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MSCs Sniff Out a Way to the Brain

"Intranasal Delivery of Neural Stem/Progenitor Cells: A Non-invasive Passage to Target Intracerebral Glioma"

The use of neural stem cells and neural progenitor cells (NSPCs) for various central nervous system (CNS) diseases is an emerging therapy which benefits from these cells restorative potential and their ability to preferentially migrate to sites of disease and injury (Muller et al). However, cellular integration after surgical implantation of allogenic cells derived from embryonic, fetal, or adult tissue is low, while intravascular administration risks intracerebral tumours and increases the risk of accumulation in peripheral organs. This has led researchers from the laboratory of Nils Ole Schmidt at the University Medical Center Hamburg-Eppendorf, Germany to investigate another method of delivery of NSPCs; intranasal administration. The intranasal cavity provides a direct passage to the intracerebral compartment along olfactory pathways and has been used for the administration of drugs and cells previously (Dhuria et al and Danielyan et al). In this study, Reitza et alshow the rapid and targeted migration of NSPCs via intranasally accessible pathways toward the intracerebral compartment in a mouse model of intracerebral glioma.

NSPCs expressing eGFP were intranasally administered in mice 10 days after injection of human glioblastoma cells (U87 or NCEG55T2) into the forebrain of nude mice. Excitingly, the NSPCs were almost exclusively localized at the site of glioblastoma cell injection, being enriched intratumorally with an inhomogeneous pattern in the immediate peritumoral area. Control animals with no tumours showed no accumulation of cells in the brain after intranasal administration of NSPCs-eGFP. Subsequent to this, another model was assessed; intranasal administration of the DiI-labelled human NSC line HB1.F3 to target intracerebral glioma in an orthotopic glioblastoma xenograft model using C57BL/6 mice and the syngenic Gl261 glioma cell line. Again, the NSCs showed almost exclusive tropism to the site of tumour cell injection, with an estimated 24% of NSCs being able to enter the intracerebral compartment and migrate toward the glioblastoma cells. Magnetic resonance (MR) imaging over 5 days was next used to assess intracerebral neural stem cell migration using intranasal administration of SPIO-labelled human NSCs (HB1.F3) in animals bearing NCE-G55T2 tumours or no tumour as control. Hypointense signals in the peritumoral and intratumoral area were observed within 3 days after intranasal application and further spread throughout the tumour area but no hypointense signals were observed in control mice. An observed frontal distribution pattern suggested that the cells migrated from the olfactory region after intranasal delivery. Histological time course analysis over 5 days was next analysed for eGFP-expressing NSPCs intranasal administered into mice injected with NCE-G55T2 glioblastoma cell injection in the right forebrain. The nasal mucosa, brain, trigeminal nerves, spleen, liver, and lungs were evaluated which confirmed the exclusive migration of intranasally administered NSPCs to the intracerebral glioma, even only after 6 hours which increased significantly at 24 hours but not beyond this time point. An estimated 14% of intranasally administered NSPCs were able to enter the intracerebral compartment and displayed a targeted tumor tropism. NSPCs entered through the nasal mucosa and seemed to enter the brain via olfactory nerve pathways; the olfactory bulb at 6 hours and the olfactory tract within 24 hours but rarely in the trigeminal nerve tissue. Single cells were found outwith the tumour area in the brain at known stem cell niches (hippocampal and hippocampal areas). No NSPCs were found in the lung or liver, although some NSPCs were found in the spleen which suggests that NSPCs could also be distributed systematically through the nasal mucosa.

Together, these data suggest that intranasal administration of NSPCs is a safe and effective non-invasive means of administering therapeutically relevant cells; high levels of administered cells migrated towards the artificially induced tumour with no sign of intracerebral tumours caused by the NSPCs administered and no accumulation in other organs apart from the spleen. Previous studies have suggested that administered mesenchymal stem cell were able to enter the brain in Parkinson disease (Danielyan et al) and neonate ischemic brain damage models (van Velthoven et al) but the study presented here additionally identified migration routes for the NSPCs; the olfactory nerve pathways and systemically through the nasal mucosa.



Danielyan L et al.
Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.
Rejuvenation Res 2011;14:3–16.

Danielyan L, et al.
Intranasal delivery of cells to the brain.
Eur J Cell Biol 2009;88:315–324.

Dhuria SV, et al.
Intranasal delivery to the central nervous system: Mechanisms and experimental considerations.
J Pharm Sci 2010;99:1654 –1673.

Muller FJ, et al.
Gene therapy: Can neural stem cells deliver?
Neurosci 2006;7:75– 84.

Van Velthoven CT et al.
Nasal administration of stem cells: A promising novel route to treat neonatal ischemic brain damage.
Pediatr Res 2010;68:419–422.



Study originally appeared in Stem Cells Translational Medicine.

STEM CELLS correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.