Toll-like receptors TLR7 and TLR9 are both implicated in the activation of autoreactive B cells and other cell types associated with systemic lupus erythematosus (SLE) pathogenesis. However, Tlr9-/- autoimmune-prone strains paradoxically develop more severe disease. We have now leveraged the negative regulatory role of TLR9 to develop an inducible rapid-onset murine model of systemic autoimmunity that depends on T cell detection of a membrane-bound OVA fusion protein expressed by MHC class II+ cells, expression of TLR7, expression of the type I IFN receptor, and loss of expression of TLR9. These mice are distinguished by a high frequency of OVA-specific Tbet+, IFN-γ+, and FasL-expressing Th1 cells as well as autoantibody-producing B cells. Unexpectedly, contrary to what occurs in most models of SLE, they also developed skin lesions that are very similar to those of human cutaneous lupus erythematosus (CLE) as far as clinical appearance, histological changes, and gene expression. FasL was a key effector mechanism in the skin, as the transfer of FasL-deficient DO11gld T cells completely failed to elicit overt skin lesions. FasL was also upregulated in human CLE biopsies. Overall, our model provides a relevant system for exploring the pathophysiology of CLE as well as the negative regulatory role of TLR9.
Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains a major health care concern affecting several million patients worldwide and for which there is no specific treatment. We have employed a 3D tissue engineered disease-like system to emulate cystic structures in vitro and analyzed the extracellular matrix (ECM) interactions in it. The tissue system was developed by culturing normal or polycystin-1 silenced mouse Inner Medullary Collecting Duct (mIMCD) cells in ECM infused into 3D porous silk protein biomaterial scaffolds. In this system, the silk scaffolds provide slow degradation, biocompatibility, and maintain structure and transport for the 3D system, while the ECM molecules retain biological signaling. Using this 3D tissue system we provide evidence for an autocrine signaling loop involving abnormal matrix deposition (collagen type IV and laminin) and its integrin receptor subunit protein (Integrin-β1) in Pkd1 silenced mIMCD cells. In addition, we report that abnormal pericystic ECM interactions between matrix molecules and integrin subunit proteins regulate the rate of cystogenesis in the disease system. Molecular signaling showed abnormalities in cyclin proteins and cell-cycle progression upon Pkd1 knockdown. Importantly, disruption of the abnormal matrix interactions by an additional knockdown (double-silencing) of integrin-β1 in Pkd1 silenced cells reversed the abnormalities and reduced the rate of cystogenesis. Together, these findings indicate that abnormal matrix deposition and altered integrin profile distribution as observed in ADPKD and are critical in cystogenesis and should be considered a target for the development of therapeutics.
Background: Preclinical studies of mesenchymal stem cells in various animal models demonstrate accelerated wound healing through a variety of mechanisms. The aim of this small-scale study was to evaluate the effectiveness of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in the treatment of patients with venous ulcers. Study design and method: A randomized, double-blind, placebo-controlled evaluation was selected to protect against bias. A total of 11 patients were randomly assigned to one of three groups: Group A (n¼4) received conventional standard therapy and control saline spray, group B (n¼3) received conventional standard therapy and fibrin spray, and group C (n¼4) received conventional standard therapy and BM-MSCs topically delivered using a fibrin spray. The total duration of the treatment was 24 weeks or earlier if the wound is completely closed. Patients were evaluated clinically at baseline and every 4 weeks up to week 24. The primary efficacy endpoint of the study is increased wound closure (cm/wk). Healing rates were calculated using the Gilman's method. Data were analyzed by comparing the mean healing rates among treatment groups. Results: The average healing rate at week-4 for groups A, B, and C was 0.0006,-0.0522, and 0.1082 cm/wk, respectively. Patients received BM-MSCs treatment (Group C) showed higher mean healing rates and a significant reduction in wound size when compared to groups A and B at all evaluation time points. No adverse events were reported. Conclusions: This pilot study shows that topical application of autologous BM-MSCs may be an effective modality to promote healing in patients with difficult-to-heal wounds. However, larger studies are needed to confirm this finding.
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