN-I through the activation of TLR7/9 signaling may induce accelerated atherosclerosis in lupus through the depletion or dysfunction of EPCs, suggesting that targeting IFN-I might have potential therapeutic effects on both lupus disease and premature atherosclerosis in SLE patients.

Mesenchymal Stem Cells Promote the Osteogenesis in Collagen-Induced Arthritic Mice through the Inhibition of TNF-α.

OBJECTIVE: To investigate the effects of umbilical cord mesenchymal stem cell (UC-MSC) transplantation on joint damage and osteoporosis in collagen-induced arthritis (CIA) mice and to explore the mechanisms by which UC-MSCs modulate the osteogenic differentiation. METHODS: CIA mice were divided into the following treated groups: UC-MSC transplantation group, antitumor necrosis factor- (TNF-) α group, and zoledronic acid (ZA) group. Microcomputed tomography (micro-CT) was used to analyze the bone morphology parameters. Osteogenic differentiation of treated CIA mice was determined. Bone marrow mesenchymal stem cells (BM-MSCs) from CIA mice were treated with TNF-α in vitro to explore their effects on osteogenesis. RESULTS: The arthritis score was significantly reduced in the UC-MSC transplantation and anti-TNF-α-treated CIA groups, compared with control mice (P < 0.001). Micro-CT showed that CIA mice developed osteoporosis at 12 weeks after immunization. The bone morphology parameters were partially improved in UC-MSC-treated CIA mice. Impaired osteogenic differentiation functions were indicated by decreased ALP activity (P < 0.001) and reduced mRNA and protein levels of osteogenic marker genes (P < 0.05) in CIA mice compared with DBA/1 mice. UC-MSC treatment significantly upregulated the impaired osteogenic differentiation ability in CIA mice. Meanwhile, the serum TNF-α level was decreased significantly in the UC-MSC group. The osteogenesis was reduced with the addition of TNF-α in vitro. CONCLUSION: This study demonstrated that UC-MSC transplantation not only significantly improved the joint damage but also played a beneficial role in osteoporosis in CIA mice. Mechanistically, the improved osteogenic differentiation of CIA under UC-MSC treatment may be achieved by inhibition of TNF-α.

Genetic contribution to mesenchymal stem cell dysfunction in systemic lupus erythematosus.

Allogeneic mesenchymal stem cell (MSC) transplantation has recently become a promising therapy for patients with systemic lupus erythematosus (SLE). MSCs are a kind of multipotent stem cell than can efficiently modulate both innate and adaptive immune responses, yet those from SLE patients themselves fail to maintain the balance of immune cells, which is partly due to the abnormal genetic background. Clarifying genetic factors associated with MSC dysfunction may be helpful to delineate SLE pathogenesis and provide new therapeutic targets. In this review, the scientific evidence on the genetic contribution to MSC dysfunction in SLE is summarized.

A Long-Term Follow-Up Study of Allogeneic Mesenchymal Stem/Stromal Cell Transplantation in Patients with Drug-Resistant Systemic Lupus Erythematosus.

Allogeneic mesenchymal stem/stromal cells (MSCs) have been widely studied as an alternative cell source for regenerative medicine. Here, we report a long-term follow-up study of allogeneic bone marrow and/or umbilical cord MSC transplantation (MSCT) in severe and drug-refractory systemic lupus erythematosus (SLE) patients. Eighty-one patients were enrolled, and the 5-year overall survival rate was 84% (68/81) after MSCT. At 5-year follow-up, 27% of patients (22/81) were in complete clinical remission and another 7% (6/81) were in partial clinical remission, with a 5-year disease remission rate of 34% (28/81). In total, 37 patients had achieved clinical remission and then 9 patients subsequently relapsed, with 5-year overall rate of relapse of 24% (9/37). SLE Disease Activity Index scores, serum albumin, complement C3, peripheral white blood cell, and platelet numbers, as well as proteinuria levels, continued to improve during the follow-up. Our results demonstrated that allogeneic MSCT is safe and resulted in long-term clinical remission in SLE patients.

Citrullinated fibrinogen impairs immunomodulatory function of bone marrow mesenchymal stem cells by triggering toll-like receptor.

Bone marrow mesenchymal stem cells (BMSC) have been shown to possess immunomodulatory activities, while its role in rheumatoid arthritis (RA) remains unknown. Citrullinated fibrinogen (cfb) has been considered as a specific autoantigen in RA pathogenesis. Our study aims to determine the role of cfb on immunomodulatory function of BMSC. We demonstrated the specific role of toll-like receptor 4 (TLR4)-NFκB pathway in the pro-inflammatory response of BMSC to cfb with increased production of interleukin (IL)-6, IL-8 and chemokine CC motif ligand 2 (CCL2). Moreover, cfb impaired BMSC-mediated suppression of peripheral blood mononuclear cells (PBMC) proliferation and reduced the production of the key immunomodulatory molecule indoleamine 2,3-dioxygenase (IDO) in BMSC. We have uncovered a previously unrecognized role of cfb in interfering BMSC-mediated immunoregulation in RA. Cfb could act as a damage-associated molecule pattern (DAMP) for BMSC and thereby contribute to the propagation of inflammation in RA.