Stem Cell Reviews and Reports

, Volume 15, Issue 4, pp 612–617 | Cite as

Umbilical Cord Cell Therapy Improves Spatial Memory in Aging Rats

  • Marianne Lehmann
  • Maria F. Zappa-Villar
  • Mariana G. García
  • Guillermo Mazzolini
  • Martina Canatelli-Mallat
  • Gustavo R. Morel
  • Paula C. Reggiani
  • Rodolfo G. GoyaEmail author


There is a growing interest in the potential of adult stem cells for implementing regenerative medicine in the brain. We assessed the effect of intracerebroventricular (icv) administration of human umbilical cord perivascular cells (HUCPVCs) on spatial memory of senile (27 mo) female rats, using intact senile counterparts as controls. Approximately one third of the animals were injected in the lateral ventricles with a suspension containing 4.8 X 105 HUCPVC in 8 μl per side. The other third received 4.8 X 105 transgenic HUCPVC overexpressing Insulin-like growth factor-1 (IGF-1) and the last third of the rats received no treatment. Spatial memory performance was evaluated using a modified version of the Barnes maze test. In order to evaluate learning ability as well as spatial memory retention, we assessed the time spent (permanence) by animals in goal sector 1 (GS1) and 3 (GS3) when the escape box was removed. Fluorescence microscopy revealed the prescence of Dil-labeled HUCPVC in coronal sections of treated brains. The HUCPVC were located in close contact with the ependymal cells with only a few labeled cells migrating into the brain parenchyma. After treatment with naïve or IGF-1 transgenic HUCPVC, permanence in GS1 and GS3 increased significantly whereas there were no changes in the intact animals. We conclude that HUCPVC injected icv are effective to improve some components of spatial memory in senile rats. The ready accessibility of HUCPVC constitutes a significant incentive to continue the exploration of their therapeutic potential on neurodegenerative diseases.


Brain aging Spatial memory Hippocampus Umbilical cord Stem cells 



The authors are indebted to Ms. Natalia Scelsio for technical work, to Mr. Mario R. Ramos for design of the figures and to Ms. Yolanda E. Sosa for editorial assistance. MGG, GM, GRM, PCR and RGG are career researchers of the Argentine Research Council (CONICET). ML, FZ and MCM are recipients of CONICET doctoral fellowships.


This study was supported by grant #PICT15–0817 from the Argentine Agency for the Promotion of Science and Technology and grant MRCF 10–10-17 from the Medical Research Charitable Foundation and the Society for Experimental Gerontological Research, New Zealand to RGG.

Compliance with Ethical Standards

Conflict of Interest

There are no conflicts of interest concerning any of the authors.


  1. 1.
    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 Signaling., 9, 12.CrossRefGoogle Scholar
  2. 2.
    Sarugaser, R., Lickorish, D., Baksh, D., Hosseini, M. M., & Davies, J. E. (2005). Human umbilical cord perivascular (HUCPV) cells: A source of mesenchymal progenitors. Stem Cells, 23, 220–229.CrossRefGoogle Scholar
  3. 3.
    Baksh, D., Yao, R., & Tuan, R. S. (2007). Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells, 25, 1384–1392.CrossRefGoogle Scholar
  4. 4.
    Hereñú, C. B., Cristina, C., Rimoldi, O. J., et al. (2007). Restorative effect of insulin-like growth factor-I gene therapy in the hypothalamus of senile rats with dopaminergic dysfunction. Gene Therapy., 14, 237–245.CrossRefGoogle Scholar
  5. 5.
    Pardo, J., Uriarte, M., Console, G. M., et al. (2016). Insulin-like growth factor-I gene therapy increases hippocampal neurogenesis, astrocyte branching and improves spatial memory in aging rats. European Journal of Neuroscience, 44, 2120–2128.CrossRefGoogle Scholar
  6. 6.
    Pardo, J., Abba, M., Lacunza, E., et al. (2017). Identification of a conserved gene signature associated with an exacerbated inflammatory environment in the hippocampus of aging rats. Hippocampus, 27, 435–449.CrossRefGoogle Scholar
  7. 7.
    Bayo J., Fiore, E, Aquino, J B, et al. (2014) Human umbilical cord perivascular cells exhibited enhanced migration capacity towards hepatocellular carcinoma in comparison with bone marrow mesenchymal stromal cells: A role for autocrine motility factor receptor. Biomed. Res. Int.
  8. 8.
    Paxinos, G., & Watson, C. (1998). The rat brain in stereotaxic coordinates (4th ed.). San Diego: Academic Press.Google Scholar
  9. 9.
    Morel, G. R., Andersen, T., Pardo, J., et al. (2015). Cognitive impairment and morphological changes in the dorsal hippocampus of very old female rats. Neuroscience, 303, 189–199.CrossRefGoogle Scholar
  10. 10.
    Venkataramana, N. K., Kumar, S. K., Balaraju, S., et al. (2010). Openlabeled study of unilateral autologous bone-marrow-derived mesenchymal stem cell transplantation in Parkinson’s disease. Translational Research, 155, 62–70.CrossRefGoogle Scholar
  11. 11.
    The Safety and The Efficacy Evaluation of NEUROSTEM®-AD in Patients With Alzheimer’s Disease. ClinicalTrialsgov Identifier: NCT01297218. 2014. NCT01297218.
  12. 12.
    Safety and efficiency of umbilical cord-derived mesenchymal stem cells (UC-MSC) in patients with Alzheimer’s disease (SEMAD). Clinical Trialsgov Identifier: NCT01547689. May. 2014
  13. 13.
    Safety and exploratory efficacy study of NEUROSTEM® versus placebo in patients with Alzheimer’s disease. Clinicaltrialsgov identifier: nct02054208. Feb. 2014
  14. 14.
    Mansilla, E., Roque, G., Sosa, Y. E., Tarditti, A., & Goya, R. G. (2016). A rat treated with mesenchymal stem cells lives to 44 months of age. Rejuvenation Research., 19, 318–321.CrossRefGoogle Scholar
  15. 15.
    Kim, D., Kyung, J., Park, D., et al. (2015). Health span-extending activity of human amniotic membrane- and adipose tissue-derived stem cells in F344 rats. Stem Cells Translational Medicine, 4, 1144–1154.CrossRefGoogle Scholar
  16. 16.
    Shen, J., Tsai, Y., DiMarco, N., Sun, X., & Tang, L. (2011). Transplantation of mesenchymal stem cells from young donors delays aging in mice. Science Reports, 1, 67.CrossRefGoogle Scholar
  17. 17.
    Kopen, G. C., Prockop, D. J., & Phinney, D. G. (1999). Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proceedings of the national Academy of Sciences USA, 96, 10711–10716.CrossRefGoogle Scholar
  18. 18.
    Qu, C., Mahmood, A., Lu, D., Goussev, A., Xiong, Y., & Chopp, M. (2008). Treatment of traumatic brain injury in mice with marrow stromal cells. Brain Research, 1208, 234–239.CrossRefGoogle Scholar
  19. 19.
    Janowski, M., Wagner, D. C., & Boltze, J. (2015). Stem cell-based tissue replacement after stroke: Factual necessity or notorious fiction? Stroke, 46(8), 2354–2363.CrossRefGoogle Scholar
  20. 20.
    Wang, N., Li, Q., Zhang, L., et al. (2012). Mesenchymal stem cells attenuate peritoneal injury through secretion of TSG-6. PLoS One, 7, e43768.CrossRefGoogle Scholar
  21. 21.
    Caplan, A. I., & Dennis, J. E. M. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98, 1076–1084.CrossRefGoogle Scholar
  22. 22.
    da Silva Meirelles, L. S., Fontes, A. M., Covas, D. T., & Caplan, A. I. (2009). Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Reviews., 20, 419–427.CrossRefGoogle Scholar
  23. 23.
    Sternberg, E. M., Glowa, J. R., Smith, M. A., et al. (1992). Corticotropin releasing hormone related behavioral and neuroendocrine responses to stress in Lewis and Fischer rats. Brain Research., 570, 54–60.CrossRefGoogle Scholar
  24. 24.
    Vargas-Lopez, V., Lamprea, M. R., & Munera, A. (2011). Characterizing spatial extinction in an abbreviated version of the Barnes maze. Behavioural Processes, 86, 30–38.CrossRefGoogle Scholar
  25. 25.
    Lee, H. J., Lee, J. K., Lee, H., et al. (2010). The therapeutic potential of human umbilical cord blood-derived mesenchymal stem cells in Alzheimer's disease. Neuroscience Letters, 481, 30–35.CrossRefGoogle Scholar
  26. 26.
    Tfilin, M., Sudai, E., Merenlender, I., Gispan, G., Yadid, G., & Turgeman, G. (2010). Mesenchymal stem cells increase hippocampal neurogenesis and counteract depressive-like behavior. Molecular Psychiatry, 5, 1164–1175.CrossRefGoogle Scholar
  27. 27.
    Fiore, E. J., Bayo, J. M., Garcia, M. G., et al. (2014). Mesenchymal stromal cells engineered to produce IGF-I by recombinant adenovirus ameliorate liver fibrosis in mice. Stem Cells Development, 24, 791–801.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Marianne Lehmann
    • 1
    • 2
  • Maria F. Zappa-Villar
    • 1
    • 2
  • Mariana G. García
    • 3
  • Guillermo Mazzolini
    • 3
  • Martina Canatelli-Mallat
    • 1
    • 2
  • Gustavo R. Morel
    • 1
    • 2
  • Paula C. Reggiani
    • 1
    • 2
  • Rodolfo G. Goya
    • 1
    • 2
    Email author
  1. 1.INIBIOLP-Pathology B, School of MedicineNational University of La PlataLa PlataArgentina
  2. 2.Department of Histology and of Embryology B, School of MedicineNational University of La PlataLa PlataArgentina
  3. 3.Gene Therapy Laboratory, IIMT, Facultad de Ciencias Biomédicas, CONICETUniversidad AustralBuenos AiresArgentina

Personalised recommendations