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Common olfactory ensheathing glial markers in the developing human olfactory system.

ABSTRACT: The in situ immunocytochemical properties of olfactory ensheathing cells (OECs) have been well studied in several small to medium sized animal models including rats, mice, guinea pigs, cats and canines. However, we know very little about the antigenic characteristics of OECs in situ within the adult and developing human olfactory bulb and nerve roots. To address this gap in knowledge we undertook an immunocytochemical analysis of the 11-19 pcw human foetal olfactory system. Human foetal OECs in situ possessed important differences compared to rodents in the expression of key surface markers. P75^NTR was not observed in OECs but was strongly expressed by human foetal Schwann cells and perineurial olfactory nerve fibroblasts surrounding OECs. We define OECs throughout the 11-19 pcw human olfactory system as S100/vimentin/SOX10+ with low expression of GFAP. Our results suggest that P75^NTR is a robust marker that could be utilised with cell sorting techniques to generate enriched OEC cultures by first removing P75^NTR expressing Schwann cells and fibroblasts, and subsequently to isolate OECs after P75^NTR upregulation in vitro. O4 and PSA-NCAM were not found to be suitable surface antigens for OEC purification owing to their ambiguous and heterogeneous expression. Our results highlight the importance of corroborating cell markers when translating cell therapies from animal models to the clinic.

SUBMITTER: Oprych K

PROVIDER: S-EPMC5406434 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Common olfactory ensheathing glial markers in the developing human olfactory system.

Oprych Karen K Cotfas Daniel D Choi David D

Brain structure & function 20161007 4

The in situ immunocytochemical properties of olfactory ensheathing cells (OECs) have been well studied in several small to medium sized animal models including rats, mice, guinea pigs, cats and canines. However, we know very little about the antigenic characteristics of OECs in situ within the adult and developing human olfactory bulb and nerve roots. To address this gap in knowledge we undertook an immunocytochemical analysis of the 11-19 pcw human foetal olfactory system. Human foetal OECs in ...[more]

PMID: 27718014

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Project description:BackgroundThe olfactory ensheathing cells (OECs) migrate from the peripheral nervous system to the central nervous system (CNS), a critical process for the development of the olfactory system and axonal extension after injury in neural regeneration. Because of their ability to migrate to the injury site and anti-inflammatory properties, OECs were tested against different neurological pathologies, but were never studied in the context of cancer. Here, we evaluated OEC tropism to gliomas and their potential as a "Trojan horse" to deliver therapeutic transgenes through the nasal pathway, their natural route to CNS.MethodsOECs were purified from the mouse olfactory bulb and engineered to express a fusion protein between cytosine deaminase and uracil phosphoribosyltransferase (CU), which convert the prodrug 5-fluorocytosine (5-FC) into cytotoxic metabolite 5-fluorouracil, leading to a bystander killing of tumor cells. These cells were injected into the nasal cavity of mice bearing glioblastoma tumors and OEC-mediated gene therapy was monitored by bioluminescence imaging and confirmed with survival and ex vivo histological analysis. All statistical tests were two-sided.ResultsOECs migrated from the nasal pathway to the primary glioma site, tracked infiltrative glioma stemlike cells, and delivered therapeutic transgene, leading to a slower tumor growth and increased mice survival. At day 28, bioluminescence imaging revealed that mice treated with a single injection of OEC-expressing CU and 5-FC had tumor-associated photons (mean [SD]) of 1.08E + 08 [9.7E + 07] vs 4.1E + 08 [2.3E + 08] for control group (P < .001), with a median survival of 41 days vs 34 days, respectively (ratio = 0.8293, 95% confidence interval = 0.4323 to 1.226, P < .001) (n = 9 mice per group).ConclusionsWe show for the first time that autologous transplantation of OECs can target and deliver therapeutic transgenes to brain tumors upon intranasal delivery, the natural route of OECs to the CNS, which could be extended to other types of cancer.

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Common olfactory ensheathing glial markers in the developing human olfactory system.

Publications

Common olfactory ensheathing glial markers in the developing human olfactory system.

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