A STAT5-Smad3 dyad regulates adipogenic plasticity of visceral adipose mesenchymal stromal cells during chronic inflammation.

Adipogenic differentiation of visceral adipose tissue-resident multipotent mesenchymal stromal cells (VA-MSC) into adipocytes is metabolically protective. Under chronic inflammatory stress, this neoadipogenesis process is suppressed by various pro-inflammatory cytokines and growth factors. However, the underlying mechanism(s) regulating VA-MSC plasticity remains largely unexplored.

Islet allografts expressing a PD-L1 and IDO fusion protein evade immune rejection and reverse preexisting diabetes in immunocompetent mice without systemic immunosuppression.

Allogeneic islet transplantation is a promising experimental therapy for poorly controlled diabetes. Despite pharmacological immunosuppression, long-term islet engraftment remains elusive. Here, we designed a synthetic fusion transgene coupling PD-L1 and indoleamine dioxygenase [hereafter PIDO] whose constitutive expression prevents immune destruction of genetically engineered islet allograft transplanted in immunocompetent mice.

Pancreatic Stellate Cells Prolong Ex Vivo Islet Viability and Function and Improve Engraftment.

Preserving islet health and function is critical during pretransplant culture to improve islet transplantation outcome and for ex vivo modeling of diabetes for pharmaceutical drug discovery. The limited islet engraftment potential is primarily attributable to loss of extracellular matrix (ECM) support and interaction. Multipotent cells with ECM depositing competency improve islet survival during short coculture period.

Minor salivary gland mesenchymal stromal cells derived from patients with Sjӧgren's syndrome deploy intact immune plasticity.

Background Aims: Mesenchymal stromal cells (MSCs) provide minor salivary glands (MSGs) with support and niche cells for epithelial glandular tissue. Little is known about resident MSG-derived MSCs (MSG-MSCs) in primary Sjӧgren's syndrome (PSS). The authors' objective is to define the immunobiology of endogenous PSS MSG-MSCs.

The Transcription Factor Nfatc2 Regulates β-Cell Proliferation and Genes Associated with Type 2 Diabetes in Mouse and Human Islets.

Human genome-wide association studies (GWAS) have shown that genetic variation at >130 gene loci is associated with type 2 diabetes (T2D). We asked if the expression of the candidate T2D-associated genes within these loci is regulated by a common locus in pancreatic islets. Using an obese F2 mouse intercross segregating for T2D, we show that the expression of ~40% of the T2D-associated genes is linked to a broad region on mouse chromosome (Chr) 2.

Histone chaperone ASF1B promotes human β-cell proliferation via recruitment of histone H3.3.

Anti-silencing function 1 (ASF1) is a histone H3-H4 chaperone involved in DNA replication and repair, and transcriptional regulation. Here, we identify ASF1B, the mammalian paralog to ASF1, as a proliferation-inducing histone chaperone in human β-cells. Overexpression of ASF1B led to distinct transcriptional signatures consistent with increased cellular proliferation and reduced cellular death.

Phosphorylation and degradation of tomosyn-2 de-represses insulin secretion.

The abundance and functional activity of proteins involved in the formation of the SNARE complex are tightly regulated for efficient exocytosis. Tomosyn proteins are negative regulators of exocytosis. Tomosyn causes an attenuation of insulin secretion by limiting the formation of the SNARE complex.

Reciprocal interaction between TRAF6 and notch signaling regulates adult myofiber regeneration upon injury.

Skeletal muscle is a postmitotic tissue that repairs and regenerates through activation of a population of stem-cell-like satellite cells. However, signaling mechanisms governing adult skeletal muscle regeneration remain less understood. In the present study, we have investigated the role of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an adaptor protein involved in receptor-mediated activation of multiple signaling pathways in regeneration of adult myofibers.

TWEAK and TRAF6 regulate skeletal muscle atrophy.

Purpose Of Review: To discuss the roles and mechanisms of action of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and tumor necrosis factor receptor-associated factor 6 (TRAF6) in skeletal muscle atrophy.

Recent Findings: Proinflammatory cytokines are known to mediate muscle atrophy in many chronic disease states. However, their role in the loss of skeletal muscle mass in disuse conditions has just begun to be elucidated.

The E3 ubiquitin ligase TRAF6 intercedes in starvation-induced skeletal muscle atrophy through multiple mechanisms.

Starvation, like many other catabolic conditions, induces loss of skeletal muscle mass by promoting fiber atrophy. In addition to the canonical processes, the starvation-induced response employs many distinct pathways that make it a unique atrophic program. However, in the multiplex of the underlying mechanisms, several components of starvation-induced atrophy have yet to be fully understood and their roles and interplay remain to be elucidated.

Elevated levels of active matrix metalloproteinase-9 cause hypertrophy in skeletal muscle of normal and dystrophin-deficient mdx mice.

Matrix metalloproteinases (MMPs) are a group of extracellular proteases involved in tissue remodeling in several physiological and pathophysiological conditions. While increased expression of MMPs (especially MMP-9) has been observed in skeletal muscle in numerous conditions, their physiological significance remains less-well understood. By generating novel skeletal muscle-specific transgenic (Tg) mice expressing constitutively active mutant of MMP-9 (i.

TRAF6 coordinates the activation of autophagy and ubiquitin-proteasome systems in atrophying skeletal muscle.

Skeletal muscle wasting is a major reason for morbidity and mortality in many chronic disease states, disuse conditions and aging. The ubiquitin-proteasome and autophagy-lysosomal systems are the two major proteolytic pathways involved in regulation of both physiological and pathological muscle wasting. Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) is an important adaptor protein involved in receptor-mediated activation of various signaling pathways in response to cytokines and bacterial products.

Targeted ablation of TRAF6 inhibits skeletal muscle wasting in mice.

Skeletal muscle wasting is a major human morbidity, and contributes to mortality in a variety of clinical settings, including denervation and cancer cachexia. In this study, we demonstrate that the expression level and autoubiquitination of tumor necrosis factor (α) receptor adaptor protein 6 (TRAF6), a protein involved in receptor-mediated activation of several signaling pathways, is enhanced in skeletal muscle during atrophy. Skeletal muscle-restricted depletion of TRAF6 rescues myofibril degradation and preserves muscle fiber size and strength upon denervation.

Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice.

Impairment in the regeneration process is a critical determinant for skeletal muscle wasting in chronic diseases and degenerative muscle disorders. Inflammatory cytokines are known to cause significant muscle wasting, however, their role in myofiber regeneration is less clear. In this study we have investigated the role of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) in skeletal muscle regeneration in vivo.

Tumor necrosis factor-related weak inducer of apoptosis augments matrix metalloproteinase 9 (MMP-9) production in skeletal muscle through the activation of nuclear factor-kappaB-inducing kinase and p38 mitogen-activated protein kinase: a potential role of MMP-9 in myopathy.

Destruction of skeletal muscle extracellular matrix is an important pathological consequence of many diseases involving muscle wasting. However, the underlying mechanisms leading to extracellular matrix breakdown in skeletal muscle tissues remain unknown. Using a microarray approach, we investigated the effect of tumor necrosis factor-related weak inducer of apoptosis (TWEAK), a recently identified muscle-wasting cytokine, on the expression of extracellular proteases in skeletal muscle.