Center of Regenerative Medicine

Dáša Čížková, DVM, DSc

Regenerative Medicine

The main objective is to identify the most effective strategies for repairing damaged nervous tissue that is dysfunctional due to trauma, aging and disease. We are achieving this through cell based therapy, particularly with the use of adult stem cells, genetically modified cells or biomaterials seeded with stem cells that are capable of mechanical and trophic support. The main impact is on autologous sources of mesenchymal stem cells (MSC) isolated from bone marrow and adipose tissue. Both are safe, relatively easily accessible cells that are tolerated without a substantial risk of immune rejection. Our previous studies clearly confirmed their paracrine actions via released trophic and growth factors, cytokines, chemokines, metabolites, and bioactive lipids which stimulate endogenous regeneration and influence immune response. Application of conditioned media (CM) containing bioactive factors released by stem cells has the same regenerative potential as direct transplantation of cells. Furthermore, CM contains extracellular vesicles (EVs) that mediate their paracrine effects by shuttling different types of RNAs (e.g., mRNA and miRNA) and proteins to recipient cells.

Prism

Therefore, in collaboration with Laboratoire PRISM – INSERM U1192, University Lille1 in France we are elucidating the protein cargo of stem cells-derived EVs and identifying candidate proteins and biological signatures associated with the postulated therapeutic effects.

Thus, delivery of CM-derived active factors may open the door to a new clinical approaches for CNS treatment. Our research efforts focus on carefully selected cell based or CM based therapy for treating: i) CNS trauma, and ii) dementia associated with cognitive impairment in older dogs. The main strategy of cell based therapy is to modulate inflammatory processes, improve recovery and axonal outgrowth and synaptic structures in damaged nerve tissue.

Lab members

  • Tomáš Smolek, DVM, PhD
  • MSc. Adriana Murgoci (PhD student)
  • MSc. Veronika Kozubíková

Projects

  • Study of functional bio-implants and cell therapy for the CNS regeneration
  • APVV grant no. 15-0613
  • Duration: 1.10. 2016- 1.9. 2020
  • Funding: 239 982 EUR

Publications

  1. Devaux S, Cizkova D, Quanico J, Franck J, Nataf S, Pays L, Hauberg-Lotte L, Maass P, Kobarg JH, Kobeissy F, Meriaux C, Wisztorski M, Slovinska L, Blasko J, Cigankova V, Fournier I, Salzet M. Proteomic analysis of the spatio-temporal based molecular kinetics of acute spinal cord injury identifies a time- and segment-specific window for effective tissue repair. Mol Cell Proteomics, 2016 Aug;15(8):2641-70
  2. Corleto JA, Bravo-Hernández M, Kamizato K, Kakinohana O, Santucci C, Navarro MR, Platoshyn O,Cizkova D, Lukacova N, Taylor J, Marsala M. Thoracic 9 Spinal Transection-Induced Model of Muscle Spasticity in the Rat: A Systematic Electrophysiological and Histopathological Characterization. PLoS One. 2015 Dec 29;10(12):e0144642. doi: 10.1371/journal.pone.0144642. eCollection 2015.
  3. Grulova I, Slovinska L, Blaško J, Devaux S, Wisztorski M, Salzet M, Fournier I, Kryukov O, Cohen S, Cizkova D. Delivery of Alginate Scaffold Releasing Two Trophic Factors for Spinal Cord Injury Repair. Sci Rep. 2015 Sep 8;5:13702. doi: 10.1038/srep13702.
  4. Dasa Cizkova, Stephanie Devaux, Françoise Le Marrec-Croq, Julien Franck, Lucia Slovinska, Juraj Blasko, Jan  Rosocha, Timea Spakova, Christophe Lefebvre, Isabelle Fournier, Michel Salzet. Modulation properties of bone  marrow stromal cells released factors on activated microglia: in vitro  study, Scientific Reports ,4: 7514, 2014
  5. Kuricova M, Ledecky V, Liptak T, Madari A, Grulova I, Slovinska L, Nagyova M,Cizkova D. Oral administration of inosine promotes recovery after experimental spinal cord injury in rat. Neurol Sci. 35:1785–1791, 2014
  6. Cizkova D, Le Marrec-Croq F, Franck J, Slovinska L, Grulova I, Devaux S, Lefebvre C, Fournier I, Salzet M. Alterations of protein composition along the rostro-caudal axis after spinal cord injury: proteomic, in vitro and in vivo analyses.Front Cell Neurosci. 2014 Apr 17;8:105. doi: 10.3389/fncel.2014.00105. e Collection 2014.
  7. Nagyova M, Slovinska L, Blasko J, Grulova I, Kuricova M, Cigankova V, Harvanova D,Cizkova D. A comparative study of PKH67, DiI, and BrdU labeling techniques for tracing rat mesenchymal stem cells. In Vitro Cell Dev Biol Anim. 2014
  8. Grulova I, Slovinska L, Nagyova M, Cizek M, Cizkova D. The effect of hypothermia on sensory-motor function and tissue sparing after spinal cord injury.Spine J. 2013 Dec;13(12):1881-91.
  9. Grulova I, Slovinska L, Nagyova M, Cizek M, Cizkova D. The effect of hypothermia on sensory- motor function and tissue sparing after spinal cord injury. Spine J. 13(12) 1881-1891, 2013 Sep 5.
  10. Cizkova D, Slovinska L, Grulova I, Salzet M, Cikos S, Kryukov O, Cohen S. The influence of sustained dual-factor presentation on the expansion and differentiation of neural progenitors in affinity-binding alginate scaffolds. J Tissue Eng Regen Med J Tissue Eng Regen Med. 2015 Aug;9(8):918-29. doi: 10.1002/term.1797.
  11. PÉGO, Ana paula – KUBINOVÁ, Sarka – ČÍŽKOVÁ, Dáša – VANICKÝ, Ivo – MAR, Fernando Milhazes – SOUSA, Mónica Mendes – SYKOVA, Eva. Regenerative medicine for the treatment of spinal cord injury: more than just promises? In Journal of Cellular and Molecular Medicine, 2012, vol. 16, no. 11, p. 2564-2582. (4.125 – IF2011). (2012 – Current Contents). ISSN 1582-1838.
  12. Cizkova D, Novotna I, Slovinska L, Vanicky I, Jergova S, Rosocha J, Radonak J. Repetitive intrathecal catheter delivery of bone marrow mesenchymal stromal cells improves functional recovery in a rat model of contusive spinal cord injury. J Neurotrauma, 28(9):1951-61, 2011
  13. Novotna I, Slovinska L, Vanicky I, Cizek M, Radonak J, Cizkova D. IT Delivery of ChABC Modulates NG2 and Promotes GAP-43 Axonal Regrowth After Spinal Cord Injury. Cell Mol Neurobiol, (8):1129-39,  2011
  14. Mashkina AP, Cizkova D, Vanicky I, Boldyrev AA. NMDA receptors are expressed in lymphocytes activated both in vitro and in vivo. Cell Mol Neurobiol, 30(6):901-7, 2010
  15. Cizkova, D., Cizek, M., Nagyova, M., Slovinska, L., Novotna, I., Jergova, S., Radonak, J., Hlucilova, J., Vanicky, I. Enrichment of rat oligodendrocyte progenitor cells by magnetic cell sorting. Journal of Neuroscience  Methods, 184(1),  88-94, 2009.
  16. Cizkova, D., Nagyova, M., Slovinska, L., Novotna, I., Radonak, J., Cizek, M., Mechirova, E., Tomori, Z., Hlucilova, J., Motlik, J., Sulla, I. Jr., Vanicky, I. Response of ependymal progenitors to spinal cord injury or enhanced physical activity in adult rat. Cellular and Molecular Neurobiology, 29(6-7), 999-1013, 2009.
  17. Saganova, K., Orendacova, J., Sulla, I. Jr., Filipcik, P., Cizkova, D., Vanicky, I. Effects of long-term FK506 administration on functional and histopathological outcome after spinal cord injury in adult rat. Cellular and Molecular Neurobiology, 29(6-7), 1045-1051, 2009.
  18. Saganova, K., Orendacova, J., Cizkova, D., Vanicky, I. Limited minocycline neuroprotection after balloon-compression spinal cord injury in the rat. Neuroscience Letters, 433(3), 246-249, 2008.
  19. Jergova, S., Kolesar, D., Cizkova, D. Expression of c-Fos in the parabrachial nucleus following peripheral nerve injury in rats. European Journal of  Pain, 12(2), 172-179,2008.
  20. Cizkova, D., Kakinohana O., Kucharova K., Marsala S., Johe, , Hazel,  T., Hefferan, M.P., Marsala, M. Functional recovery in rats with ischemic paraplegia after spinal grafting of human spinal stem cells. Neuroscience, 147(2), 546-560, 2007.
  21. Jergova S., Cizkova D.: Microglial activation in different models of peripheral nerve injury of the rat. Journal of Molecular Histology, 38(3), 245-51, 2007.
  22. Cizkova, D., Rosocha, J., Vanicky, I., Jergova, S., Cizek, M. Transplants of human mesenchymal stem cells improve functional recovery after spinal cord injury in the rat. Cellular and Molecular  Neurobiology, 26(7-8), 1167-1180, 2006.
  23. Cizkova, D., Rosocha, J., Vanicky, I., Radonak, J., Galik, J., Cizek, M. Induction of mesenchymal stem cells leads to HSP72 synthesis and higher resistance to oxidative stress. Neurochemical Research, 31(8), 1011-1120, 2006.
  24. Saganova, K., Burda, J., Orendacova, J., Cizkova, D., Vanicky, I. Fluoro-Jade B staining following zymosan microinjection into the spinal cord white matter. Cellular and Molecular  Neurobiology, 26(7-8), 1463-1473, 2006.
  25. Allen, J.W., Mantyh, P.W., Horais, K., Tozier, N., Rogers, S.D., Ghilardi, J.R., Cizkova, D., Grafe, M.R., Richter, P., Lappi, D.A., Yaksh, T.L. Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs. Toxicological Sciences, 91(1), 286-298, 2006.
  26. Racekova, E., Martoncikova, M., Mitruskova, B., Cizkova, D., Orendacova, J. Age-related changes of NADPH-diaphorase positivity in the rat rostral migratory stream. Cellular and Molecular  Neurobiology, 25(7), 1093-1105, 2005.
  27. Cizkova, D., Lukacova, N., Marsala, M., Kafka, J., Lukac, I., Jergova, S., Cizek, M., Marsala, J. Experimental cauda equina compression induces HSP70 synthesis in dog. Physiological Research, 54(3), 349-356, 2005.
  28. Orendacova, J., Ondrejcak, T., Kucharova, K., Cizkova, D., Jergova, S., Mitruskova, B., Racekova, E., Vanicky, I., Marsala, J. Fluoro-Jade B evidence of induced ischemic tolerance in the rat spinal cord ischemia: physiological, neurological and histopathological consequences. General Physiology and Biophysics, 24(1), 75-87, 2005.
  29. Jergova, S., Cizkova, D. Long-term changes of c-Fos expression in the rat spinal cord following chronic constriction injury. European Journal of  Pain, 9(3), 345-354, 2005.
  30. Marsala, M., Kakinohana, O., Hefferan, M.P., Cizkova, D., Kinjoh, K., Marsala, S. Synaptogenesis and amino acid release from long term embryonic rat spinal cord neuronal culture using tissue culture inserts. Journal of Neuroscience Methods, 141(1), 21-27, 2005.
  31. Marsala, M., Kakinohana, O., Yaksh, T.L., Tomori, Z., Marsala, S., Cizkova, D. Spinal implantation of hNT neurons and neuronal precursors: graft survival and functional effects in rats with ischemic spastic paraplegia. European Journal of Neuroscience, 20(9), 2401-2014, 2004.
  32. Kakinohana, O., Cizkova, D., Tomori, Z., Hedlund, E., Marsala, S., Isacson, O., Marsala, M. Region-specific cell grafting into cervical and lumbar spinal cord in rat: a qualitative and quantitative stereological study. Experimental Neurology, 190(1), 122-132, 2004.
  33. Marsala, J., Lukacova, N., Cizkova, D., Lukac, I., Kucharova, K., Marsala, M. Premotor nitric oxide synthase immunoreactive pathway connecting lumbar segments with the ventral motor nucleus of the cervical enlargement in the dog. Journal of Chemical Neuroanatomy, 27(1), s. 43-54, 2004.
  34. Lukacova, N., Kafka, J., Cizkova, D., Marsala, M., Marsala, J. The effect of cauda equina constriction on nitric oxide synthase activity. Neurochemical Research, 29(2), 429-439, 2004.
  35. Cizkova, D., Carmel, J.B., Yamamoto, K., Kakinohana, O., Sun, D., Hart, R.P., Marsala, M. Characterization of spinal HSP72 induction and development of ischemic tolerance after spinal ischemia in rats. Experimental Neurology, 185(1),  97-108, 2004.
  36. Tokumine, J., Kakinohana, O., Cizkova, D., Smith, D.W., Marsala, M. Changes in spinal GDNF, BDNF, and NT-3 expression after transient spinal cord ischemia in the rat Journal of  Neuroscience  Research, 74(4), 552-561, 2003.
  37. Sasara, T., Cizkova, D., Mestril, R., Galik, J., Sugahara, K., Marsala, M. Spinal heat shock protein (70) expression: effect of spinal ischemia, hyperthermia (42 degrees C)/hypothermia (27 degrees C), NMDA receptor activation and potassium evoked depolarization on the induction. Neurochemistry International, 44(1), 53-64, 2004.
  38. Marsala, J., Kafka, J., Lukacova, N., Cizkova, D., Marsala M., Katsube N. Cauda equina syndrome and nitric oxide synthase immunoreactivity in the spinal cord of the dog. Physiological Research, 52(4), 2003, s. 481-496.
  39. Burda, J., Hrehorovska, M., Bonilla, L.G., Danielisova, V., Cizkova, D., Burda, R., Nemethova, M., Fando, J.L., Salinas, M. Role of protein synthesis in the ischemic tolerance acquisition induced by transient forebrain ischemia in the rat. Neurochemical Research, 28(8), 2003, s. 1213-1219.
  40. Hayes, C.S., Mulkmus, S.A., Cizkova, D., Yaksh, T.L., Hua, X.Y. A double-lumen intrathecal catheter for studies of modulation of spinal opiate tolerance. Journal of Neuroscience  Methods, 30;126(2), 2003 s.165-173.
  41. Marsala, J., Marsala, M., Lukacova, N., Ishikawa, T., Cizkova, D. Localization and distribution patterns of nicotinamide adenine dinucleotide phosphate diaphorase exhibiting axons in the white matter of the spinal cord of the rabbit. Cellular and Molecular Neurobiology, 23(1), 2003, s. 57-92.
  42. Horais, K., Hruby, V., Rossi, S., Cizkova, D., Meschter, C., Dorr, R., Yaksh, T.L. Effects of chronic intrathecal infusion of a partial differential opioid agonist in dogs. Toxicological Sciences, 71(2), 2003, s. 263-275.
  43. Jergova, S., Cizkova, D., Orendacova, J, Cizek, M., Marsala, J. Localization of c-Fos protein in the rat spinal cord after carrageenan treatment. Acta Histochemica, 104(4), 2002, s. 381-385
  44. Lukacova, N., Cizkova, D., Krizanova, O., Pavel, J., Marsala, M., Marsala, J. Peripheral axotomy affects nicotinamide adenine dinucleotide phosphate diaphorase and nitric oxide synthases in the spinal cord of the rabbit. Journal of Neuroscience  , 71(2), 2003, s. 300-313.
  45. Cizkova, D., Marsala, J., Lukacova, N., Marsala, M., Jergova, S., Orendacova, J., Yaksh, T.L. Localization of N-type Ca2+ channels in the rat spinal cord following chronic constrictive nerve injury. Experimental Brain Research, 147(4), 2002, s. 456-463.
  46. Marsala, J., Lukacova, N., Cizkova, D., Kafka, J., Katsube, N., Kucharova, K., Marsala, M. The case for the bulbospinal respiratory nitric oxide synthase-immunoreactive pathway in the dog. Experimental Neurology, 177(1), 2002, s. 115-132.
  47. Lukacova, N., Cizkova, D., Marsala, M., Lukac, I., Marsala, J. The regional distribution of nitric oxide synthase activity in the spinal cord of the dog. Brain Research Bulletin, 58(2), 2002, s. 173-178.
  48. Cizkova, D., Lukacova, N., Marsala, M., Marsala, J. Neuropathic pain is associated with alterations of nitric oxide synthase immunoreactivity and catalytic activity in dorsal root ganglia and spinal dorsal horn. Brain Research Bulletin, 58(2), 2002, s. 161-71.
  49. Malatova, Z., Cizkova, D. Effect of ethanol on axonal transport of cholinergic enzymes in rat sciatic nerve. Alcohol, 26(2), 2002, s. 115-120.
  50. Vanicky, I., Urdzikova, L., Saganova, K., Cizkova, D., Galik, J. A simple and reproducible model of spinal cord injury induced by epidural balloon inflation in the rat. J.ournal of Neurotrauma, 18(12), 2001, s. 1399-407.
  51. Orendacova, J., Marsala, M., Cizkova, D., Kafka, J., Racekova, E., Sulla, I., Vanicky, I., Marsala J. Fos protein expression in sacral spinal cord in relation to early phase of cauda equina syndrome in dogs. Cellular and Molecular  Neurobiology, 21(4), 2001, s. 413-419.
  52. Orendacova, J., Cizkova, D., Kafka, J., Lukacova, N., Marsala, M., Sulla, I., Marsala, J., Katsube, N.: Cauda equina syndrome. Progress in Neurobiology, 64(6), 613-637, 2001.
  53. Luo, ZD., Cizkova, D. The role of nitric oxide in nociception. Current Review of  Pain, 4(6), 2000, s. 459-466.
  54. Lukacova, N., Cizkova, D., Marsala, M., Pavel, J., Jalc, P., Sulla, I., Kafka, J., Marsala, J. Effect of midthoracic spinal cord constriction on catalytic nitric oxide synthase activity in the white matter columns of rabbit. Neurochemical Research, 25(8), 2000, s. 1139-1148.
  55. Cizkova, D., Vanicky, I., Ishikawa, T., Marsala, M. Time course of brain neuronal degeneration and heat shock protein (72) expression following neck tourniquet-induced cerebral ischemia in the rat. Cellular and Molecular  Neurobiology, 20(3), 2000, s. 367-381.
  56. Orendacova, J., Marsala, M., Sulla I., Kafka, J., Jalc, P., Cizkova, D., Taira, Y., Marsala, J. Incipient cauda equina syndrome as a model of somatovisceral pain in dogs: spinal cord structures involved as revealed by the expression of c-fos and NADPH diaphorase activity. Neuroscience, 95(2), 2000, s.543-557.
  57. Lukacova, N., Cizkova, D., Marsala, M., Jalc, P., Marsala, J. Segmental and laminar distributions of nicotinamide adenine dinucleotide phosphate-diaphorase-expressing and neuronal nitric oxide synthase-immunoreactive neurons versus radioassay detection of catalytic nitric oxide synthase activity in the rabbit spinal cord. Neuroscience, 94(1), 1999, s. 229-37.
  58. Cizkova, D., Dillmann, W., Mestril, R., Cizek, M., Marsala, M. Regional distribution of HSP72 in brain and spinal cord in transgenic rats. Biologia, 54, Suppl.6, 1999, 93-101.
  59. Luo, ZD., Chaplan, SR., Scott, B.P., Cizkova, D., Calcutt, N.A., Yaksh, T.L:. Neuronal nitric oxide synthase mRNA upregulation in rat sensory neurons after spinal nerve ligation: lack of a role in allodynia development. The Journal of Neuroscience., 19(21), 1999, s. 9201-9208.
  60. Vanicky, I., Cizkova, D., Prosbova, T., Marsala, M. Audiogenic seizures after neck tourniquet-induced cerebral ischemia in the rat. Brain Research, 766(1-2), 1997, 262-265.
  61. Cizkova, D., Racekova, E., Vanicky, I. The expression of B-50/GAP-43 and GFAP after bilateral olfactory bulbectomy in rats. Physiological Research, 46(6), 1997, s. 487-495.
  62. Cizkova, D., Vanicky, I., Gottlieb, M., Marsala, J. Ischemic damage in the hippocampus: a silver impregnation and immunocytochemical study in the rat. Archives Italiennes de Biologie, 134(4), 1996, s. 279-290.
  63. Cizkova, D., Sekerkova, G., Oestreicher, A.B., Gispen, W.H., Zigova, T. Distribution of growth associated protein (B-50/GAP-43) and glial fibrillary acidic protein (GFAP) immunoreactivity in rat homotopic olfactory bulb transplants. Archives Italiennes de Biologie, 133(4), 1995, s.237-250.
  64. Pechan, P., Cizkova, D., Murgacova, M., Malatova, Z. Effect of nerve growth factor on lesioned PC12 cells. Cell Biology International Reports, 15(6), 1991, s.527-535.