Explore the vast range of titles available.

Changes in extracellular matrix proteins may contribute significantly to the adaptation of vein grafts to the arterial circulation. We examined the production and distribution of versican and hyaluronan in intact human vein rings cultured ex vivo, veins perfused ex vivo, and cultured venous adventitial and smooth muscle cells. Immunohistochemistry revealed higher levels of versican in the intima/media compared to the adventitia, and no differences in hyaluronan. In the vasa vasorum, versican and hyaluronan associated with CD34+ progenitor cells. Culturing the vein rings for 14 days revealed increased versican immunostaining of 30-40% in all layers, with no changes in hyaluronan. Changes in versican accumulation appear to result from increased synthesis in the intima/media and decreased degradation in the adventitia as versican transcripts were increased in the intima/media, but unchanged in the adventitia, and versikine (the ADAMTS-mediated cleavage product of versican) was increased in the intima/media, but decreased in the adventitia. In perfused human veins, versican was specifically increased in the intima/media in the presence of venous pressure, but not with arterial pressure. Unexpectedly, cultured adventitial cells express and accumulate more versican and hyaluronan than smooth muscle cells. These data demonstrate a differential regulation of versican and hyaluronan in human venous adventitia vs. intima/media and suggest distinct functions for these extracellular matrix macromolecules in these venous wall compartments during the adaptive response of vein grafts to the arterial circulation.

Background A major class of axon growth-repulsive molecules associated with CNS scar tissue is the family of chondroitin sulphate proteoglycans (CSPGs). Experimental spinal cord injury (SCI) has demonstrated rapid re-expression of CSPGs at and around the lesion site. The pharmacological digestion of CSPGs in such lesion models results in substantially enhanced axonal regeneration and a significant functional recovery. The potential therapeutic relevance of interfering with CSPG expression or function following experimental injuries seems clear, however, the spatio-temporal pattern of expression of individual members of the CSPG family following human spinal cord injury is only poorly defined. In the present correlative investigation, the expression pattern of CSPG family members NG2, neurocan, versican and phosphacan was studied in the human spinal cord. Methods An immunohistochemical investigation in post mortem samples of control and lesioned human spinal cords was performed. All patients with traumatic SCI had been clinically diagnosed as having \"complete\" injuries and presented lesions of the maceration type. Results In sections from control spinal cord, NG2 immunoreactivity was restricted to stellate-shaped cells corresponding to oligodendrocyte precursor cells. The distribution patterns of phosphacan, neurocan and versican in control human spinal cord parenchyma were similar, with a fine reticular pattern being observed in white matter (but also located in gray matter for phosphacan). Neurocan staining was also associated with blood vessel walls. Furthermore, phosphacan, neurocan and versican were present in the myelin sheaths of ventral and dorsal nerve roots axons. After human SCI, NG2 and phosphacan were both detected in the evolving astroglial scar. Neurocan and versican were detected exclusively in the lesion epicentre, being associated with infiltrating Schwann cells in the myelin sheaths of invading peripheral nerve fibres from lesioned dorsal roots. Conclusion NG2 and phosphacan were both present in the evolving astroglial scar and, therefore, might play an important role in the blockade of successful CNS regeneration. Neurocan and versican, however, were located at the lesion epicentre, associated with Schwann cell myelin on regenerating peripheral nerve fibres, a distribution that was unlikely to contribute to failed CNS axon regeneration. The present data points to the importance of such correlative investigations for demonstrating the clinical relevance of experimental data.

The proteoglycan versican is implicated in growth and metastases of several cancers. Here we investigated a potential contribution of stromal versican to tumor growth and angiogenesis. We initially determined versican expression by several cancer cell lines. Among these, MDA-MB231 and B16F10 had none to minimal expression in contrast to Lewis lung carcinoma (LLC). Notably, tumors arising from these cell lines had higher versican levels than the cell lines themselves suggesting a contribution from the host-derived tumor stroma. In LLC-derived tumors, both the tumor and stroma expressed versican at high levels. Thus, tumor stroma can make a significant contribution to tumor versican content. Versican localized preferentially to the vicinity of tumor vasculature and macrophages in the tumor. However, an ADAMTS protease-generated versican fragment uniquely localized to vascular endothelium. To specifically determine the impact of host/stroma-derived versican we therefore compared growth of tumors from B16F10 cells, which produced littleversican, in Vcan hdf/ + mice and wild-type littermates. Tumors in Vcan hdf/ + mice had reduced growth with a lower capillary density and accumulation of capillaries at the tumor periphery. These findings illustrate the variability of tumor cell line expression of versican, and demonstrate that versican is consistently contributed by the stromal tissue, where it contributes to tumor angiogenesis.

Androgenic alopecia (AGA) is the most common type of hair loss, where local high concentrations of dihydrotestosterone (DHT) in the scalp cause progressive shrinkage of the hair follicles, eventually contributing to hair loss. Due to the limitations of existing methods to treat AGA, the use of multi-origin mesenchymal stromal cell-derived exosomes has been proposed. However, the functions and mechanisms of action of exosomes secreted by adipose mesenchymal stromal cells (ADSCs-Exos) in AGA are still unclear. Using Cell Counting Kit-8 (CCK8) analysis, immunofluorescence staining, scratch assays, and Western blotting, it was found that ADSC-Exos contributed to the proliferation, migration, and differentiation of dermal papilla cells (DPCs) and up-regulated the expression of cyclin, β-catenin, versican, and BMP2. ADSC-Exos also mitigated the inhibitory effects of DHT on DPCs and down-regulated transforming growth factor-beta1 (TGF-β1) and its downstream genes. Moreover, high-throughput miRNA sequencing and bioinformatics analysis identified 225 genes that were co-expressed in ADSC-Exos; of these, miR-122-5p was highly enriched and was found by luciferase assays to target SMAD3. ADSC-Exos carrying miR-122-5p antagonized DHT inhibition of hair follicles, up-regulated the expression of β-catenin and versican in vivo and in vitro, restored hair bulb size and dermal thickness, and promoted the normal growth of hair follicles. So, ADSC-Exos enhanced the regeneration of hair follicles in AGA through the action of miR-122-5p and the inhibition of the TGF-β/SMAD3 axis. These results suggest a novel treatment option for the treatment of AGA.

Versican has been reported to participate in carcinogenesis in several malignant tumors. However, the accurate role of VersicanV1, a predominant isoform of Versican in liver, remains an enigma in hepatocellular carcinoma (HCC). The expression of VersicanV1 in HCC tissues and adjacent tissues was detected by Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western Blot (WB) and inmumohistochemistry (IHC). Gain and loss of function assays were performed to examine the role of VersicanV1 in proliferation and metastasis of HCC. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in vitro and PET-CT (positron emission tomography/computed tomography) analysis in vivo were applied to evaluate the effects of VersicanV1 on glycolysis. RNA sequencing, Co-IP (Co-immunoprecipitation) and MS (mass spectrometry) were utilized to investigate the molecular mechanisms. Our current study reveals that VersicanV1, regulated by direct interaction with Linc01225, is significantly upregulated in HCC tissues and correlates with poor prognosis. Both in vitro and in vivo experiments show that knockdown of VersicanV1 in HCC cells attenuates cancer cells malignancy. Further studies identify the positive role of VersicanV1 in aerobic glycolysis. Mechanistic investigation discovers the activation of EGFR–PI3K–AKT pathway in HCC cells expressing high VersicanV1. Moreover, EGF-like motif is indispensable for VersicanV1 to promote Warburg effect of HCC cells and subsequently, proliferation, invasion, and metastasis ability via activation of EGFR–PI3K–AKT axis. In sum, our research highlights a novel role of VersicanV1 in the progression of HCC, suggesting that VersicanV1 is an indicator for prognosis and a potential therapeutic target of HCC.

Versican drives metastasis Distant-site metastases are the leading cause of cancer-associated mortality. A study of the inflammatory microenvironment of cancer cells has identified versican, an extracellular matrix proteoglycan, as a possible factor in driving metastasis. It was isolated from the highly metastatic Lewis lung carcinoma cells as a potent inducer of macrophage activation. Versican, which is upregulated in many human tumours, stimulates bone marrow cells via the Toll-like receptor TLR2 to produce the inflammatory protein TNF-?, which enhances the spread of metastases. This points to versican and the other components of this signalling pathway as potential targets for antimetastatic intervention. Lung carcinoma cells were found to secrete the extracellular matrix proteoglycan versican. Versican directly activates the TLR2 receptor complex on macrophages, which in turn promotes tumour metastasis by producing TNF-?. Thus cancer cells utilize signalling pathways of the innate immune system to support metastatic spread. Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours 1 , 2 . To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) 3 were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-α (TNF-α) through activation of the Toll-like receptor (TLR) family members 4 TLR2 and TLR6. Both TNF-α and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer 5 , 6 , as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-α secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors 7 , to generate an inflammatory microenvironment hospitable for metastatic growth.

Hyaluronan is a structural component of the expanded cumulus matrix, and hyaluronan synthase 2 is the major enzyme for the synthesis of hyaluronan in humans. Versican cross-links the hyaluronan-rich matrix to cumulus cells and is critical for successful ovulation. Activin A is a critical intrafollicular regulator of ovarian function. Although activin A has been shown to promote cumulus matrix expansion in mice, the functional role of activin A in the regulation of cumulus expansion in the human ovary remains to be elucidated. Using primary and immortalized human granulosa-lutein cells as study models, we provide the first data showing that activin A increased the production of hyaluronan by upregulating the expression of hyaluronan synthase 2 in these cells. Additionally, activin A also promoted the expression of the hyaluronan-binding protein versican. Moreover, using inhibitor- and small interfering RNA-mediated inhibition approaches, we found that these stimulatory effects of activin A are most likely mediated through the type I receptor activin receptor-like kinase (ALK4)-mediated Sma- and Mad-related protein (SMAD2)/SMAD3-SMAD4 signaling pathway. Notably, the chromatin immunoprecipitation analyses demonstrated that SMAD4 could bind to human hyaluronan synthase 2 and VERSICAN promoters. The results obtained from this in vitro study suggest that locally produced activin A plays a functional role in the regulation of hyaluronan production and stabilization in human granulosa-lutein cells. Summary sentence The results obtained from this in vitro study suggest that a locally produced intraovarian growth factor (activin A) may play a functional role in the regulation of hyaluronan production and stabilization in the human ovary. Graphical Abstract

The tumor cell-intrinsic cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway is critical for activating anti-tumor immunity and enhancing immune checkpoint blockade therapy in colorectal cancer (CRC). Cancer-associated fibroblasts (CAFs), key components of the CRC tumor microenvironment, negatively regulate the anti-tumor immune response. However, their impact on tumor cell-intrinsic cGAS–STING expression remains unclear. In the present study, we investigated whether CAFs can downregulate cGAS–STING expression in CRC. We found that cGAS–STING expression in tumor cells inversely correlated with stromal expression of versican (VCAN), an immunosuppressive CAF marker, in CRC tissues. Co-culture experiments using primary human CAFs derived from CRC tissues revealed that CAFs downregulated cGAS and/or STING expression in CRC cell lines (WiDr, LoVo, HCT116). Furthermore, CAFs expressing VCAN and fibronectin 1 appeared to mediate this suppression. These findings suggest that immunosuppressive CAFs contribute to the downregulation of tumor cell-intrinsic cGAS–STING expression in CRC. Therefore, targeting CAFs to restore cGAS–STING expression may represent a promising strategy to enhance the efficacy of CRC treatment.

Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2 CreER :MAPT mGFP mice illuminating newly formed GFP +  oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP +  profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS. Ghorbani and colleagues describe versican-V1 as an inhibitor of remyelination using transgenic mice that illuminate new GFP  +  oligodendrocytes. Mechanisms of versican-V1 include the direct inhibition of oligodendrocytes, and elevating Th17 cells.