Abstract
Human umbilical cord blood (HUCB) transplantation has become an alternative cell therapy for hematological and oncological malignancies in the clinic and is considered for neurological disorders. The heterogeneity in the content of the different stem and progenitor cells composing HUCB mononuclear cells (MNC) may influence their engraftment and neurotherapeutic effect. We hypothesized that CD45 pan-hematopoietic marker expression is heterogeneous in MNC, and therefore, CD45+ subpopulation enrichment for neurotherapy may provide a tool to overcome cellular variance in different HUCB units. We employed an immunomagnetic separation method to isolate and characterize HUCB CD45+ pan-hematopoietic subpopulation and to investigate whether the vaginal or cesarean deliveries influence their neurotherapeutic effect in a traumatic brain injury (TBI) mouse model. Adult C57BL/6J male mice were subjected to moderate TBI and intravenously xenotransplanted with 1 × 106 CD45+ cells derived from either vaginal or cesarean HUCB units. A large heterogeneity in the expression of CD45 marker in MNC, both in vaginal and cesarean HUCB units, was found, regardless of the number of live births. A higher expression of hematopoietic markers was found in the CD45+ subpopulation while low expressional levels of typical mesenchymal markers were detected. Neurotherapeutic effects, evaluated with an established neurological severity score and novel object recognition test, indicated improved functional motor and memory recovery and found independent of delivery type. Cytokine analysis in extracts of TBI brain cortices indicated an acute immunomodulatory effect by HUCB CD45+ subpopulation upon xenotransplantation. These results may provide insights to CD45 marker as a predictor of HUCB units’ quality for neurotherapy in TBI.
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Acknowledgments
We would like to express our appreciation to the maternity ward staff of the Department of Obstetrics and Gynecology at Hadassah-Hebrew University Medical Center, Jerusalem for their cooperation during the project and their help in collecting the cord blood units. We are also grateful to Dr. Victoria Trembovler and Dr. Alexander G. Alexandrovich from the School of Pharmacy, Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, for the technical help with TBI experiments.
Funding
ES was partly supported by a grant from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation. PL holds the Jacob Gitlin Chair in Physiology and is affiliated with and supported by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Bretler Center for Research in Molecular Pharmacology and Therapeutics at the Hebrew University of Jerusalem, Israel. The funding sources had no involvement in the conduction, data collection, and analysis and preparation of the article.
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The study was approved by the Institutional Animal Ethics Committee of the Hebrew University (MD-14-14143-4) and complied with the guidelines of the National Research Council Guide for the Care and Use of Laboratory Animals (NIH Publication no. 85-23, revised 1996).
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Gincberg, G., Shohami, E., Lazarovici, P. et al. Human Umbilical Cord Blood CD45+ Pan-Hematopoietic Cells Induced a Neurotherapeutic Effect in Mice with Traumatic Brain Injury: Immunophenotyping, Comparison of Maternal and Neonatal Parameters, and Immunomodulation. J Mol Neurosci 64, 185–199 (2018). https://doi.org/10.1007/s12031-017-1008-8
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DOI: https://doi.org/10.1007/s12031-017-1008-8