Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse

Vanessa Donega, Cora H Nijboer, Cindy T J van Velthoven, Sameh A Youssef, Alain de Bruin, Frank van Bel, Annemieke Kavelaars, Cobi J Heijnen

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: For clinical translation, we assessed whether intranasal mesenchymal stem cell (MSC) treatment after hypoxia-ischemia (HI) induces neoplasia in the brain or periphery at 14 mo. Furthermore, the long-term effects of MSCs on behavior and lesion size were determined.

METHOD: HI was induced in 9-d-old mice. Pups received an intranasal administration of 0.5 × 10(6) MSCs or vehicle at 10 d post-HI. Full macroscopical and microscopical pathological analysis of 39 organs per mouse was performed. Sensorimotor behavior was assessed in the cylinder-rearing test at 10 d, 28 d, 6 mo, and 9 mo. Cognition was measured with the novel object recognition test at 3 and 14 mo post-HI. Lesion size was determined by analyzing mouse-anti-microtubule-associated protein 2 (MAP2) and mouse-anti-myelin basic protein (MBP) staining at 5 wk and 14 mo.

RESULTS: At 14 mo post-HI, we did not observe any neoplasia in the nasal turbinates, brain, or other organs of HI mice treated with MSCs. Furthermore, our results show that MSC-induced improvement of sensorimotor and cognitive function is long lasting. In contrast, HI-vehicle mice showed severe behavioral impairment. Recovery of MAP2- and MBP-positive area lasted up to 14 mo following MSC treatment.

CONCLUSION: Our results provide strong evidence of the long-term safety and positive effects of MSC treatment following neonatal HI in mice.

Original languageEnglish
Pages (from-to)520-6
Number of pages7
JournalPediatric Research
Volume78
Issue number5
DOIs
Publication statusPublished - Nov 2015
Externally publishedYes

Keywords

  • Animals
  • Animals, Newborn
  • Behavior, Animal
  • Biomarkers/metabolism
  • Brain/metabolism
  • Cells, Cultured
  • Cognition
  • Disease Models, Animal
  • Hypoxia-Ischemia, Brain/metabolism
  • Mesenchymal Stem Cell Transplantation/adverse effects
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins/metabolism
  • Motor Activity
  • Myelin Basic Protein/metabolism
  • Recognition, Psychology
  • Recovery of Function
  • Risk Assessment
  • Time Factors

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