Matricellular proteins SPARC in ECM organizationVertebrate SPARC binds to a number of different ECM components including thrombospondin 1, vitronectin, entactin/nidogen, fibrillar collagens (types I, II, III, and V), and collagen type IV, the prevalent collagen in basement membranes (1).Therefore, SPARC has the potential to contribute to the organization of matrix in connective tissue as well as basement membranes.Interestingly, SPARC is expressed abundantly in basement membranes and in capsules that surround a variety of organs and tissues.In this regard, SPARC-null mice display early cataractogenesis, a phenotype with 100% penetrance (2).Transmission electron microscopy of lens epithelial cells in SPARC-null mice shows an intrusion of cellular processes into the basement membrane of the lens capsule, whereas wild-type lens epithelial cells exhibit a precise border at the cell-matrix interface (3).We have proposed that this phenotype reflects aberrant cell behavior or differentiation resulting from altered composition or structure of the basement membrane formed in the absence of SPARC.
Post-traumatic stress disorder (PTSD) is a disabling psychological disorder characterized by chronic symptoms of intrusiveness, avoidance, and hyperarousal after a traumatic event. Retrospective studies have indicated PTSD increases the risk for cardiovascular disease (CVD) including arrhythmia, hypertension, and myocardial infarction. The goal of this study was to: 1) use a murine model of cued fear conditioning (inescapable foot shock, IFS) to develop a scoring method to distinguish a PTSD-like phenotype, and 2) use this model system to characterize the cardiac phenotype and function in mice with extreme PTSD-like behaviors. We compared 3 groups, controls, non-responders (NR), and PTSD-like mice at 2 time points [4-weeks and 8-weeks post-IFS] to compare left ventricular structure and function. Assessment of cardiac function showed both male and female PTSD-like mice had increased isovolumetric relaxation time at 8-weeks post-IFS, whereas only females demonstrated increases in E/e', left atrial diameter, and decreased ejection fraction compared to control mice. Female PTSD-like mice also demonstrated increased interstitial fibrosis through picrosirius red staining and increased expression of fibrotic genes including Col3a1 and Lox. Overall, our data indicated that mice displaying behavioral characteristics associated with PTSD present with sex-dependent diastolic dysfunction likely due, at least in part, to an activation of cardiac fibrosis.
As the number of patients with diabetes continues to increase in the United States, novel approaches to clinical care access should be considered to meet the care needs for this population, including support for diabetes-related technology.To evaluate a virtual clinic to facilitate comprehensive diabetes care, support continuous glucose monitoring (CGM) integration into diabetes self-management, and provide behavioral health support for diabetes-related issues.This cohort study was a prospective, single-arm, remote study involving adult participants with type 1 or type 2 diabetes who were referred through community resources. The study was conducted virtually from August 24, 2020, to May 26, 2022; analysis was conducted at the clinical coordinating center.Training and education led by a Certified Diabetes Care and Education Specialist for CGM use through a virtual endocrinology clinic structure, which included endocrinologists and behavioral health team members.Main outcomes included CGM-measured mean glucose level, coefficient of variation, and time in range (TIR) of 70 to 180 mg/dL, time with values greater than 180 mg/dL or 250 mg/dL, and time with values less than 70 mg/dL or 54 mg/dL. Hemoglobin A1c was measured at baseline and at 12 and 24 weeks.Among the 234 participants, 160 had type 1 diabetes and 74 had type 2 diabetes. The mean (SD) age was 47 (14) years, 123 (53%) were female, and median diabetes duration was 20 years. Median (IQR) CGM use over 6 months was 96% (91%-98%) for participants with type 1 diabetes and 94% (85%-97%) for those with type 2 diabetes. Mean (SD) hemoglobin A1c (HbA1c) in those with type 1 diabetes decreased from 7.8% (1.6%) at baseline to 7.1% (1.0%) at 3 months and 7.1% (1.0%) at 6 months (mean change from baseline to 6 months, -0.6%, 95% CI, -0.8% to -0.5%; P < .001), with an 11% mean TIR increase over 6 months (95% CI, 9% to 14%; P < .001). Mean HbA1c in participants with type 2 diabetes decreased from 8.1% (1.7%) at baseline to 7.1% (1.0%) at 3 months and 7.1% (0.9%) at 6 months (mean change from baseline to 6 months, -1.0%; 95% CI, -1.4% to -0.7%; P < .001), with an 18% TIR increase over 6 months (95% CI, 13% to 24%; P < .001). In participants with type 1 diabetes, mean percentage of time with values less than 70 mg/dL and less than 54 mg/dL decreased over 6 months by 0.8% (95% CI, -1.2% to -0.4%; P = .001) and by 0.3% (95% CI, -0.5% to -0.2%, P < .001), respectively. In the type 2 diabetes group, hypoglycemia was rare (mean [SD] percentage of time <70 mg/dL, 0.5% [0.6%]; and <54 mg/dL, 0.07% [0.14%], over 6 months).Results from this cohort study demonstrated clinical benefits associated with implementation of a comprehensive care model that included diabetes education. This model of care has potential to reach a large portion of patients with diabetes, facilitate diabetes technology adoption, and improve glucose control.
Abstract Epithelial adherens junctions (AJs) are cell-cell adhesion complexes that are influenced by tissue mechanics, such as those emanating from the extracellular matrix (ECM). Here, we introduce a mechanism whereby epithelial AJs can also regulate the ECM. We show that the AJ component PLEKHA7 regulates levels and activity of the key ECM remodeling components MMP1 and LOX in well-differentiated colon epithelial cells, through the miR-24 and miR-30c miRNAs. PLEKHA7 depletion in epithelial cells results in LOX-dependent ECM remodeling in culture and in the colonic mucosal lamina propria in mice. Furthermore, PLEKHA7-depleted cells exhibit increased migration and invasion rates that are MMP1- and LOX-dependent, and form colonies in 3D cultures that are larger in size and acquire aberrant morphologies in stiffer matrices. These results reveal an AJ-mediated mechanism, through which epithelial cells drive ECM remodeling to modulate their behavior, including acquisition of phenotypes that are hallmarks of conditions such as fibrosis and tumorigenesis. Teaser Epithelial cells instruct ECM remodeling to modulate their behavior, as a result of adherens junction and miRNA disruption.
SPARC (osteonectin, BM-40) is a matricellular glycoprotein that is expressed in many embryogenic and adult tissues undergoing remodeling or repair. SPARC modulates cellular interaction with the extracellular matrix (ECM), inhibits cell adhesion and proliferation, and regulates growth factor activity. To explore further the function and activity of this protein in tissue homeostasis, we have developed several monoclonal antibodies (MAbs) that recognize distinct epitopes on SPARC. The MAbs bind to SPARC with high affinity and identify SPARC by ELISA, Western blotting, immunoprecipitation, immunocytochemistry, and/or immunohistochemistry. The MAbs were also characterized in functional assays for potential alteration of SPARC activity. SPARC binds to collagen I and laminin-1 through an epitope defined by MAb 293; this epitope is not involved in the binding of SPARC to collagen III. The other MAbs did not interfere with the binding of SPARC to collagen I or III or laminin-1. Inhibition of the anti-adhesive effect of SPARC on endothelial cells by MAb 236 was also observed. Functional analysis of SPARC in the presence of these novel MAbs now confirms that the activities ascribed to this matricellular protein can be assigned to discrete subdomains.
