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

doi:10.1038/pr.2015.145

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 journal › Article › Academic › peer-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 language	English
Pages (from-to)	520-6
Number of pages	7
Journal	Pediatric Research
Volume	78
Issue number	5
DOIs	https://doi.org/10.1038/pr.2015.145
Publication status	Published - Nov 2015
Externally published	Yes

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10.1038/pr.2015.145

Cite this

@article{6b9f0f0ea24445c1aac964d9bae48f19,

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

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.",

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",

author = "Vanessa Donega and Nijboer, {Cora H} and {van Velthoven}, {Cindy T J} and Youssef, {Sameh A} and {de Bruin}, Alain and {van Bel}, Frank and Annemieke Kavelaars and Heijnen, {Cobi J}",

year = "2015",

month = nov,

doi = "10.1038/pr.2015.145",

language = "English",

volume = "78",

pages = "520--6",

journal = "Pediatric Research",

issn = "0031-3998",

publisher = "Lippincott Williams and Wilkins",

number = "5",

}

TY - JOUR

T1 - Assessment of long-term safety and efficacy of intranasal mesenchymal stem cell treatment for neonatal brain injury in the mouse

AU - Donega, Vanessa

AU - Nijboer, Cora H

AU - van Velthoven, Cindy T J

AU - Youssef, Sameh A

AU - de Bruin, Alain

AU - van Bel, Frank

AU - Kavelaars, Annemieke

AU - Heijnen, Cobi J

PY - 2015/11

Y1 - 2015/11

N2 - 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.

AB - 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.

KW - Animals

KW - Animals, Newborn

KW - Behavior, Animal

KW - Biomarkers/metabolism

KW - Brain/metabolism

KW - Cells, Cultured

KW - Cognition

KW - Disease Models, Animal

KW - Hypoxia-Ischemia, Brain/metabolism

KW - Mesenchymal Stem Cell Transplantation/adverse effects

KW - Mice, Inbred C57BL

KW - Microtubule-Associated Proteins/metabolism

KW - Motor Activity

KW - Myelin Basic Protein/metabolism

KW - Recognition, Psychology

KW - Recovery of Function

KW - Risk Assessment

KW - Time Factors

U2 - 10.1038/pr.2015.145

DO - 10.1038/pr.2015.145

M3 - Article

C2 - 26270577

SN - 0031-3998

VL - 78

SP - 520

EP - 526

JO - Pediatric Research

JF - Pediatric Research

IS - 5

ER -