Institute of Experimental Medicine CAS

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Head of the Center:

Prof. James Fawcett
Cambridge Centre for Brain Repair
E-mail: jf108@cam.ac.uk
Phone: +420 241 062 828

eu-msmt-b

 

The project is financed by the Operational Program Research, Development and Education (OP RDE), which is a multi-annual thematic program backed by the Ministry of Education, Youth and Sports, which allows access to funding from European structural and investment funds in the 2014-2020 programming period. (ESIF).
 
The research team of the project is composed of researchers from the Institute of Experimental Medicine CAS (IEM), and partly from newly hired employees. The team is led by a leading foreign scientist prof. J. Fawcett (KZVP), who also works at the University of Cambridge, Department of Clinical Neurosciences. Currently, the progress of work and strategic issues are determined by the project steering committee (J. Fawcett, J. Kwok, P. Jendelová, L. Machová) and an external advisory team.

Prof. Fawcett prepared the strategic direction of a project focused on basic neuroscience research, aimed at using the results in medicine for the treatment of serious diseases and injuries of the central nervous system. The main goal is to increase the regeneration of axons and the plasticity of nerve tissue, both by genetic and enzymatic manipulation of the extracellular matrix and by altering the expression of endogenous molecules necessary for the transport of building molecules and axon growth., The research procedures and methods were specified, based on an internal discussion by the Steering Committee. The research agenda is divided into eight work packages (partial research projects) with relevant milestones and outputs.

Deputy Head of the Center:

Assoc. Prof. Pavla Jendelová, PhD
E-mail: pavla.jendelova@iem.cas.cz
Tel.: +420 241 062 828

Researchers:

Slaven Erceg, PhD
Milada Chudíčková, PhD
Kristýna Kárová, PhD
Jessica Kwok, PhD
Lucia Urdzíková-Machová, PhD
Jiří Růžička, PhD
Jana Svobodová Burianová, PhD

Postgraduate students:

Anda Cimpean
Noelia Martinez-Varea
Barbora Smejkalová
Kateřina Štěpánková
Ingrid Vargová
Michaela Petrovičová

Undergraduate students:

Tereza Špundová
Lenka Gmiterková

Technical staff:

Lucie Svobodová, PhD
Karel Třešňák

2020

  • presentation of results at the VIBes in Biosciences 2020 conference, Belgium

2019 

  • lecture by prof. Mark H. Tuszynski, M.D., Ph.D. (Director, Center for Neural Repair, Department of Neurosciences, University of California - San Diego) - Neural Stem Cells for Spinal Cord Injury
  • lecture by prof. Martin E. Schwab (Institute for Regenerative Medicine, University of Zurich and Dept. of Health Sciences and Technology, ETH Zurich) - Neurobiological mechanisms of functional recovery after spinal cord injury or stroke; from the lab bench to the clinic with a neurite growth-enhancing therapy
  • presentation of project results at the TERMIS European Chapter Meeting 2019, Greece
  • presentation of results at conference XIV. European Meeting on Glial Cells in Health and Diseases, Portugal
  • study stay of a member of the implementation team at the University of Leeds, Great Britain - the study of the effect of ECM disruption in the spinal cord lesion on the regeneration of spinal cord tissue
  • lecture by prof. Catherina G. Becker, FRSB (Center for Discovery Brain Sciences, The University of Edinburgh) - The immune systems controls successful spinal cord repair in zebrafish
  • presentation of results at the SFN Neuroscience 2019 conference

2018

  • lecture by Dr. Elisabeth Bradbury (King's College London) - Restoring function after spinal cord injury: targeting glial scar matrix and endogenous repair processes
  • lecture by Dr. Kristiana Franzeho (Department of Physiology, Development and Neuroscience University of Cambridge) - The mechanical regulation of neuronal development and regeneration
  • lecture by prof. Joosta Verhaagena (Netherlands Institute for Neuroscience) - Neuronal regeneration: from gene networks to gene therapy
  • lecture by prof. Britty Eickholt (Charité - Universitätsmedizin Berlin) - Injury induced drebrin controls astrogliosis and scar formation by regulating tubular endosomes and adhesion responses
  • Mgr. Neumann participated in a 3-day workshop on the application of viral vectors to spinal ganglia at the Netherlands Institute for Neuroscience, Amsterdam
  • three-month internship with Mgr. Hahn in the laboratory of Joao Relvas, Institute for Molecular and Cell Biology, University of Porto
  • Conference - Controlling neuronal plasticity - developmental disorders and repair in Villa Lanna, Prague

2017

  • conference - Regeneration, Plasticity, Protection (Prof. James Fawcett)
  • a two-day workshop of experts from the JOHN VAN GEEST CENTER FOR BRAIN REPAIR, which falls under the Department of Clinical Neuroscience at the University of Cambridge
  • DRG INJECTION WORKSHOP (Dr. Menghon Cheah)
  • Perineuronal net treatments for memory loss (Dr. Sujeong Yang)
  • training workshop on the topic of in situ isolation of DRG in the cervical and lumbar spine, accompanied by practical examples of how to open the correct vertebrae and identify the appropriate dorsal ganglia
  • established cooperation with Dr. Vincenzo de Paola of Imperial College London (in vivo imaging of organotypic sections) and Dr. Diego Peretti of the University of Cambridge (hibernation model)
  • three-month internship with Dr. Růžičky at the workplace of Dr. Vincenza di Paola
  • lecture by prof. Toshitaka Oohashi - The Hyaluronan and Proteoglycan Link Proteins: Organizers of the Brain ECM and Key Molecules for Neuronal Function and Plasticity
  • internship Mgr. Dubišová at the University of Cambridge
  • participation of project members at the TERMIS EU 2017 Congress of Tissue Engineering and Regenerative Medicine, organization of the symposium "New trends in CNS repair" within the congress, three lectures and two poster presentations
  • established cooperation with the group of Dr. Andras Lakatos from Cambridge, lecture on the topic: Regulatory networks controlling protective and detrimental astrocyte phenotypes in injury and ALS.
  • During the year, the Center's workplace was gradually built and investment equipment, including a Lightsheet microscope, was purchased

The role of perineural networks in-memory storage

Perineuronal networks (PNNs) play a key role in the maturation and plasticity of neurons and synapses. PNNs affect the formation, retention, and extinction of memory in various animal models. According to a recently published study, the eyes and cavities in the PNN contain synapses and can therefore function as a memory repository that is even stable in conditions during which synapse retraction occurs, such as anoxia or hibernation. We studied this theory in mice put into a state resembling hibernation, in which there is a retraction of synapses and, at the same time, we monitored the spatial memory of these animals before and after hibernation. We used normal animals and animals that had an absence of nets in the hippocampus area; either due to cleavage by the enzyme chondroitinase ABC or genetically removed aggrecan, which is an important part of PNN. In our model, synapse retraction during hibernation caused memory deficits, but not to the level of naive animals. Both groups with enzymatically cleaved networks (hibernating and non-hibernating) had changes in the level of synaptic proteins located on parvalbumin neurons in the hippocampus during and after hibernation, which resulted in faster re-learning in the Morris water maze compared to mice in hibernation and the retraction of synapses preserved by PNN. Chondroitinase did not alter the memory deficit, while the long-term absence of PNN in the aggrecan knockout group led to partial memory retention, but there was no improvement in re-learning the task in the water maze.

neurorecon1

Description of the figure: Electron beam electron microscopy was used to examine the number of active synapses in the CA1 region before, immediately and 24 hours after hibernation. We evaluated the number of active synapses at 37 ° C before and after cooling (16-18 ° C) (A). Only fully active synapses were taken for analysis, which newly appeared on the analyzed section (A1, detail A2). Both mice with intact and enzymatically cleaved perineural networks had a significantly reduced number of synapses immediately after hibernation, which resumed 24 hours later. However, in chondroitinase-treated animals, the number of synapses only returned to the level of the control animals and not to their own initial values. Also, the amount of the presynaptic marker Bassoon on parvalbumin-positive neurons temporarily decreased during hibernation and returned after 24 hours. HLS - a state resembling hibernation, CHABC chondroitinase, AGGKO aggrecan knockout.

 

The reduction of perineural networks by a hyaluronan synthase inhibitor improves the cognitive memory in mice

Hyaluronan (HA) is the basic molecule of the extracellular matrix in the central nervous system that forms the perineuronal networks (PNNs) that surround the subpopulations of neurons. PNNs control synaptic stabilization both during development and in the adult brain, and PNN disruption has shown the reactivation of nerve plasticity. We investigated the possibility of memory prolongation by reducing PNN production by an inhibitor of HA synthesis. Adult mice were fed a diet containing a 5% HA synthesis inhibitor for 6 months. This application reduced the level of glycosaminoglycans in the brain to 72% compared to the controls. The memory was tested using the New-Object Recognition Test (NOR) and the Spontaneous Alternation Test (SA). NOR tests were performed at 2, 3, 6 and 7 months with a delay of 3 h and 24 h after exposure to the subjects. A significant improvement in the NOR score was found in the animals treated with 4-MU at 3 and 6 months after a 24-hour delay, compared to the control group. However, 1 month after the end of treatment, the effect of the HA synthesis inhibitor on memory increase did not persist. Immunohistochemistry confirmed a decrease in PNN by lower intensity staining of Wisteria floribunda around neurons. In addition, a shorter and less arborization of aggrecan networks was observed around dendrites in the hippocampus after 6 months of HA synthesis inhibitor treatment.

neurorecon2

Description of the figure: Representative immunofluorescence staining of WFA in the hippocampal region of CA1-CA3 in the control group, the group treated for 6 months with an HA synthesis inhibitor and after 1 month of elution. (B) WFA staining intensity and a total number of WFA-positive cells in the hippocampal region. A significant decrease in WFA intensity staining was observed after 6 months of HA synthesis inhibitor administration and persisted after 1 month of washout compared to control. WOE - washing effect. Scale: 50 μm.

  • Koseki H, Donegá M, Lam BY, Petrova V, van Erp S, Yeo GS, Kwok JC, Ffrench-Constant C, Eva R, Fawcett JW. (2017) Selective Rab11 transport and the intrinsic regenerative ability of CNS axons. Elife. 6,  e26956. doi: 10.7554/eLife.26956.
  • Lukovic D, Diez Lloret A, Stojkovic P, Rodríguez-Martínez D, Perez Arago MA, Rodriguez-Jimenez FJ, González-Rodríguez P, López-Barneo J, Sykova E, Jendelova P, Kostic J, Moreno-Manzano V, Stojkovic M, Bhattacharya SS, Erceg S. Highly Efficient Neural Conversion of Human Pluripotent Stem Cells in Adherent and Animal-Free Conditions. Stem Cells Transl Med. 2017 Apr;6(4):1217-1226. doi: 10.1002/sctm.16-0371. Epub 2017 Feb 18.
  • Ruzicka J, Machova-Urdzikova L, Gillick J, Amemori T, Romanyuk N, Karova K, Zaviskova K, Dubisova J, Kubinova S, Murali R, Sykova E, Jhanwar-Uniyal M, Jendelova P. A Comparative Study of Three Different Types of Stem Cells for Treatment of Rat Spinal Cord Injury. Cell Transplant. 2017 Apr 13;26(4):585-603. doi: 10.3727/096368916X693671. Epub 2016 Nov 2. PubMed PMID: 27938489.
  • Kočí Z, Výborný K, Dubišová J, Vacková I, Jäger A, Lunov O, Jiráková K, Kubinová Š. Extracellular Matrix Hydrogel Derived from Human Umbilical Cord as a Scaffold for Neural Tissue Repair and Its Comparison with Extracellular Matrix from Porcine Tissues. Tissue Eng Part C Methods. 2017 Jun;23(6):333-345. doi: 10.1089/ten.TEC.2017.0089
  • Krupa P, Vackova I, Ruzicka J, Zaviskova K, Dubisova J, Koci Z, Turnovcova K, Urdzikova LM, Kubinova S, Rehak S, Jendelova P. The Effect of Human Mesenchymal Stem Cells Derived from Wharton's Jelly in Spinal Cord Injury Treatment Is Dose-Dependent and Can Be Facilitated by Repeated Application. Int J Mol Sci. 2018 May 17;19(5). pii: E1503. doi: 10.3390/ijms19051503.
  • Fawcett JW. The Paper that Restarted Modern Central Nervous System Axon Regeneration Research. Trends Neurosci. 2018 May;41(5):239-242. doi:10.1016/j.tins.2018.02.012.
  • Irvine SF, Kwok JCF. Perineuronal Nets in Spinal Motoneurones: Chondroitin Sulphate Proteoglycan around Alpha Motoneurones. Int J Mol Sci. 2018 Apr 12;19(4). pii: E1172. doi: 10.3390/ijms19041172.
  • Aggrecan directs extracellular matrix mediated neuronal plasticity. Daire Rowlands, Kristian K. Lensjø, Tovy Dinh, Sujeong Yang, Melissa R. Andrews, Torkel Hafting, Marianne Fyhn, James W. Fawcett and Gunnar Dick. JOURNAL OF NEUROSCIENCE, 10.1523/JNEUROSCI.1122-18.2018, 03.10.2018
  • Karova K, Wainwright, J. V. Machova-Urdzikova L, Pisal RV, Schmidt M, Jendelova P, Jhanwar-Uniyal, M.Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-B pathway inhibition. JOURNAL OF NEUROINFLAMMATION, 10.1186/s12974-019-1394-7, JAN 17 2019
  • Řehořová M, Vargová I, Forostyak S, Vacková I, Turnovcová K, Kupcová Skalníková H, Vodička P, Kubinová Š, Syková E, Jendelová P. A Combination of Intrathecal and Intramuscular Application of Human Mesenchymal Stem Cells Partly Reduces the Activation of Necroptosis in the Spinal Cord of SOD1(G93A) Rats. Stem Cells Transl Med. 2019 Feb 25. doi: 10.1002/sctm.18-0223. [Epub ahead of print] PubMed PMID: 30802001.
  • Duncan J, Foster R, Kwok JCF (2019) The Potential of Memory Enhancement through Perineuronal Net Modulation. Br J Pharmacol SEP 2019 DOI: 10.1111/bph.14672
  • Fawcett JW, Oohashi T, Pizzorusso T. The roles of perineuronal nets and the perinodal extracellular matrix in neuronal function. NATURE REVIEWS NEUROSCIENCE DOI: 10.1038/s41583-019-0196-3 AUG 2019
  • Vyborny K, Vallova J, Koci Z, Kekulova K, Jirakova K, Jendelova P, Hodan J, Kubinova S. Genipin and EDC crosslinking of extracellular matrix hydrogel derived from human umbilical cord for neural tissue repair. SCIENTIFIC REPORTS. DOI: 10.1038/s41598-019-47059-x. JUL 23 2019
  • Chudickova M, Vackova I, Urdzikova LM, Jancova P, Kekulova K, Rehorova M, Turnovcova K,  Jendelova P, Kubinova S. The Effect of Wharton Jelly-Derived Mesenchymal Stromal Cells and Their Conditioned Media in the Treatment of a Rat Spinal Cord Injury. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Doi:10.3390/ijms20184516 SEP 2 2019
  • Van't Spijker HM, Rowlands D, Rossier J, Haenzi B, Fawcett JW, Kwok JCF. Neuronal Pentraxin 2 Binds PNNs and Enhances PNN Formation. Neural Plast. 2019 Oct 20;2019:6804575. doi: 10.1155/2019/6804575. eCollection 2019. PubMed PMID: 31772567; PubMed Central PMCID: PMC6854953.
  • Neumannova K, Machova-Urdzikova L, Kwok JCF, Fawcett JW, Jendelova P. Adaptation of tape removal test for measurement of sensitivity in perineal area of rat. Exp Neurol. 2020 Feb;324:113097. doi: 10.1016/j.expneurol.2019.113097. Epub 2019 Nov 9. PubMed PMID: 31707082.
  • Rodriguez-Jimenez FJ, Clemente E, Moreno-Manzano V, Erceg S. Organized Neurogenic-Niche-Like Pinwheel Structures Discovered in Spinal Cord Tissue-Derived Neurospheres. Front Cell Dev Biol. 2019 Dec 20;7:334. doi: 10.3389/fcell.2019.00334. eCollection 2019. PubMed PMID: 31921846; PubMed Central PMCID: PMC6932972.
  • Svobodova B, Kloudova A, Ruzicka J, Kajtmanova L, Navratil L, Sedlacek R, Suchy T, Jhanwar-Uniyal M, Jendelova P, Urdzikova LM. ]The effect of 808 nm and 905 nm wavelength light on recovery after spinal cord injury. SCIENTIFIC REPORTS DOI: 10.1038/s41598-019-44141-2 MAY 21 2019
  • Burianová JS, Syka J. Postnatal exposure to an acoustically enriched environment alters the morphology of neurons in the adult rat auditory systém. BRAIN STRUCTURE & FUNCTIONDOI: 10.1007/s00429-020-02104-8  JUN 2020
  • Nieuwenhuis, B., A.C. Barber, R.S. Evans, C.S. Pearson, J. Fuchs, A.R. MacQueen, S. van Erp, B. Haenzi, L.A. Hulshof, A. Osborne, R. Conceicao, T.Z. Khatib, S.S. Deshpande, J. Cave, C. Ffrench-Constant, P.D. Smith, K. Okkenhaug, B.J. Eickholt, K.R. Martin, J.W. Fawcett, and R. Eva. 2020. PI 3-kinase delta enhances axonal PIP3 to support axon regeneration in the adult CNS. EMBO Mol Med:e11674.
  • Nieuwenhuis, B., B. Haenzi, S. Hilton, A. Carnicer-Lombarte, B. Hobo, J. Verhaagen, and J.W. Fawcett. 2020. Optimization of adeno-associated viral vector-mediated transduction of the corticospinal tract: comparison of four promoters. Gene Ther.  10.1038/s41434-020-0169-
  • Warren, P.M., M.R. Andrews, M. Smith, K. Bartus, E.J. Bradbury, J. Verhaagen, J.W. Fawcett, and J.C.F. Kwok. 2020. Secretion of a mammalian chondroitinase ABC aids glial integration at PNS/CNS boundaries. Sci Rep. 10:11262.
  • Balogova Z,  Popelar J, Chiumenti F, T, Burianova JS, Rybalko N, Syka J, Age-Related Differences in Hearing Function and Cochlear Morphology between Male and Female Fischer 344 Rats. FRONTIERS IN AGING NEUROSCIENCE DOI:10.3389/fnagi.2017.00428 JAN 4 2018
  • Forostyak S, Forostyak O, Kwok JCF, Romanyuk N, Rehorova M, Kriska J, Dayanithi G, Raha-Chowdhury R, Jendelova P, Anderova M, Fawcett JW, Sykova E. Transplantation of Neural Precursors Derived from Induced Pluripotent Cells Preserve Perineuronal Nets and Stimulate Neural Plasticity in ALS Rats. Int Mol Sci. 2020 Dec 16;21(24):9593. doi: 10.3390/ijms21249593. PMID: 33339362; PMCID: PMC7766921.
  • Krupa P, Stepankova K, Kwok JC, Fawcett JW, Cimermanova V, Jendelova P, Machova Urdzikova L. New Model of Ventral Spinal Cord Lesion Induced by Balloon Compression in Rats. Biomedicines. 2020 Nov 5;8(11):477. doi: 10.3390/biomedicines8110477. PMID: 33167447; PMCID: PMC7694490.
  • Petrova V, Pearson CS, Ching J, Tribble JR, Solano AG, Yang Y, Love FM, Watt RJ, Osborne A, Reid E, Williams PA, Martin KR, Geller HM, Eva R, Fawcett JW. Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS. Nat Commun. 2020 Nov 5;11(1):5614. doi: 10.1038/s41467-020-19436-y. PMID: 33154382; PMCID: PMC7645621.
  • University of Leeds, Faculty of Biological science
  • University of Cambridge, Cambridge Centre for Brain Repair
  • Netherlands Institute for Neuroscience
  • Imperial College London

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Building La 2nd floor, Office No. 2.18
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