SummaryThe radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.
Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called glioma stem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional subtypes. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.
Key Points• IL-33-induced neutrophil recruitment in vivo is mast celldependent. This is partly mediated through the mast cell release of TNF-␣.• IL-33-treated human mast cells induce neutrophil migration in vitro. IL-33 is a recently discovered cytokine involved in induction of IntroductionIL-33 is a recently described cytokine of the IL-1 family that is expressed by a variety of cell types, most notably by epithelial and endothelial cells. 1 IL-33 promotes Th2 responses 2,3 and has been suggested to function as an alarmin when released on necrosis. 4-7 IL-33 is inactivated during apoptosis, 8 and unlike IL-1 and IL-18, it does not require proteolytical processing for activation. 4,9 Recently, we demonstrated that of all endogenous compounds released on necrosis, IL-33 alone is a key alarmin responsible for mast-cell activation. 5 Furthermore, IL-33 has emerged as a potent regulator of mast cell activity; inducing cytokine release, adhesion, maturation, and IgE-mediated degranulation. [10][11][12][13][14][15][16][17] In addition to mast cells, IL-33 activates several other cell types by signaling through the IL-33 receptor (IL-33R), including eosinophils, 18-20 basophils, 21-24 and dendritic cells. [25][26][27] Furthermore, a new family of IL-33R-positive innate lymphoid cells, including nuocytes, has been described during the last years. 28 Moreover, IL-33 has been implicated in the pathogenesis of several diseases (reviewed by Liew et al 1 ), including asthma 29,30 and arthritis. 31,32 Importantly, mast cells might have a central role in IL-33-associated diseases, as IL-33 for instance has been shown to exacerbate collagen-induced arthritis through a mast celldependent mechanism. 32 On the other hand, IL-33 has been ascribed several beneficial functions, including a cardioprotective function, 33 a protective role in atherosclerosis, 34 as well as an important role in helminth infections. 3 Thus, IL-33, similar to mast cells, exerts beneficial or detrimental effects depending on the local environment, which makes IL-33 an interesting cytokine with therapeutic potential.Despite this accumulated knowledge, much remains to be investigated regarding IL-33 functions in vivo. It was previously reported that IL-33 participates in the recruitment of mononuclear cells, 35 and a recent study reported that mice injected intravenously with IL-33 before cecal ligation and puncture recruited more neutrophils to the peritoneum than did mice treated with PBS, 36 thus displaying a reduced sepsis mortality rate.In this study we investigated the cellular responses to intraperitoneal IL-33 injections in mice and further addressed the responsiveness of human mast cells to IL-33. Our data demonstrate that a large proportion of the IL-33R ϩ cells in the peritoneal cavity are c-Kit ϩ Fc⑀RI ϩ mast cells, and that IL-33 induces neutrophil influx in the peritoneum of mice through a mast cell-dependent mechanism partly dependent on mast cell-derived TNF. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From Methods ...
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