Institute of Experimental Medicine CAS

The main topics studied in the Department are isolation, labelling and the use of stem cells for the treatment of brain injury, spinal cord and neurodegenerative diseases. Various types of cells (mesenchymal stem cells, neural precursor cell lines derived from fetal spinal cord, or from induced pluripotent cells) are studied, together with anti-inflammatory substances for their potential to promote the regeneration of nervous tissue. Macroporous polymeric hydrogels are used as suitable carriers for cell growth in in vitro cultures as well as for in vivo implantations facilitating the regeneration of the injured tissue. The aim of the cell therapy is to repair, replace or improve biological functions of the damaged neural tissue. For in vivo imaging of grafted cells and drug delivery we utilize magnetic nanoparticles, which are characterized in terms of cytotoxicity and genotoxicity and their influence on grafted cells and host tissue.

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Deputy Head:

Lucia Urdzíková-Machová, MD, PhD.
E-mail: lucia.machova@iem.cas.cz
Tel.: +420 241 062 619

Research Scientists:

Slaven Erceg, PhD.
Aleš Hejčl, MD, PhD.
Assoc. Prof. Pavla Jendelová, PhD.
Kristýna Kárová, PhD.
Petr Krůpa, MD, PhD.
Yuriy Petrenko, PhD.
Nataliya Romanyuk, PhD.
Jiří Růžička, PhD.
Karolína Turnovcová, MD, PhD.
Lucia Urdzíková-Machová, MD, PhD.
Barbora Valášková, PhD.

PhD. Students:

Ivan Arzhanov, MSc
Kateřina Havelíková, MSc
Dana Mareková, MSc
Michaela Petrovičová
Barbora Smejkalová, MSc
Kateřina Štěpánková, MSc
Ingrid Vargová, MSc
Eliška Vavřinová

Pre-Grad Students:

Lenka Gmiterková
Zuzana Šimková
Kristýna Šintáková
Tereza Špundová

Technicans:

Zuzana Čermáková
Michal Douděra
Lenka Kohoutová
Karel Třešňák

Important result in 2020

Ventral lesion - new experimental model of spinal cord

There is currently no suitable experimental model of ventral spinal cord injury, which is relatively common in humans. Ventral spinal cord compression was induced by epidural insertion of a 2F Fogarty catheter balloon at the level of the thoracic spinal cord. The balloon was quickly inflated with 10 or 15 μl of saline and left in place for 5 minutes. The size of the lesion correlates well with the volume of the catheter balloon. Compression of 15 μL led to severe motor and sensory damage, loss of motoneurons, and increased astrogliosis.

2020-ventralni-leze

Micro computed tomography (CT) images of ventral epidural catheter placement

In order to evaluate the position of the catheter (red arrows) in front of the spinal cord, micro CT with bone window (A,C) and soft tissue window (B) were applied. Furthermore, detailed images of the deflated balloon (D), as well as inflated to 10 µL (E) and 15 µL (F) volume balloon were obtained. Black arrows show the wire of the catheter, whereas white arrows point to the imaged saline solution indicating the amount of inflated Fogarty´s balloon. Scale bar: 2 mm.

 

Important result in 2019

The effect of hMSCs on cell death pathways in the spinal cord of ALS rats

An increasing number of studies have demonstrated the beneficial effects of human mesenchymal stem cells (hMSC) in the treatment of amyotrophic lateral sclerosis (ALS). We compared the effect of repeated intrathecal applications of hMSCor their conditioned medium (CondM) using lumbar puncture or injection into the muscle (quadriceps femoris), or a combination of both applications in symptomatic SOD1G93A rats. We further assessed the effect of the treatment on 3 major cell death pathways (necroptosis, apoptosis and autophagy) in the spinal cord tissue.

All symptomatic SOD1 rats treated with hMSC had a significantly increased lifespan, improved motor activity and reduced number of TUNEL positive cells. Moreover, a combined hMSC delivery increased motor neuron survival, maintained neuromuscular junctions in quadriceps femoris and substantially reduced the levels of proteins involved in necroptosis (Rip1, MLKL,cl-casp8), apoptosis (cl-casp 9) and autophagy (beclin 1). Furthermore, astrogliosis and elevated levels of Connexin 43 were decreased after combined hMSC treatment. The repeated application of CondM, or intramuscular injections alone, improved motor activity however, this improvement was not supported by changes at the molecular level. Our results provide new evidence that a combination of repeated intrathecal and intramuscular hMSC applications protects motor neurons and neuromuscular junctions, not only through a reduction of apoptosis and autophagy but also through the necroptosis pathway, which is significantly involved in cell death in rodent SOD1G93A model of ALS.

Repeated application of stem cells (hMSC) into spinal cord and muscles increased lifespan of the ALS rats, reduced expression of apoptotic protein cleaved caspase 9, necroptotic protein MLKL and beclin involved in autophagy (C). As a result we observed rescued motoneurons (D) and neuromuscular junctions (E) in cell treated ALS rats.

 

Important result in 2018

Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition

Transcription factors from the NFkB family are involved in a number of processes throughout cellular life. Mainly, they include immune responses including inflammation, cell survival, growth and development.

In our projects, we focused on determining levels of NFκB activation after experimental compression spinal cord trauma and changes in its activation after in situ transplantation of neural precursors (SPC-01) as well as on identifying mechanisms behind functional improvements induced by SPC-01 cells.

We found that activation of the NFκB pathway in the first month after injury has a bimodal character with the highest levels of activity at days 3 and 28, which reflected the host cellular response at the injury site and also correlated with infiltration waves of peripheral immune cells, which were determined by other research groups. Previously, a subacute administration of cells at 1 week after injury has been shown to be the most beneficial in transplantation therapies. In our work we showed that one of the reasons for this may be the observed decrease in NFκB activity at 7 days after the induction of injury. Administration of stem cells inhibited the pro-inflammatory NF-κB pathway with reduced TNF-α levels, and thus ameliorated the development of spinal cord injury.

  obrazek-vysledek-2018

Stem cells inhibit activation of inflammatory pathway in spinal cord injury

Immunohistochemical staining with hematoxylin and DAB (NF-kB p65) of spinal cord from uninjured rats (A, A1, A2), or 28 days after injury from rats treated with saline (B, B1, B2) or 28 days from rats transplanted with SPC-01 (C, C1, C2). Black arrows point to nuclei void of NF-kB p65 expression, red arrows highlight nuclei with translocated p65 and green arrows indicate cells with nuclei negative to p65 surrounded by p65+ cytoplasm (A1, A2, B1, B2, C1, C2). In the lesion center of spinal cords, a significantly lower NF-κB p65 activity was observed at 28 days in the group treated with SPC-01 cells (D). Transplantation of SPC-01 cells resulted in marked reduction of TNF-α levels 10 and 14 days after injury when compared with animals injected with saline only (E). Rats transplanted with SPC-01 cells displayed a significantly smaller cavity size than rats treated with saline (F). Reduction in gliosis was observed in the central parts of spinal cord lesion in rats transplanted with SPC-01 (G).

2020

Krůpa, P., Stěpánková, K., Kwok, J.C.F., Fawcett, J.W., Cimermanová, V., Jendelová, P., Machová Urdzíková, L.: (2020) New Model of Ventral Spinal Cord Lesion Induced by Balloon Compression in Rats. Biomedicines. 8(11): E477.

Artero-Castro, A., Rodriguez-Jiménez, F.J.,  Jendelová, P., VanderWall, K.B., Meyer, J.S., Erceg, S.: (2020) Glaucoma as a Neurodegenerative Disease Caused by Intrinsic Vulnerability Factors. Progress in Neurobiology. 193: 101817

Mareková, D., Turnovcová, K., Sursal, T.H., Gandhi, C.D., Jendelová, P., Jhanwar-Uniyal, M.: (2020) Potential for treatment of glioblastoma: New aspects of superparamagnetic iron oxide nanoparticles. Anticancer Research. 40(11): 5989-5994.

Petrenko, Y., Vacková, I., Kekulová, K., Chudičková, M., Koči, Z., Turnovcová, K., Skalníková-Kupcová, H., Vodička, P., Kubinová, Š.: (2020) A Comparative Analysis of Multipotent Mesenchymal Stromal Cells derived from Different Sources, with a Focus on Neuroregenerative Potential. Scientific Reports. 10(1): 4290.

Rodriguez-Jimenez, F.J., Vilches, A., Perez-Arago, M.A., Clemente, E., Roman, R., Leal, J., Castro, A.A., Fustero, S., Moreno-Manzano, V.,  Jendelová, P., Stojkovic, M., Erceg, S.: (2020) Activation of Neurogenesis in Multipotent Stem Cells Cultured in Vitro and in the Spinal Cord Tissue After Severe Injury by Inhibition of Glycogen Synthase Kinase-3. Neurotherapeutics. IN PRESS

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 J Mol Sci. 2020 Dec 16;21(24):9593.

 

2019

Androvic, P., Romanyuk, N., Urdziková-Machová, L., Rohlová, E,., Kubista, M., Valihrach, L.: (2019) Two-tailed RT-qPCR panel for quality control of circulating microRNA studies.  Scientific Reports. 9: 4255.

Artero Castro, A., Machuca, C., Rodriguez Jimenez, F.J., Jendelová, P., Erceg, S.: (2019) Short Review: Investigating ARSACS: models for understanding cerebellar degeneration. Neuropathology and Applied Neurobiology.45(6): 531-537.

Artero Castro, A., Rodríguez Jimenez, F.J., Jendelová, P., Erceg, S.: (2019) Deciphering Retinal Diseases through the Generation of Three Dimensional Stem Cell-derived Organoids. Stem Cells.

Artero-Castro, A., Popelka, Š., Jendelová, P., Motlík, J., Ardan, T., Jimenez, F.J.R., Erceg, S.: (2019)  The identification of small molecules that stimulate retinal pigment epithelial cells: potential novel therapeutic options for treating retinopathies. Expert Opinion on Drug Discovery. 14 (2): 169-177.

Herynek, V., Turnovcová, K., Galisová, A., Kaman, O., Mareková, D., Koktan, J., Vosmanská, M., Kosinoá, L., Jendelová, P.: (2019) Manganese-Zinc Ferrites: Safe and Efficient Nanolabels for Cell Imaging and Tracking In Vivo. ChemistryOpen. 8(2): 155-165.

Horák, D., Plichta, Z., Mareková, D., Turnovcová, K., Kaiser, R., Jendelová, P.: (2019) Poly[N‐(2‐hydroxypropyl)methacrylamide]‐modified magnetic γ‐F2O3 nanoparticles conjugated with doxorubicin for glioblastoma treatment. ChemMedChem.

Chudíčková, M., Vacková, I., Machová Urdzíková L., Jancová, P., Kekulová, K., Řehořová, M., Turnovcová, K., Jendelová, P., Kubinová, S. : (2019) 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. 20: 4516.

Jirák, D., Ziolkowska, N., Turnovcová, K., Kárová, K., Syková, E., Jendelová, P., Romanyuk, N.: (2019) Metabolic Changes in Focal Brain Ischemia in Rats Treated With Human Induced Pluripotent Stem Cell-Derived Neural Precursors Confirm the Beneficial Effect of Transplanted Cells. Frontiers in Neurology.10:1074.

Jiráková, K., Moskvin, M., Machová Urdzíková, L., Rössner, P., Elzeinová, F., Chudíčková, M., Jirák, D., Ziolkowská, N., Horák, D., Kubinová, Š., Jendelová, P.: (2019) The negative effect of magnetic nanoparticles with ascorbic acid on peritoneal macrophages. Neurochemical Research.

Krůpa, P., Svobodová, B., Dubišová, J., Kubinová, Š., Jendelová, P., Machová Urdzíková, L. : (2019) Nano-formulated curcumin (Lipodisq (TM)) modulates the local inflammatory response, reduces glial scar and preserves the white matter after spinal cord injury in rats. Neuropharmacology. 155: 54-64.

Machuca, C., Vilches, A., Clemente, E., Pascual-Pascual, S.I., Bolinches-Amoros, A., Castro, A.A., Espinos, C., Leon, M., Jendelová, P., Erceg, S.: (2018) Generation of human induced pluripotent stem cell (iPSC) line from an unaffected female carrier of mutation in SACSIN gene. Stem Cell Research. 33: 166-170.

Neumannová, K., Machová-Urdzíková, L., Kwok, J.C.F., Fawcett, J.W., Jendelová, P. : (2019) Adaptation of tape removal test for measurement of sensitivity in perineal area of rat. Experimental Neurology.

Opattová A., Horák, J., Vodenková, S., Kostovciková K., Čumová, A., Macinga,P., Galanová, N., Rejhová, A., Vodičková, L., Kozics, K., Turnovcová, K., Hucl, T., Slíva, D., Vodička, P.: (2019) Ganoderma Lucidum induces oxidative DNA damage and enhances the effect of 5-Fluorouracil in colorectal cancer in vitro and in vivo. Mutation Research - Genetic Toxicology and Environmental Mutagenesis. 845: 403065.

Petrenko, Y., Chudičková, M., Vacková, I., Groh, T., Košnarová, E., Čejková, J., Turnovcová, K., Petrenko, A., Syková, E., Kubinová, Š.: (2019) Clinically Relevant Solution for the Hypothermic Storage and Transportation of Human Multipotent Mesenchymal Stromal Cells. Stem Cells International. 2019: 590952.

Růžička, J., Romanyuk, N., Jiráková, K., Hejčl, A., Janoušková, O., Machová Urdziková, L., Bochin, M., Přádný, M., Vargová, L., Jendelová, P.: (2019) The Effect of iPS-Derived Neural Progenitors Seeded on Laminin-Coated pHEMA-MOETACl Hydrogel with Dual Porosity in a Rat Model of Chronic Spinal Cord Injury. Cell Transplantation. 28 (4): 400-412.

Růžička, J., Urdziková Machová, L., Kloudová, A., Amin, A.G., Vallová, J., Kubinová, Š., Schmidt, M.H., Jhanwar-Uniyal, M., Jendelová, P.: (2018) Anti-inflammatory compound curcumin and mesenchymal stem cells in the treatment of spinal cord injury in rats. Acta Neurobiologiae Experimentalis. 78(4): 358-374.

Řehořová, M., Vargová, I., Forostyak, S., Vacková, I., Turnovcová, K., Kupcová Skalníková, H., Vodička, P., Kubinová, S., Syková, E., Jendelová, P.: (2019) 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 Translational Medicine. 8 (6): 535-547.

Svobodová, B., Kloudová, A., Růžička, J., Kajtmanová, L., Navrátil, L., Sedláček, R., Suchý, T., Jhanwar-Uniyal, M., Jendelová, P., Machová Urdziková, L.: (2019) The effect of 808 nm and 905 nm wavelength light on recovery after spinal cord injury. Scientific Reports. 9: 7660.

Výborný, K., Vallová, J., Kočí, Z., Kekulová, Jiráková, K., Jendelová, P., Hodan, J., Kubinová, Š.: (2019) Genipin and EDC crosslinking of extracellular matrix hydrogel derived from human umbilical cord for neural tissue repair.  Scientific Reports. 9: 10674.

Skalnikova HK, Bohuslavova B, Turnovcova K, Juhasova J, Juhas S, Rodinova M, Vodicka P. Isolation and Characterization of Small Extracellular Vesicles from Porcine Blood Plasma, Cerebrospinal Fluid, and Seminal Plasma. Proteomes. 2019 Apr 25;7(2). pii: E17. doi: 10.3390/proteomes7020017. PubMed PMID: 31027284; PubMed Central PMCID: PMC6630935.

Petrenko Y, Chudickova M, Vackova I, Groh T, Kosnarova E, Cejkova J, Turnovcova K, Petrenko A, Sykova E, Kubinova S. Clinically Relevant Solution for the Hypothermic Storage and Transportation of Human Multipotent Mesenchymal
Stromal Cells. Stem Cells Int. 2019 Jan 20;2019:5909524. doi: 10.1155/2019/5909524. eCollection 2019. PubMed PMID: 30805009; PubMed Central PMCID: PMC6360551.

 

2018

Ruzicka J, Urdzikova LM, Kloudova A, Amin AG, Vallova J, Kubinova S, Schmidt MH, Jhanwar-Uniyal M, Jendelova P. Anti-inflammatory compound curcumin and mesenchymal stem cells in the treatment of spinal cord injury in rats. Acta Neurobiol Exp (Wars). 2018;78(4):358-374.

Artero-Castro A, Popelka S, Jendelova P, Motlik J, Ardan T, Rodriguez Jimenez FJ, Erceg S. The identification of small molecules that stimulate retinal pigment epithelial cells: potential novel therapeutic options for treating retinopathies. Expert Opin Drug Discov. 2019 Jan 8:1-9. doi: 10.1080/17460441.2019.1559148.

Plichta Z, Kozak Y, Panchuk R, Sokolova V, Epple M, Kobylinska L, Jendelová P, Horák D. Cytotoxicity of doxorubicin-conjugated poly[N-(2-hydroxypropyl)methacrylamide]-modified γ-Fe(2)O(3) nanoparticles towards human tumor cells. Beilstein J Nanotechnol. 2018 Sep 25;9:2533-2545. doi: 10.3762/bjnano.9.236.

Jendelova P, Sykova E, Erceg S. Neural Stem Cells Derived from Human-Induced Pluripotent Stem Cells and Their Use in Models of CNS Injury. Results Probl Cell Differ. 2018;66:89-102. doi: 10.1007/978-3-319-93485-3_3.

Hejčl A, Růžička J, Kekulová K, Svobodová B, Proks V, Macková H, Jiránková K, Kárová K, Machová Urdziková L, Kubinová Š, Cihlář J, Horák D, Jendelová P. Modified Methacrylate Hydrogels Improve Tissue Repair after Spinal Cord Injury. Int J Mol Sci. 2018 Aug 22;19(9). pii: E2481. doi: 10.3390/ijms19092481.

Hejčl A, Růžička J, Proks V, Macková H, Kubinová Š, Tukmachev D, Cihlář J, Horák D, Jendelová P. Dynamics of tissue ingrowth in SIKVAV-modified highly superporous PHEMA scaffolds with oriented pores after bridging a spinal cord transection. J Mater Sci Mater Med. 2018 Jun 25;29(7):89. doi: 10.1007/s10856-018-6100-2.

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.

Bolinches-Amorós A, Lukovic D, Castro AA, León M, Kamenarova K, Kaneva R, Jendelova P, Blanco-Kelly F, Ayuso C, Cortón M, Erceg S. Generation of a human iPSC line from a patient with congenital glaucoma caused by mutation in CYP1B1 gene. Stem Cell Res. 2018 Apr;28:96-99. doi: 10.1016/j.scr.2018.01.004.

Ruzicka J, Urdzikova LM, Svobodova B, Amin AG, Karova K, Dubisova J, Zaviskova K, Kubinova S, Schmidt M, Jhanwar-Uniyal M, Jendelova P. Does combined therapy of curcumin and epigallocatechin gallate have a synergistic neuroprotective effect against spinal cord injury? Neural Regen Res. 2018 Jan;13(1):119-127. doi: 10.4103/1673-5374.224379.

Artero Castro A, Lukovic D, Jendelova P, Erceg S. Concise Review: Human Induced Pluripotent Stem Cell Models of Retinitis Pigmentosa. Stem Cells. 2018 Apr;36(4):474-481. doi: 10.1002/stem.2783. Epub 2018 Feb 7. Review.

Karova, K., Wainwright, J.V, Machova-Urdzikova, L., Rishikaysh Pisal, R.V., Schmidt, M., Jendelova, P., Jhanwar-Uniyal, M. Transplantation of neural precursors generated from spinal progenitor cells reduces inflammation in spinal cord injury via NF-κB pathway inhibition. J Neuroinflammation in press doi: 10.1186/s12974-019-1394-7.

Center of Reconstruction Neuroscience – NEURORECON CZ.02.1.01/0.0/0.0/15_003/0000419 Coordinator Pavla Jendelova 2017–2022

 

GAČR 19-10365S Tuning perineuronal nets and glial scar as a treatment strategy for spinal cord injury

Co.Principal Investigator Milada Chudíčková, 2019-2021

 

GAČR 21-04420S Protective coatings against dissolution/disintegration of upconverting lanthanide-based nanoparticles in biological media

Co.Principal Investigator Lucia Machová Urdzíková MD, PhD 2021-2023

Institute for Clinical and Experimental Medicine
Institute of Macromolecular Chemistry CAS
Physical Institute CAS
2nd Faculty of Medicine, Charles University
Faculty of Medicine Hradec Králové, Charles University
Faculty of Biomedical Engineering, Czech Technical University
Faculty of Mechanical Engineering, Czech Technical University
Cambridge University, UK
University of Leeds, UK
Centro de Investigación Príncipe Felipe, Valencia, Spain
New York Medical College, Valhalla, USA

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