Extracellular deposition of matrilin-2 controls the timing of the myogenic program during muscle regeneration.

Here, we identify a role for the matrilin-2 (Matn2) extracellular matrix protein in controlling the early stages of myogenic differentiation. We observed Matn2 deposition around proliferating, differentiating and fusing myoblasts in culture and during muscle regeneration in vivo. Silencing of Matn2 delayed the expression of the Cdk inhibitor p21 and of the myogenic genes Nfix, MyoD and Myog, explaining the retarded cell cycle exit and myoblast differentiation. Rescue of Matn2 expression restored differentiation and the expression of p21 and of the myogenic genes. TGF-β1 inhibited myogenic differentiation at least in part by repressing Matn2 expression, which inhibited the onset of a positive-feedback loop whereby Matn2 and Nfix activate the expression of one another and activate myoblast differentiation. In vivo, myoblast cell cycle arrest and muscle regeneration was delayed in Matn2(-/-) relative to wild-type mice. The expression levels of Trf3 and myogenic genes were robustly reduced in Matn2(-/-) fetal limbs and in differentiating primary myoblast cultures, establishing Matn2 as a key modulator of the regulatory cascade that initiates terminal myogenic differentiation. Our data thus identify Matn2 as a crucial component of a genetic switch that modulates the onset of tissue repair

Heart failure as a predictor of functional dependence in hospitalized elderly

AbstractOBJECTIVEIdentify whether Heart Failure (HF) is a predictor of functional dependence for Basic Activities of Daily Living (BADL) in hospitalized elderly.METHODSWe investigated medical records and assessed dependence to BADL (by the Katz Index) of 100 elderly admitted to a geriatric ward of a university hospital. In order to verify if HF is a predictor of functional dependence, linear regression analyzes were performed.RESULTSThe prevalence of HF was 21%; 95% of them were dependent for BADLs. Bathing was the most committed ADL. HF is a predictor of dependence in hospitalized elderlies, increasing the chance of functional decline by 5 times (95% CI, 0.94-94.48), the chance of functional deterioration by 3.5 times (95% CI, 1.28-11.66; p <0.02) and reducing 0.79 points in the Katz Index score (p <0.05).CONCLUSIONHF is a dependency predictor of ADL in hospitalized elderly, who tend to be more dependent, especially for bathing

Basement Membrane Zone Collagens XV and XVIII/Proteoglycans Mediate Leukocyte Influx in Renal Ischemia/Reperfusion

Collagen type XV and XVIII are proteoglycans found in the basement membrane zones of endothelial and epithelial cells, and known for their cryptic anti-angiogenic domains named restin and endostatin, respectively. Mutations or deletions of these collagens are associated with eye, muscle and microvessel phenotypes. We now describe a novel role for these collagens, namely a supportive role in leukocyte recruitment. We subjected mice deficient in collagen XV or collagen XVIII, and their compound mutant, as well as the wild-type control mice to bilateral renal ischemia/reperfusion, and evaluated renal function, tubular injury, and neutrophil and macrophage influx at different time points after ischemia/reperfusion. Five days after ischemia/reperfusion, the collagen XV, collagen XVIII and the compound mutant mice showed diminished serum urea levels compared to wild-type mice (all

New Insight on Human Type 1 Diabetes Biology: nPOD and nPOD-Transplantation

The Juvenile Diabetes Research Foundation (JDRF) Network for Pancreatic Organ Donors with Diabetes (JDRF nPOD) was established to obtain human pancreata and other tissues from organ donors with type 1 diabetes (T1D) in support of research focused on disease pathogenesis. Since 2007, nPOD has recovered tissues from over 100 T1D donors and distributed specimens to approximately 130 projects led by investigators worldwide. More recently, nPOD established a programmatic expansion that further links the transplantation world to nPOD, nPOD-Transplantation; this effort is pioneering novel approaches to extend the study of islet autoimmunity to the transplanted pancreas and to consent patients for postmortem organ donation directed towards diabetes research. Finally, nPOD actively fosters and coordinates collaborative research among nPOD investigators, with the formation of working groups and the application of team science approaches. Exciting findings are emerging from the collective work of nPOD investigators, which covers multiple aspects of islet autoimmunity and beta cell biology

Comparative analysis of the mouse and human genes (Matn2 and MATN2) for matrilin-2, a filament-forming protein widely distributed in extracellular matrices

We previously identified matrilin-2 (MATN2), the largest member of the novel family of matrilins. These filament-forming adapter proteins expressed in a distinct, but partially overlapping, pattern in all tissues were implicated in the organization of the extracellular matrix. Matrilin-2 functions in a great variety of tissues. Here, we present the genomic organization of the highly conserved mouse and human MATN2 loci, which cover > 100 kb and 167.167 kb genomic regions, respectively, and are composed of 19 exons. RT-PCR analysis revealed that alternative transcripts with identical protein coding regions are transcribed from two promoters in both species. The upstream, housekeeping type promoter is functional in all tissues and cell types tested. The activity of the downstream, TATA-like promoter preceded with putative motifs for the homeobox transcription factor PRRX2 is restricted to embryonic fibroblasts and certain cell lines. The oligomerization module is split by an U12-type AT-AC intron found in conserved position in all four matrilin genes. We assigned Matn2 to mouse chromosome 15, linked to Trhr and Sntb1 in a region synthenic to human chromosome 8q22-24

CCL21 Expression in β-Cells Induces Antigen-Expressing Stromal Cell Networks in the Pancreas and Prevents Autoimmune Diabetes in Mice

Tumors induce tolerance toward their antigens by producing the chemokine CCL21, leading to the formation of tertiary lymphoid organs (TLOs). Ins2-CCL21 transgenic, nonobese diabetic (NOD) mice express CCL21 in pancreatic β-cells and do not develop autoimmune diabetes. We investigated by which mechanisms CCL21 expression prevented diabetes. Ins2-CCL21 mice develop TLOs by 4 weeks of age, consisting of naive CD4 T cells compartmentalized within networks of CD45 gp38 CD31 fibroblastic reticular cell (FRC)-like cells. Importantly, 12-week-old Ins2-CCL21 TLOs contained FRC-like cells with higher contractility, regulatory, and anti-inflammatory properties and enhanced expression of β-cell autoantigens compared with nontransgenic NOD TLOs found in inflamed islets. Consistently, transgenic mice harbored fewer autoreactive T cells and a higher proportion of regulatory T cells in the islets. Using adoptive transfer and islet transplantation models, we demonstrate that TLO formation in Ins2-CCL21 transgenic islets is critical for the regulation of autoimmunity, and although the effect is systemic, the induction is mediated locally likely by lymphocyte trafficking through TLOs. Overall, our findings suggest that CCL21 promotes TLOs that differ from inflammatory TLOs found in type 1 diabetic islets in that they resemble lymph nodes, contain FRC-like cells expressing β-cell autoantigens, and are able to induce systemic and antigen-specific tolerance leading to diabetes prevention