Robin J M Franklin

University of Cambridge, Cambridge, England, United Kingdom

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Publications (250)1656.75 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Remyelination within the central nervous system (CNS) most often is the result of oligodendrocyte progenitor cells differentiating into myelin-forming oligodendrocytes. In some cases, however, Schwann cells, the peripheral nervous system myelinating glia, are found remyelinating demyelinated regions of the CNS. The reason for this peripheral type of remyelination in the CNS and what governs it is unknown. Here, we used a conditional astrocytic phosphorylated signal transducer and activator of transcription 3 knockout mouse model to investigate the effect of abrogating astrocyte activation on remyelination after lysolecithin-induced demyelination of spinal cord white matter. We show that oligodendrocyte-mediated remyelination decreases and Schwann cell remyelination increases in lesioned knockout mice in comparison with lesioned controls. Our study shows that astrocyte activation plays a crucial role in the balance between Schwann cell and oligodendrocyte remyelination in the CNS, and provides further insight into remyelination of CNS axons by Schwann cells. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 07/2015; DOI:10.1016/j.ajpath.2015.05.011 · 4.60 Impact Factor
  • Robin J M Franklin
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    ABSTRACT: Stimulating an endogenous regenerative response is a powerful approach for potential treatment of chronic demyelinating diseases such as multiple sclerosis. Recently in Nature, Najm et al. (2015) identified two clinically relevant, FDA-approved compounds that promote oligodendrocyte progenitor cell differentiation and induce remyelination in demyelinating disease models. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell stem cell 06/2015; 16(6):576-577. DOI:10.1016/j.stem.2015.05.010 · 22.15 Impact Factor
  • Robin J M Franklin, Steven A Goldman
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    ABSTRACT: The inability of the mammalian central nervous system (CNS) to undergo spontaneous regeneration has long been regarded as a central tenet of neurobiology. However, although this is largely true of the neuronal elements of the adult mammalian CNS, save for discrete populations of granular neurons, the same is not true of its glial elements. In particular, the loss of oligodendrocytes, which results in demyelination, triggers a spontaneous and often highly efficient regenerative response, remyelination, in which new oligodendrocytes are generated and myelin sheaths are restored to denuded axons. Yet, remyelination in humans is not without limitation, and a variety of demyelinating conditions are associated with sustained and disabling myelin loss. In this review, we will review the biology of remyelination, including the cells and signals involved; describe when remyelination occurs and when and why it fails and the consequences of its failure; and discuss approaches for therapeutically enhancing remyelination in demyelinating diseases of both children and adults, both by stimulating endogenous oligodendrocyte progenitor cells and by transplanting these cells into demyelinated brain. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor perspectives in biology 05/2015; DOI:10.1101/cshperspect.a020594 · 8.23 Impact Factor
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    ABSTRACT: This study investigated the role of the complement activation fragment C5a in secondary pathology following contusive spinal cord injury (SCI). C5ar(-/-) mice, which lack the signaling receptor for C5a, displayed signs of improved locomotor recovery and reduced inflammation during the first week of SCI compared with wild-type mice. Intriguingly, the early signs of improved recovery in C5ar(-/-) mice deteriorated from day 14 onward, with absence of C5aR ultimately leading to poorer functional outcomes, larger lesion volumes, reduced myelin content, and more widespread inflammation at 35 d SCI. Pharmacological blockade of C5aR with a selective antagonist (C5aR-A) during the first 7 d after SCI improved recovery compared with vehicle-treated mice, and this phenotype was sustained up to 35 d after injury. Consistent with observations made in C5ar(-/-) mice, these improvements were, however, lost if C5aR-A administration was continued into the more chronic phase of SCI. Signaling through the C5a-C5aR axis thus appears injurious in the acute period but serves a protective and/or reparative role in the post-acute phase of SCI. Further experiments in bone marrow chimeric mice suggested that the dual and opposing roles of C5aR on SCI outcomes primarily relate to its expression on CNS-resident cells and not infiltrating leukocytes. Additional in vivo and in vitro studies provided direct evidence that C5aR signaling is required during the postacute phase for astrocyte hyperplasia, hypertrophy, and glial scar formation. Collectively, these findings highlight the complexity of the inflammatory response to SCI and emphasize the importance of optimizing the timing of therapeutic interventions. Copyright © 2015 the authors 0270-6474/15/356517-15$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 04/2015; 35(16):6517-31. DOI:10.1523/JNEUROSCI.5218-14.2015 · 6.75 Impact Factor
  • Miki Furusho, Aude J. Roulois, Robin J. M. Franklin, Rashmi Bansal
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    ABSTRACT: Remyelination is a potent regenerative process in demyelinating diseases, such as multiple sclerosis, the effective therapeutic promotion of which will fill an unmet clinical need. The development of proregenerative therapies requires the identification of key regulatory targets that are likely to be involved in the integration of multiple signaling mechanisms. Fibroblast growth factor (FGF) signaling system, which comprises multiple ligands and receptors, potentially provides one such target. Since the FGF/FGF receptor (FGFR) interactions are complex and regulate multiple diverse functions of oligodendrocyte lineage cells, it is difficult to predict their overall therapeutic potential in the regeneration of oligodendrocytes and myelin. Therefore, to assess the integrated effects of FGFR signaling on this process, we simultaneously inactivated both FGFR1 and FGFR2 in oligodendrocytes and their precursors using two Cre-driver mouse lines. Acute and chronic cuprizone-induced or lysolecithin-induced demyelination was established in Fgfr1/Fgfr2 double knockout mice (dKO). We found that in the acute cuprizone model, there was normal differentiation of oligodendrocytes and recovery of myelin in the corpus callosum of both control and dKO mice. Similarly, in the spinal cord, lysolecithin-induced demyelinated lesions regenerated similarly in the dKO and control mice. In contrast, in the chronic cuprizone model, fewer differentiated oligodendrocytes and less efficient myelin recovery were observed in the dKO compared to control mice. These data suggest that while cell-autonomous FGF signaling is redundant during recovery of acute demyelinated lesions, it facilitates regenerative processes in chronic demyelination. Thus, FGF-based therapies have potential value in stimulating oligodendrocyte and myelin regeneration in late-stage disease. GLIA 2015. © 2015 Wiley Periodicals, Inc.
    Glia 04/2015; DOI:10.1002/glia.22838 · 6.03 Impact Factor
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    ABSTRACT: The presence of neural stem/progenitor cells (NSPCs) in specific areas of the central nervous system (CNS) supports tissue maintenance as well as regeneration. The subependymal zone (SEZ), located at the lateral ventricle's wall, represents a niche for NSPCs and in response to stroke or demyelination becomes activated with progenitors migrating towards the lesion and differentiating into neurons and glia. The mechanisms that underlie this phenomenon remain largely unknown. The vascular niche and in particular blood-derived elements such as platelets, has been shown to contribute to CNS regeneration in different pathological conditions. Indeed, intracerebroventricularly administrated platelet lysate (PL) stimulates angiogenesis, neurogenesis and neuroprotection in the damaged CNS. Here, we explored the presence of platelets in the activated SEZ after a focal demyelinating lesion in the corpus callosum of mice and we studied the effects of PL on proliferating SEZ-derived NSPCs in vitro. We showed that the lesion-induced increase in the size of the SEZ and in the number of proliferating SEZ-resident NSPCs correlates with the accumulation of platelets specifically along the activated SEZ vasculature. Expanding on this finding, we demonstrated that exposure of NSPCs to PL in vitro led to increased numbers of cells by enhanced cell survival and reduced apoptosis without differences in proliferation and in the differentiation potential of NSPCs. Finally, we demonstrate that the accumulation of platelets within the SEZ is spatially correlated with reduced numbers of apoptotic cells when compared to other periventricular areas. In conclusion, our results show that platelet-derived compounds specifically promote SEZ-derived NSPC survival and suggest that platelets might contribute to the enlargement of the pool of SEZ NSPCs that are available for CNS repair in response to injury. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 03/2015; 269. DOI:10.1016/j.expneurol.2015.03.018 · 4.62 Impact Factor
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    ABSTRACT: The declining efficiency of myelin regeneration in individuals with multiple sclerosis has stimulated a search for ways by which it might be therapeutically enhanced. Here we have used gene expression profiling on purified murine oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the adult CNS, to obtain a comprehensive picture of how they become activated after demyelination and how this enables them to contribute to remyelination. We find that adult OPCs have a transcriptome more similar to that of oligodendrocytes than to neonatal OPCs, but revert to a neonatal-like transcriptome when activated. Part of the activation response involves increased expression of two genes of the innate immune system, IL1β and CCL2, which enhance the mobilization of OPCs. Our results add a new dimension to the role of the innate immune system in CNS regeneration, revealing how OPCs themselves contribute to the postinjury inflammatory milieu by producing cytokines that directly enhance their repopulation of areas of demyelination and hence their ability to contribute to remyelination. Copyright © 2015 the authors 0270-6474/15/350004-17$15.00/0.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 01/2015; 35(1):4-20. DOI:10.1523/JNEUROSCI.0849-14.2015 · 6.75 Impact Factor
  • Irish Journal of Medical Science 01/2015; 184:5-6. · 0.57 Impact Factor
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    Bangfu Zhu, Chao Zhao, Fraser I Young, Robin J M Franklin, Bing Song
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    ABSTRACT: Oligodendrocytes are the myelinating cells of the central nervous system (CNS). The isolation of purified oligodendrocyte progenitor cells (OPCs) in large numbers has been sought after as a source of cells for repair following CNS-demyelinating diseases and injuries, such as multiple sclerosis (MS) and spinal cord injury (SCI). Methods for isolation of OPCs from rodent neonatal brains are well established and have formed the basis for research in myelin repair within the CNS for many years. However, long-term maintenance of OPCs has been a challenge owing to small cellular yields per animal and spontaneous differentiation within a short period of time. Much effort has been devoted to achieving long-term culture and maintenance of OPCs, but little progress has been made. Here, protocols are presented for preparation of highly enriched rat OPC populations and for their long-term maintenance as oligospheres using mixed-glial-conditioned medium. Functional myelinating oligodendrocytes can be achieved from such protocols, when co-cultured with primary neurons. This approach is an extension of our normal shaking method for isolating OPCs, and incorporates some adaptations from previous OPC culture methods. © 2014 by John Wiley & Sons, Inc.
    Current Protocols in Stem Cell Biology 11/2014; 31:2D.17.1-2D.17.15. DOI:10.1002/9780470151808.sc02d17s31
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    Robin J M Franklin, Vittorio Gallo
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    ABSTRACT: Amongst neurological diseases, multiple sclerosis (MS) presents an attractive target for regenerative medicine. This is because the primary pathology, the loss of myelin-forming oligodendrocytes, can be followed by a spontaneous and efficient regenerative process called remyelination. While cell transplantation approaches have been explored as a means of replacing lost oligodendrocytes, more recently therapeutic approaches that target the endogenous regenerative process have been favored. This is in large part due to our increasing understanding of (1) the cell types within the adult brain that are able to generate new oligodendrocytes, (2) the mechanisms and pathways by which this achieved, and (3) an emerging awareness of the reasons why remyelination efficiency eventually fails. Here we review some of these advances and also highlight areas where questions remain to be answered in both the biology and translational potential of this important regenerative process. GLIA 2014;
    Glia 11/2014; 62(11). DOI:10.1002/glia.22622 · 6.03 Impact Factor
  • Robin J. M. Franklin, Evan Y. Snyder
    Experimental Neurology 10/2014; 260:1-2. DOI:10.1016/j.expneurol.2014.06.010 · 4.62 Impact Factor
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    ABSTRACT: The vacuole formation (VF) rat is an autosomal recessive myelin mutant characterized by generalized tremor, hypomyelination, and periaxonal vacuole formation of the central nervous system (CNS). Here, we report the most likely causative gene for neurological disease in the VF rat and pursue its roles in the development and maintenance of the CNS myelin. We identified a nonsense mutation in the dopey family member 1 (Dopey1) located on rat chromosome 8. Expression level of Dopey1 mRNA was decreased and DOPEY1 protein was undetectable both in the white and gray matter of the spinal cords in the VF rats. Double immunohistochemistry demonstrated that DOPEY1 was mainly expressed in neurons and oligodendrocytes in the wild-type rats, whereas no positive cells were detected in the VF rats. We also demonstrated a marked reduction in myelin components both at mRNA and protein levels during myelinogenesis in the VF rats. In addition, proteolipid protein and myelin-associated glycoprotein accumulated in oligodendrocyte cell body, suggesting that Dopey1 is likely to be involved in the traffic of myelin components. Our results highlighted the importance of Dopey1 for the development and maintenance of the CNS myelin. GLIA 2014.
    Glia 09/2014; 62(9). DOI:10.1002/glia.22698 · 6.03 Impact Factor
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    ABSTRACT: Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood-brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte-derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre-lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin-induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte-derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS. GLIA 2014
    Glia 08/2014; DOI:10.1002/glia.22748 · 6.03 Impact Factor
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    ABSTRACT: The role of remote astrocyte (AC) reaction to central or peripheral axonal insult is not clearly understood. Here we use a transgenic approach to compare the direct influence of normal with diminished AC reactivity on neuronal integrity and synapse recovery following extracranial facial nerve transection in mice. Our model allows straightforward interpretations of AC-neuron signalling by reducing confounding effects imposed by inflammatory cells. We show direct evidence that perineuronal reactive ACs play a major role in maintaining neuronal circuitry following distant axotomy. We reveal a novel function of astrocytic signal transducer and activator of transcription-3 (STAT3). STAT3 regulates perineuronal astrocytic process formation and re-expression of a synaptogenic molecule, thrombospondin-1 (TSP-1), apart from supporting neuronal integrity. We demonstrate that, through this new pathway, TSP-1 is responsible for the remote AC-mediated recovery of excitatory synapses onto axotomized motor neurons in adult mice. These data provide new targets for neuroprotective therapies via optimizing AC-driven plasticity.
    Nature Communications 07/2014; 5:4294. DOI:10.1038/ncomms5294 · 10.74 Impact Factor
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    ABSTRACT: Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis.
    Nature Medicine 07/2014; 20(8). DOI:10.1038/nm.3618 · 28.05 Impact Factor
  • Stephen Sawcer, Robin J M Franklin, Maria Ban
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    ABSTRACT: Genome-wide association studies have revolutionised the genetic analysis of multiple sclerosis. Through international collaborative efforts involving tens of thousands of cases and controls, more than 100 associated common variants have now been identified. These variants consistently implicate genes associated with immunological processes, overwhelmingly lie in regulatory rather than coding regions, and are frequently associated with other autoimmune diseases. The functional implications of these associated variants are mostly unknown; however, early work has shown that several variants have effects on splicing that result in meaningful changes in the balance between different isoforms in relevant tissues. Including the well established risk attributable to variants in genes encoding human leucocyte antigens, only about a quarter of reported heritability can now be accounted for, suggesting that a substantial potential for further discovery remains.
    The Lancet Neurology 07/2014; 13(7). DOI:10.1016/S1474-4422(14)70041-9 · 21.82 Impact Factor
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    ABSTRACT: Oligodendrocyte progenitors (OPs) are a major proliferating cell population within the adult CNS. In response to myelin loss or increasing demand, OPs have the capacity to differentiate into mature, myelinating oligodendrocytes. The name 'oligodendrocyte progenitor' suggests restriction to the oligodendrocyte cell lineage. However, with growing evidence of the lineage plasticity of OPs both in vitro and in vivo, we discuss whether they have potential beyond that expected of dedicated progenitor cells, and hence may justify categorization as adult stem cells.
    Experimental Neurology 05/2014; 260. DOI:10.1016/j.expneurol.2014.04.027 · 4.62 Impact Factor
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    ABSTRACT: Embryonic stem cells (ESCs) self-renew in a state of naïve pluripotency in which they are competent to generate all somatic cells. It has been hypothesized that, before irreversibly committing, ESCs pass through at least one metastable transition state. This transition would represent a gateway for differentiation and reprogramming of somatic cells. Here, we show that during the transition, the nuclei of ESCs are auxetic: they exhibit a cross-sectional expansion when stretched and a cross-sectional contraction when compressed, and their stiffness increases under compression. We also show that the auxetic phenotype of transition ESC nuclei is driven at least in part by global chromatin decondensation. Through the regulation of molecular turnover in the differentiating nucleus by external forces, auxeticity could be a key element in mechanotransduction. Our findings highlight the importance of nuclear structure in the regulation of differentiation and reprogramming.
    Nature Material 04/2014; 13(6). DOI:10.1038/nmat3943 · 36.43 Impact Factor
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    ABSTRACT: Myelination allows rapid saltatory propagation of action potentials along the axon and is an essential prerequisite for the normal functioning of the nervous system. During peripheral nervous system (PNS) development, myelin-forming Schwann cells (SCs) generate radial lamellipodia to sort and ensheath axons. This process requires controlled cytoskeletal remodeling, and we show that SC lamellipodia formation depends on the function of profilin 1 (Pfn1), an actin-binding protein involved in microfilament polymerization. Pfn1 is inhibited upon phosphorylation by ROCK, a downstream effector of the integrin linked kinase pathway. Thus, a dramatic reduction of radial lamellipodia formation is observed in SCs lacking integrin-linked kinase or treated with the Rho/ROCK activator lysophosphatidic acid. Knocking down Pfn1 expression by lentiviral-mediated shRNA delivery impairs SC lamellipodia formation in vitro, suggesting a direct role for this protein in PNS myelination. Indeed, SC-specific gene ablation of Pfn1 in mice led to profound radial sorting and myelination defects, confirming a central role for this protein in PNS development. Our data identify Pfn1 as a key effector of the integrin linked kinase/Rho/ROCK pathway. This pathway, acting in parallel with integrin β1/LCK/Rac1 and their effectors critically regulates SC lamellipodia formation, radial sorting and myelination during peripheral nervous system maturation.
    Development 03/2014; 141(7). DOI:10.1242/dev.101840 · 6.27 Impact Factor
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    Veronique E. Miron, Robin J. M. Franklin
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    ABSTRACT: Microglia are the resident macrophages of the central nervous system that survey the microenvironment for signals of injury or infection. The response to such signals induces an inflammatory response involving macrophages derived from both resident microglia and recruited circulating monocytes. Although implicated as contributors to autoimmune-mediated injury, microglia/ macrophages have recently been shown to be critical for the important central nervous system regenerative process of remyelination. This functional dichotomy may reflect their ability to be polarized along a continuum of activation states including the well-characterized cytotoxic M1 and regenerative M2 phenotypes. Here we review the roles of microglia, monocytes and the macrophages they give rise to in creating lesion environments favourable to remyelination, highlighting the specific roles of M1 and M2 phenotypes and how the pro-regenerative role of the innate immune system is altered by ageing. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 03/2014; DOI:10.1111/jnc.12705 · 4.24 Impact Factor

Publication Stats

12k Citations
1,656.75 Total Impact Points

Institutions

  • 1990–2015
    • University of Cambridge
      • • Department of Veterinary Medicine
      • • Brain Repair Centre
      Cambridge, England, United Kingdom
  • 2012–2013
    • The University of Edinburgh
      • • MRC Centre for Regenerative Medicine
      • • Centre for Neuroregeneration
      Edinburgh, SCT, United Kingdom
    • RWTH Aachen University
      • Department of Neuroanatomy
      Aachen, North Rhine-Westphalia, Germany
    • Massachusetts Institute of Technology
      • Department of Materials Science and Engineering
      Cambridge, MA, United States