23 results found
Clements MP, Byrne E, Camarillo Guerrero LF, et al., 2017, The wound microenvironment reprogrammes Schwann cells to invasive mesenchymal- like cells to drive peripheral nerve regeneration, Neuron, Vol: 96, Pages: 98-114.e7, ISSN: 0896-6273
Schwann cell dedifferentiation from a myelinating to a progenitor-like cell underlies the remarkable ability of peripheral nerves to regenerate following injury. However, the molecular identity of the differentiated and dedifferentiated states in vivo has been elusive. Here, we profiled Schwann cells acutely purified from intact nerves and from the wound and distal regions of severed nerves. Our analysis reveals novel facets of the dedifferentiation response, including acquisition of mesenchymal traits and a Myc module. Furthermore, wound and distal dedifferentiated Schwann cells constitute different populations, with wound cells displaying increased mesenchymal character induced by localized TGFβ signaling. TGFβ promotes invasion and crosstalks with Eph signaling via N-cadherin to drive collective migration of the Schwann cells across the wound. Consistently, Tgfbr2 deletion in Schwann cells resulted in misdirected and delayed reinnervation. Thus, the wound microenvironment is a key determinant of Schwann cell identity, and it promotes nerve repair through integration of multiple concerted signals.
Brooks LJ, Parrinello S, 2017, Vascular regulation of glioma stem-like cells: a balancing act, Current Opinion in Neurobiology, Vol: 47, Pages: 8-15, ISSN: 1873-6882
Glioblastoma (GBM) are aggressive and therapy-resistant brain tumours driven by glioma stem-like cells (GSCs). GSC behaviour is controlled by the microenvironment, or niche, in which the cells reside. It is well-established that the vasculature is a key component of the GSC niche, which drives maintenance in the tumour bulk and invasion at the margin. Emerging evidence now indicates that the specific properties of the vasculature within these two regions impose different functional states on resident GSCs, generating distinct subpopulations. Here, we review these recent findings, focusing on the mechanisms that underlie GSC/vascular communication. We further discuss how plasticity enables GSCs to respond to vascular changes by interconverting bidirectionally between states, and address the therapeutic implications of this dynamic response.
Krusche B, Ottone C, Clements MP, et al., 2016, EphrinB2 drives perivascular invasion and proliferation of glioblastoma stem-like cells, eLife, Vol: 5, ISSN: 2050-084X
Glioblastomas (GBM) are aggressive and therapy-resistant brain tumours, which contain a subpopulation of tumour-propagating glioblastoma stem-like cells (GSC) thought to drive progression and recurrence. Diffuse invasion of the brain parenchyma, including along preexisting blood vessels, is a leading cause of therapeutic resistance, but the mechanisms remain unclear. Here, we show that ephrin-B2 mediates GSC perivascular invasion. Intravital imaging, coupled with mechanistic studies in murine GBM models and patient-derived GSC, revealed that endothelial ephrin-B2 compartmentalises non-tumourigenic cells. In contrast, upregulation of the same ephrin-B2 ligand in GSC enabled perivascular migration through homotypic forward signalling. Surprisingly, ephrin-B2 reverse signalling also promoted tumourigenesis cell-autonomously, by mediating anchorage-independent cytokinesis via RhoA. In human GSC-derived orthotopic xenografts, EFNB2 knock-down blocked tumour initiation and treatment of established tumours with ephrin-B2-blocking antibodies suppressed progression. Thus, our results indicate that targeting ephrin-B2 may be an effective strategy for the simultaneous inhibition of invasion and proliferation in GBM.
Kwakwa K, Savell A, Davies T, et al., 2016, easySTORM: a robust, lower-cost approach to localisation and TIRF microscopy, Journal of Biophotonics, Vol: 9, Pages: 948-957, ISSN: 1864-0648
TIRF and STORM microscopy are super-resolving fluorescence imaging modalities for which current implementations on standard microscopes can present significant complexity and cost. We present a straightforward and low-cost approach to implement STORM and TIRF taking advantage of multimode optical fibres and multimode diode lasers to provide the required excitation light. Combined with open source software and relatively simple protocols to prepare samples for STORM, including the use of Vectashield for non-TIRF imaging, this approach enables TIRF and STORM imaging of cells labelled with appropriate dyes or expressing suitable fluorescent proteins to become widely accessible at low cost.
Cattin A-L, Burden JJ, Van Emmenis L, et al., 2015, Macrophage-Induced Blood Vessels Guide Schwann Cell-Mediated Regeneration of Peripheral Nerves, Cell, Vol: 162, Pages: 1127-1139, ISSN: 0092-8674
The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a ‘bridge’ of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as “tracks” to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue.
O'Loghlen A, Martin N, Krusche B, et al., 2015, The nuclear receptor NR2E1/TLX controls senescence, Oncogene, Vol: 34, Pages: 4069-4077, ISSN: 0950-9232
The nuclear receptor NR2E1 (also known as TLX or tailless) controls the self-renewal of neural stem cells (NSCs) and has been implied as an oncogene which initiates brain tumors including glioblastomas. Despite NR2E1 regulating targets like p21CIP1 or PTEN we still lack a full explanation for its role in NSC self-renewal and tumorigenesis. We know that polycomb repressive complexes also control stem cell self-renewal and tumorigenesis, but so far, no formal connection has been established between NR2E1 and PRCs. In a screen for transcription factors regulating the expression of the polycomb protein CBX7, we identified NR2E1 as one of its more prominent regulators. NR2E1 binds at the CBX7 promoter, inducing its expression. Notably CBX7 represses NR2E1 as part of a regulatory loop. Ectopic NR2E1 expression inhibits cellular senescence, extending cellular lifespan in fibroblasts via CBX7-mediated regulation of p16INK4a and direct repression of p21CIP1. In addition NR2E1 expression also counteracts oncogene-induced senescence. The importance of NR2E1 to restrain senescence is highlighted through the process of knocking down its expression, which causes premature senescence in human fibroblasts and epithelial cells. We also confirmed that NR2E1 regulates CBX7 and restrains senescence in NSCs. Finally, we observed that the expression of NR2E1 directly correlates with that of CBX7 in human glioblastoma multiforme. Overall we identified control of senescence and regulation of polycomb action as two possible mechanisms that can join those so far invoked to explain the role of NR2E1 in control of NSC self-renewal and cancer.
Whitby, Faisal AA, Parrinello S, 2015, Entropy measures of collective cell migration, Bulletin of the American Physical Society 60
Collective cell migration is a critical process during tissue formation and repair. To this end there is a need to develop tools to quantitatively measure the dynamics of collective cell migration obtained from microscopy data. Drawing on statistical physics we use entropy of velocity fields derived from dense optic flow to quantitatively measure collective migration. Using peripheral nerve repair after injury as experimental system, we study how Schwann cells, guided by fibroblasts, migrate in cord-like structures across the cut, paving a highway for neurons. This process of emergence of organised behaviour is key for successful repair, yet the emergence of leader cells and transition from a random to ordered state is not understood. We find fibroblasts induce correlated directionality in migrating Schwann cells as measured by a decrease in the entropy of motion vector. We show our method is robust with respect to image resolution in time and space, giving a principled assessment of how various molecular mechanisms affect macroscopic features of collective cell migration. Finally, the generality of our method allows us to process both simulated cell movement and microscopic data, enabling principled fitting and comparison of in silico to in vitro.
Ottone C, Krusche B, Whitby A, et al., 2014, Direct cell–cell contact with the vascular niche maintains quiescent neural stem cells, Nature Cell Biology, Vol: 16, Pages: 1045-1056, ISSN: 1465-7392
Guo L, Davis B, Nizari S, et al., 2014, Direct optic nerve sheath (DONS) application of Schwann cells prolongs retinal ganglion cell survival in vivo, Cell Death and Disease, Vol: 5, ISSN: 2041-4889
Cell-based therapies are increasingly recognized as a potential strategy to treat retinal neurodegenerative disease. Their administration, however, is normally indirect and complex, often with an inability to assess in real time their effects on cell death and their migration/integration into the host retina. In the present study, using a partial optic nerve transection (pONT) rat model, we describe a new method of Schwann cell (SC) delivery (direct application to injured optic nerve sheath, SC/DONS), which was compared with intravitreal SC delivery (SC/IVT). Both SC/DONS and SC/IVT were able to be assessed in vivo using imaging to visualize retinal ganglion cell (RGC) apoptosis and SC retinal integration. RGC death in the pONT model was best fitted to the one-phase exponential decay model. Although both SC/DONS and SC/IVT altered the temporal course of RGC degeneration in pONT, SC/DONS resulted in delayed but long-lasting effects on RGC protection, compared with SC/IVT treatment. In addition, their effects on primary and secondary degeneration, and axonal regeneration, were also investigated, by histology, whole retinal counting, and modelling of RGC loss. SC/DONS was found to significantly reduce RGC apoptosis in vivo and significantly increase RGC survival by targeting secondary rather than primary degeneration. Both SC/DONS and SC/IVT were found to promote RGC axonal regrowth after optic nerve injury, with evidence of GAP-43 expression in RGC somas and axons. SC/DONS may have the potential in the treatment of optic neuropathies, such as glaucoma. We show that SC transplantation can be monitored in real time and that the protective effects of SCs are associated with targeting secondary degeneration, with implications for translating cell-based therapies to the clinic.
Ribeiro S, Napoli I, White IJ, et al., 2013, Injury Signals Cooperate with Nf1 Loss to Relieve the Tumor-Suppressive Environment of Adult Peripheral Nerve, CELL REPORTS, Vol: 5, Pages: 126-136, ISSN: 2211-1247
Napoli I, Noon LA, Ribeiro S, et al., 2012, A Central Role for the ERK-Signaling Pathway in Controlling Schwann Cell Plasticity and Peripheral Nerve Regeneration In Vivo, NEURON, Vol: 73, Pages: 729-742, ISSN: 0896-6273
Cattin A-L, Rosenberg L, Quereda V, et al., 2012, The vasculature guides the collective migration of Schwann cells during peripheral nerve regeneration, MOLECULAR BIOLOGY OF THE CELL, Vol: 23, ISSN: 1059-1524
Parrinello S, Napoli I, Ribeiro S, et al., 2010, EphB Signaling Directs Peripheral Nerve Regeneration through Sox2-Dependent Schwann Cell Sorting, CELL, Vol: 143, Pages: 145-155, ISSN: 0092-8674
Danovi D, Cremona CA, Machado-da-Silva G, et al., 2010, A Genetic Screen for Anchorage-Independent Proliferation in Mammalian Cells Identifies a Membrane-Bound Neuregulin, PLOS ONE, Vol: 5, ISSN: 1932-6203
Coppe J-P, Patil CK, Rodier F, et al., 2010, A Human-Like Senescence-Associated Secretory Phenotype Is Conserved in Mouse Cells Dependent on Physiological Oxygen, PLOS ONE, Vol: 5, ISSN: 1932-6203
Parrinello S, Noon L, Harrisingh M, et al., 2009, NF1 LOSS DISRUPTS SCHWANN CELL-AXONAL INTERACTIONS: A NOVEL ROLE FOR SEMAPHORIN 4F, 9th European Meeting on Glial Cells in Health and Disease, Publisher: WILEY-LISS, Pages: S43-S43, ISSN: 0894-1491
Parrinello S, Lloyd AC, 2009, Neurofibroma development in NF1-insights into tumour initiation, TRENDS IN CELL BIOLOGY, Vol: 19, Pages: 395-403, ISSN: 0962-8924
Parrinello S, Noon LA, Harrisingh MC, et al., 2008, NF1 loss disrupts Schwann cell-axonal interactions: a novel role for semaphorin 4F, GENES & DEVELOPMENT, Vol: 22, Pages: 3335-3348, ISSN: 0890-9369
Parrinello S, Coppe JP, Krtolica A, et al., 2005, Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation, JOURNAL OF CELL SCIENCE, Vol: 118, Pages: 485-496, ISSN: 0021-9533
Parrinello S, Samper E, Krtolica A, et al., 2003, Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts, NATURE CELL BIOLOGY, Vol: 5, Pages: 741-747, ISSN: 1465-7392
Kim SH, Parrinello S, Kim J, et al., 2003, Mus musculus and Mus spretus homologues of the human telomere-associated protein TIN2, GENOMICS, Vol: 81, Pages: 422-432, ISSN: 0888-7543
Krtolica A, Parrinello S, Lockett S, et al., 2001, Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 98, Pages: 12072-12077, ISSN: 0027-8424
Lin CQ, Singh J, Murata K, et al., 2000, A role for Id-1 in the aggressive phenotype and steroid hormone response of human breast cancer cells, CANCER RESEARCH, Vol: 60, Pages: 1332-1340, ISSN: 0008-5472
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