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


METHODS
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.


CONCLUSIONS
Our results provide strong evidence of the long-term safety and positive effects of MSC treatment following neonatal HI in mice.
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Vanessa
V
Donega
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Cora H
CH
Nijboer
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
Cindy T J
CT
van Velthoven
Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Sameh A
SA
Youssef
Dutch Molecular Pathology Center, Department of Pathobiology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Alain
A
de Bruin
Department of Neonatology, University Medical Center Utrecht, Utrecht, The Netherlands.
Frank
F
van Bel
Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas, MD Anderson Cancer Center, Houston, Texas.
Annemieke
A
Kavelaars
Laboratory of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.|Laboratory of Neuroimmunology, Department of Symptom Research, University of Texas, MD Anderson Cancer Center, Houston, Texas.
Cobi J
CJ
Heijnen
D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D002478:Cells, Cultured; D003071:Cognition; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000523:psychology / Q000601:surgery*; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009043:Motor Activity; D004676:Myelin Basic Protein / Q000378:metabolism; D021641:Recognition, Psychology; D020127:Recovery of Function; D018570:Risk Assessment; D013997:Time Factors
D015415:Biomarkers; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D004676:Myelin Basic Protein