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Bone Marrow Nucleated Cells and Bone Marrow-Derived CD271+ Mesenchymal Stem Cell in Treatment of Encephalopathy and Drug-Resistant Epilepsy

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Abstract

The broad spectrum of brain injuries in preterm newborns and the plasticity of the central nervous system prompts us to seek solutions for neurodegeneration to prevent the consequences of prematurity and perinatal problems. The study aimed to evaluate the safety and efficacy of the implantation of autologous bone marrow nucleated cells and bone marrow mesenchymal stem cells in different schemes in patients with hypoxic-ischemic encephalopathy and immunological encephalopathy. Fourteen patients received single implantation of bone marrow nucleated cells administered intrathecally and intravenously, followed by multiple rounds of bone marrow mesenchymal stem cells implanted intrathecally, and five patients were treated only with repeated rounds of bone marrow mesenchymal stem cells. Seizure outcomes improved in most cases, including fewer seizures and status epilepticus and reduced doses of antiepileptic drugs compared to the period before treatment. The neuropsychological improvement was more frequent in patients with hypoxic-ischemic encephalopathy than in the immunological encephalopathy group. Changes in emotional functioning occurred with similar frequency in both groups of patients. In the hypoxic-ischemic encephalopathy group, motor improvement was observed in all patients and the majority in the immunological encephalopathy group. The treatment had manageable toxicity, mainly mild to moderate early-onset adverse events. The treatment was generally safe in the 4-year follow-up period, and the effects of the therapy were maintained after its termination.

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References

  1. Passera, S., Boccazzi, M., Bokobza, C., Faivre, V., Mosca, F., Van Steenwinckel, J., & Fleiss, B. (2021). Therapeutic potential of stem cells for preterm infant brain damage: Can we move from the heterogeneity of preclinical and clinical studies to established therapeutics? Biochemical Pharmacology, 186, 114461. https://doi.org/10.1016/j.bcp.2021.114461

    Article  CAS  PubMed  Google Scholar 

  2. Vogel, J. P., Chawanpaiboon, S., Moller, A. B., Watananirun, K., Bonet, M., & Lumbiganon, P. (2018). The global epidemiology of preterm birth. Best Practice & Research Clinical Obstetrics Gynaecology, 52, 3–12. https://doi.org/10.1016/j.bpobgyn.2018.04.003

    Article  PubMed  Google Scholar 

  3. Hirvonen, M., Ojala, R., Korhonen, P., Haataja, P., Eriksson, K., Gissler, M., & Tammela, O. (2014). Cerebral palsy among children born moderately and late preterm. Pediatrics, 134(6), e1584–1593. https://doi.org/10.1542/peds.2014-0945

    Article  PubMed  Google Scholar 

  4. Tibrewal, M., Cheng, B., Dohare, P., Hu, F., Mehdizadeh, R., Wang, P., & Ballabh, P. (2018). Disruption of Interneuron Neurogenesis in premature newborns and reversal with Estrogen Treatment. The Journal Neuroscience, 38(5), 1100–1113. https://doi.org/10.1523/jneurosci.1875-17.2017

    Article  CAS  Google Scholar 

  5. Stolp, H. B., Fleiss, B., Arai, Y., Supramaniam, V., Vontell, R., Birtles, S., & Gressens, P. (2019). Interneuron Development is disrupted in Preterm brains with diffuse White Matter Injury: Observations in mouse and human. Frontiers in Physiology, 10, 955. https://doi.org/10.3389/fphys.2019.00955

    Article  PubMed  PubMed Central  Google Scholar 

  6. Back, S. A., & Miller, S. P. (2014). Brain injury in premature neonates: A primary cerebral dysmaturation disorder? Annals of Neurology, 75(4), 469–486. https://doi.org/10.1002/ana.24132

    Article  PubMed  PubMed Central  Google Scholar 

  7. Dean, J. M., McClendon, E., Hansen, K., Azimi-Zonooz, A., Chen, K., Riddle, A., & Back, S. A. (2013). Prenatal cerebral ischemia disrupts MRI-defined cortical microstructure through disturbances in neuronal arborization. Science Translational Medicine, 5(168), 168ra167. https://doi.org/10.1126/scitranslmed.3004669

    Article  CAS  Google Scholar 

  8. Rogers, C. E., Lean, R. E., Wheelock, M. D., & Smyser, C. D. (2018). Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children. Journal of Neurodevelopmental Disordders, 10(1), 38. https://doi.org/10.1186/s11689-018-9253-x

    Article  Google Scholar 

  9. Bobis, S., Jarocha, D., & Majka, M. (2006). Mesenchymal stem cells: Characteristics and clinical applications. Folia Histochemica et Cytobiologica, 44(4), 215–230.

    CAS  PubMed  Google Scholar 

  10. Compagna, R., Amato, B., Massa, S., Amato, M., Grande, R., Butrico, L., & Serra, R. (2015). Cell Therapy in Patients with Critical Limb Ischemia. Stem Cells International, 2015, 931420. https://doi.org/10.1155/2015/931420

  11. Milczarek, O., Jarocha, D., Starowicz-Filip, A., Kwiatkowski, S., Badyra, B., & Majka, M. (2018). Multiple autologous bone marrow-derived CD271(+) mesenchymal stem cell transplantation overcomes Drug-Resistant Epilepsy in Children. Stem Cells Translational Medicine, 7(1), 20–33. https://doi.org/10.1002/sctm.17-0041

    Article  CAS  PubMed  Google Scholar 

  12. Dimos, J. T., Rodolfa, K. T., Niakan, K. K., Weisenthal, L. M., Mitsumoto, H., Chung, W., & Eggan, K. (2008). Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science, 321(5893), 1218–1221. https://doi.org/10.1126/science.1158799

    Article  CAS  PubMed  Google Scholar 

  13. Civin, C. I., Strauss, L. C., Brovall, C., Fackler, M. J., Schwartz, J. F., & Shaper, J. H. (1984). Antigenic analysis of hematopoiesis. III. A hematopoietic progenitor cell surface antigen defined by a monoclonal antibody raised against KG-1a cells. Journal of Immunology, 133(1), 157–165.

    Article  CAS  Google Scholar 

  14. Kucia, M., Zhang, Y. P., Reca, R., Wysoczynski, M., Machalinski, B., Majka, M., & Ratajczak, M. Z. (2006). Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following Stroke. Leukemia, 20(1), 18–28. https://doi.org/10.1038/sj.leu.2404011

    Article  CAS  PubMed  Google Scholar 

  15. Majka, M., Janowska-Wieczorek, A., Ratajczak, J., Ehrenman, K., Pietrzkowski, Z., Kowalska, M. A., & Ratajczak, M. Z. (2001). Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood, 97(10), 3075–3085. https://doi.org/10.1182/blood.v97.10.3075

    Article  CAS  PubMed  Google Scholar 

  16. Taguchi, A., Soma, T., Tanaka, H., Kanda, T., Nishimura, H., Yoshikawa, H., & Matsuyama, T. (2004). Administration of CD34 + cells after Stroke enhances neurogenesis via angiogenesis in a mouse model. The Journal Clinical Investigation, 114(3), 330–338. https://doi.org/10.1172/jci20622

    Article  CAS  Google Scholar 

  17. Shyu, W. C., Lin, S. Z., Chiang, M. F., Su, C. Y., & Li, H. (2006). Intracerebral peripheral blood stem cell (CD34+) implantation induces neuroplasticity by enhancing beta1 integrin-mediated angiogenesis in chronic Stroke rats. The Journal of Neuroscience, 26(13), 3444–3453. https://doi.org/10.1523/jneurosci.5165-05.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao, L. R., Duan, W. M., Reyes, M., Keene, C. D., Verfaillie, C. M., & Low, W. C. (2002). Human bone marrow stem cells exhibit neural phenotypes and ameliorate neurological deficits after grafting into the ischemic brain of rats. Experimental Neurology, 174(1), 11–20. https://doi.org/10.1006/exnr.2001.7853

    Article  PubMed  Google Scholar 

  19. Hass, R., Kasper, C., Böhm, S., & Jacobs, R. (2011). Different populations and sources of human mesenchymal stem cells (MSC): A comparison of adult and neonatal tissue-derived MSC. Cell Communication and Signaling, 9, 12. https://doi.org/10.1186/1478-811x-9-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ullah, I., Subbarao, R. B., & Rho, G. J. (2015). Human mesenchymal stem cells - current trends and future prospective. Bioscience Reports, 35(2). https://doi.org/10.1042/bsr20150025

  21. Franco Lambert, A. P., Fraga Zandonai, A., Bonatto, D., Cantarelli Machado, D., & Pêgas Henriques, J. A. (2009). Differentiation of human adipose-derived adult stem cells into neuronal tissue: Does it work? Differentiation, 77(3), 221–228. https://doi.org/10.1016/j.diff.2008.10.016

    Article  CAS  PubMed  Google Scholar 

  22. Ma, K., Fox, L., Shi, G., Shen, J., Liu, Q., Pappas, J. D., & Qu, T. (2011). Generation of neural stem cell-like cells from bone marrow-derived human mesenchymal stem cells. Neurological Research, 33(10), 1083–1093. https://doi.org/10.1179/1743132811y.0000000053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Le Blanc, K. (2003). Immunomodulatory effects of fetal and adult mesenchymal stem cells. Cytotherapy, 5(6), 485–489. https://doi.org/10.1080/14653240310003611

    Article  PubMed  Google Scholar 

  24. Wechsler, L. R. (2009). Clinical trials of Stroke therapy: Which cells, which patients? Stroke, 40(3 Suppl), 149–151. https://doi.org/10.1161/strokeaha.108.533208

    Article  Google Scholar 

  25. Kode, J. A., Mukherjee, S., Joglekar, M. V., & Hardikar, A. A. (2009). Mesenchymal stem cells: Immunobiology and role in immunomodulation and tissue regeneration. Cytotherapy, 11(4), 377–391. https://doi.org/10.1080/14653240903080367

    Article  CAS  PubMed  Google Scholar 

  26. Ahn, S. Y., Chang, Y. S., Sung, D. K., Sung, S. I., Yoo, H. S., Lee, J. H., & Park, W. S. (2013). Mesenchymal stem cells prevent hydrocephalus after severe intraventricular Hemorrhage. Stroke, 44(2), 497–504. https://doi.org/10.1161/strokeaha.112.679092

    Article  CAS  PubMed  Google Scholar 

  27. Jiang, X. X., Zhang, Y., Liu, B., Zhang, S. X., Wu, Y., Yu, X. D., & Mao, N. (2005). Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood, 105(10), 4120–4126. https://doi.org/10.1182/blood-2004-02-0586

    Article  CAS  PubMed  Google Scholar 

  28. Park, K. I., Hack, M. A., Ourednik, J., Yandava, B., Flax, J. D., Stieg, P. E., & Snyder, E. Y. (2006). Acute injury directs the migration, proliferation, and differentiation of solid organ stem cells: Evidence from the effect of hypoxia-ischemia in the CNS on clonal reporter neural stem cells. Experimental Neurology, 199(1), 156–178. https://doi.org/10.1016/j.expneurol.2006.04.002

    Article  PubMed  Google Scholar 

  29. van Velthoven, C. T., Kavelaars, A., van Bel, F., & Heijnen, C. J. (2010). Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behaviour Immunity, 24(3), 387–393. https://doi.org/10.1016/j.bbi.2009.10.017

    Article  CAS  Google Scholar 

  30. Tan, J., Zheng, X., Zhang, S., Yang, Y., Wang, X., Yu, X., & Zhong, L. (2014). Response of the sensorimotor cortex of cerebral palsy rats receiving transplantation of vascular endothelial growth factor 165-transfected neural stem cells. Neural Regeneration Research, 9(19), 1763–1769. https://doi.org/10.4103/1673-5374.141785

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jarocha, D., Milczarek, O., Wedrychowicz, A., Kwiatkowski, S., & Majka, M. (2015). Continuous improvement after multiple mesenchymal stem cell transplantations in a patient with complete spinal cord injury. Cell Transplantion, 24(4), 661–672. https://doi.org/10.3727/096368915x687796

    Article  Google Scholar 

  32. Matczak, A., Jaworska, A., & Ciechanowicz, A. (2007). Dziecieca skala rozwojowa, skala wykonaniowa, skala obserwacyjna Retrieved from Warsaw.

  33. Ahn, S. Y., Park, W. S., Sung, S. I., & Chang, Y. S. (2021). Mesenchymal stem cell therapy for intractable neonatal disorders. Pediatrics and Neonatology, 62 Suppl(1), S16–s21. https://doi.org/10.1016/j.pedneo.2020.11.007

    Article  Google Scholar 

  34. Wang, X., Cheng, H., Hua, R., Yang, J., Dai, G., Zhang, Z., & An, Y. (2013). Effects of bone marrow mesenchymal stromal cells on gross motor function measure scores of children with cerebral palsy: A preliminary clinical study. Cytotherapy, 15(12), 1549–1562. https://doi.org/10.1016/j.jcyt.2013.06.001

    Article  PubMed  Google Scholar 

  35. Chen, G., Wang, Y., Xu, Z., Fang, F., Xu, R., Wang, Y., & Liu, H. (2013). Neural stem cell-like cells derived from autologous bone mesenchymal stem cells for the treatment of patients with cerebral palsy. Journal of Translational Mededicine, 11, 21. https://doi.org/10.1186/1479-5876-11-21

    Article  CAS  Google Scholar 

  36. Pimentel-Coelho, P. M., Magalhães, E. S., Lopes, L. M., deAzevedo, L. C., Santiago, M. F., & Mendez-Otero, R. (2010). Human cord blood transplantation in a neonatal rat model of hypoxic-ischemic brain damage: Functional outcome related to neuroprotection in the striatum. Stem Cells and Development, 19(3), 351–358. https://doi.org/10.1089/scd.2009.0049

    Article  PubMed  Google Scholar 

  37. Sun, J., Allison, J., McLaughlin, C., Sledge, L., Waters-Pick, B., Wease, S., & Kurtzberg, J. (2010). Differences in quality between privately and publicly banked umbilical cord blood units: A pilot study of autologous cord blood infusion in children with acquired neurologic disorders. Transfusion, 50(9), 1980–1987. https://doi.org/10.1111/j.1537-2995.2010.02720.x

    Article  PubMed  Google Scholar 

  38. Zali, A., Arab, L., Ashrafi, F., Mardpour, S., Niknejhadi, M., Hedayati-Asl, A. A., & Aghdami, N. (2015). Intrathecal injection of CD133-positive enriched bone marrow progenitor cells in children with cerebral palsy: Feasibility and safety. Cytotherapy, 17(2), 232–241. https://doi.org/10.1016/j.jcyt.2014.10.011

    Article  CAS  PubMed  Google Scholar 

  39. Lee, Y. H., Choi, K. V., Moon, J. H., Jun, H. J., Kang, H. R., Oh, S. I., & Yang, Y. S. (2012). Safety and feasibility of countering neurological impairment by intravenous administration of autologous cord blood in cerebral palsy. Journal of Translational Medicine, 10, 58. https://doi.org/10.1186/1479-5876-10-58

    Article  PubMed  PubMed Central  Google Scholar 

  40. Luan, Z., Liu, W., Qu, S., Du, K., He, S., Wang, Z., & Gong, X. (2012). Effects of neural progenitor cell transplantation in children with severe cerebral palsy. Cell Transplantation, 21(Suppl 1), S91–98. https://doi.org/10.3727/096368912x633806

    Article  PubMed  Google Scholar 

  41. Gao, H. M., & Hong, J. S. (2008). Why neurodegenerative Diseases are Progressive: Uncontrolled inflammation drives Disease progression. Trends in Immunology, 29(8), 357–365. https://doi.org/10.1016/j.it.2008.05.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bazhanova, E. D., Kozlov, A. A., & Litovchenko, A. V. (2021). Mechanisms of Drug Resistance in the pathogenesis of Epilepsy: Role of Neuroinflammation. A literature review. Brain Sciences, 11(5). https://doi.org/10.3390/brainsci11050663

  43. Abushanab, E., Pestana Knight, E., & Moosa, A. N. (2021). Characterizing the phenotype of drug-resistant childhood Epilepsy associated with Leukemia: A case series. Epilepsy & Behavior Reports, 15, 100432. https://doi.org/10.1016/j.ebr.2021.100432

    Article  Google Scholar 

  44. Jafarian, M., Modarres Mousavi, S. M., Alipour, F., Aligholi, H., Noorbakhsh, F., Ghadipasha, M., & Gorji, A. (2019). Cell injury and receptor expression in the epileptic human amygdala. Neurobiology of Disease, 124, 416–427. https://doi.org/10.1016/j.nbd.2018.12.017

    Article  CAS  PubMed  Google Scholar 

  45. Mesraoua, B., Deleu, D., Kullmann, D. M., Shetty, A. K., Boon, P., Perucca, E., & Asadi-Pooya, A. A. (2019). Novel therapies for Epilepsy in the pipeline. Epilepsy & Behavior, 97, 282–290. https://doi.org/10.1016/j.yebeh.2019.04.042

    Article  Google Scholar 

  46. Waldau, B., Hattiangady, B., Kuruba, R., & Shetty, A. K. (2010). Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe Epilepsy. Stem Cells, 28(7), 1153–1164. https://doi.org/10.1002/stem.446

    Article  CAS  PubMed  Google Scholar 

  47. van Velthoven, C. T., Kavelaars, A., van Bel, F., & Heijnen, C. J. (2011). Mesenchymal stem cell transplantation changes the gene expression profile of the neonatal ischemic brain. Brain Behavior Immunity, 25(7), 1342–1348. https://doi.org/10.1016/j.bbi.2011.03.021

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Marcin Balcerzak of Medink for editorial support.

Funding

The study had no external funding.

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Author notes

  1. Stanisław Kwiatkowski and Marcin Majka are co-senior authors.

Authors and Affiliations

  1. Faculty of Medicine, Department of Children’s Neurosurgery, Jagiellonian University Medical College Institute of Pediatrics, Cracow, Poland

    Olga Milczarek, Anna Starowicz–Filip & Stanisław Kwiatkowski

  2. Hematology Department, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Danuta Jarocha

  3. Faculty of Medicine, Department of Psychology, Jagiellonian University Medicl College, Cracow, Poland

    Anna Starowicz–Filip

  4. Students’ Scientific Group at the Department of Pediatric Neurosurgery, Jagiellonian University Medical College Institute of Pediatrics, Cracow, Poland

    Maciej Kasprzycki

  5. Faculty of Medicine, Department of Transplantation, Jagiellonian University Medical College Institute of Pediatrics, Cracow, Poland

    Jacek Kijowski, Anna Mordel & Marcin Majka

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  1. Olga Milczarek
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Correspondence to Olga Milczarek.

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The Bioethical Committee of the Jagiellonian University Medical College approved the project (KBET/241/L/2011 and KBET/242/B/2014).

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Milczarek, O., Jarocha, D., Starowicz–Filip, A. et al. Bone Marrow Nucleated Cells and Bone Marrow-Derived CD271+ Mesenchymal Stem Cell in Treatment of Encephalopathy and Drug-Resistant Epilepsy. Stem Cell Rev and Rep 20, 1015–1025 (2024). https://doi.org/10.1007/s12015-023-10673-4

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