title: Intranasally administered mesenchymal stem cells promote a regenerative niche for repair of neonatal ischemic brain injury.
abstract: Previous work from our group has shown that intranasal MSC-treatment decreases lesion volume and improves motor and cognitive behavior after hypoxic-ischemic (HI) brain damage in neonatal mice. Our aim was to determine the kinetics of MSC migration after intranasal administration, and the early effects of MSCs on neurogenic processes and gliosis at the lesion site. HI brain injury was induced in 9-day-old mice and MSCs were administered intranasally at 10days post-HI. The kinetics of MSC migration were investigated by immunofluorescence and MRI analysis. BDNF and NGF gene expression was determined by qPCR analysis following MSC co-culture with HI brain extract. Nestin, Doublecortin, NeuN, GFAP, Iba-1 and M1/M2 phenotypic expression was assessed over time. MRI and immunohistochemistry analyses showed that MSCs reach the lesion site already within 2h after intranasal administration. At 12h after administration the number of MSCs at the lesion site peaks and decreases significantly at 72h. The number of DCX(+) cells increased 1 to 3days after MSC administration in the SVZ. At the lesion, GFAP(+)/nestin(+) and DCX(+) expression increased 3 to 5days after MSC-treatment. The number of NeuN(+) cells increased within 5days, leading to a dramatic regeneration of the somatosensory cortex and hippocampus at 18days after intranasal MSC administration. Interestingly, MSCs expressed significantly more BDNF gene when exposed to HI brain extract in vitro. Furthermore, MSC-treatment resulted in the resolution of the glial scar surrounding the lesion, represented by a decrease in reactive astrocytes and microglia and polarization of microglia towards the M2 phenotype. In view of the current lack of therapeutic strategies, we propose that intranasal MSC administration is a powerful therapeutic option through its functional repair of the lesion represented by regeneration of the cortical and hippocampal structure and decrease of gliosis.
authors.affiliation: Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Donega
authors.affiliation: Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Cora H
authors.initials: CH
authors.lastname: Nijboer
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, The Netherlands.
authors.forename: Geralda
authors.initials: G
authors.lastname: van Tilborg
authors.affiliation: Biomedical MR Imaging and Spectroscopy Group, Image Sciences Institute, University Medical Center Utrecht, The Netherlands.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Dijkhuizen
authors.affiliation: Lab. of Neuroimmunology, Department of Symptom Research, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Kavelaars
authors.affiliation: Lab. of Neuroimmunology and Developmental Origins of Disease, University Medical Center Utrecht, Utrecht, The Netherlands; Lab. of Neuroimmunology, Department of Symptom Research, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: CJHeijnen@mdanderson.org.
authors.forename: Cobi J
authors.initials: CJ
authors.lastname: Heijnen
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000831:Animals, Newborn; D001930:Brain Injuries / Q000209:etiology / Q000601:surgery*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D018920:Coculture Techniques; D000089662:Doublecortin Protein; D005456:Fluorescent Dyes; D007839:Functional Laterality; D007511:Ischemia / Q000150:complications; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D009416:Nerve Regeneration / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D009930:Organic Chemicals; D013997:Time Factors
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D005456:Fluorescent Dyes; D009419:Nerve Tissue Proteins; D009930:Organic Chemicals; C070080:PKH 26; D020932:Nerve Growth Factor
keywords: Microglia polarization; Nasal MSC therapy; Neonatal hypoxia–ischemia; Neurogenesis; Neuroregeneration; Scar formation