Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke
Woei-Cherng Shyu, … , Chang-Hai Tsai, Hung Li
Woei-Cherng Shyu, … , Chang-Hai Tsai, Hung Li
Published June 5, 2008
Citation Information: J Clin Invest. 2008;118(7):2482-2495. https://doi.org/10.1172/JCI34363.
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Research Article Neuroscience

Implantation of olfactory ensheathing cells promotes neuroplasticity in murine models of stroke

Abstract

Murine olfactory ensheathing cells (OECs) promote central nervous system axonal regeneration in models of spinal cord injury. We investigated whether OECs could induce a neuroplastic effect to improve the neurological dysfunction caused by hypoxic/ischemic stress. In this study, human OECs/olfactory nerve fibroblasts (hOECs/ONFs) specifically secreted trophic factors including stromal cell–derived factor–1α (SDF-1α). Rats with intracerebral hOEC/ONF implantation showed more improvement on behavioral measures of neurological deficit following stroke than control rats. [18F]fluoro-2-deoxyglucose PET (FDG-PET) showed increased glucose metabolic activity in the hOEC/ONF-treated group compared with controls. In mice, transplanted hOECs/ONFs and endogenous homing stem cells including intrinsic neural progenitor cells and bone marrow stem cells colocalized with specific neural and vascular markers, indicating stem cell fusion. Both hOECs/ONFs and endogenous homing stem cells enhanced neuroplasticity in the rat and mouse ischemic brain. Upregulation of SDF-1α and CXCR4 in hOECs/ONFs promoted neurite outgrowth of cocultured primary cortical neurons under oxygen glucose deprivation conditions and in stroke animals through upregulation of cellular prion protein (PrPC) expression. Therefore, the upregulation of SDF-1α and the enhancement of CXCR4 and PrPC interaction induced by hOEC/ONF implantation mediated neuroplastic signals in response to hypoxia and ischemia.

Authors

Woei-Cherng Shyu, Demeral David Liu, Shinn-Zong Lin, Wen-Wen Li, Ching-Yuan Su, Ying-Chen Chang, Hsiao-Jung Wang, Hsing-Won Wang, Chang-Hai Tsai, Hung Li

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Figure 7

Intracerebral transplantation of hOECs/ONFs enhanced neurite regeneration through upregulation of PrPC and CXCR4 expression.

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Intracerebral transplantation of hOECs/ONFs enhanced neurite regeneratio...
(A) In immunohistochemical analysis, hOEC/ONF + IgG (control human IgG) implantation significantly improved neurite outgrowth in the penumbral area of rats in comparison with hOECs/ONFs plus Ab1 (PrPC-blocking antibody), hOECs/ONFs plus Ab2 (CXCR4-neutralizing antibody), and vehicle (Control) treatment. (B) hOEC/ONF + IgG (S) implantation produced neurites significantly longer than those found in rats treated with S + Ab1, S + Ab2, and vehicle (control [C]). Moreover, hOEC/ONF + IgG–treated rats had more neurite-bearing neurons than the control rats. (C) In colocalization analyses, PrPC and CXCR4 coexpressed around the region of bis-benzimide–labeled hOECs/ONFs and GFP+ cells on the cerebral ischemic microenviroment. (D) In a Western blot analysis, PrPC and CXCR4 expression was upregulated in the hOEC/ONF-treated rats compared with control rats. (E) The neurological behavior measurement modalities showed no significant difference between the 3 therapeutic groups (C, S + Ab1, S + Ab2). (F) In evaluating neurite regeneration, hOEC/ONF implantation in the PrPo/o mice did not increase the neurite length and number of neurite-bearing cells in contrast to those of PrP+/+ mice after cerebral ischemia. Data are expressed as mean ± SEM. *P < 0.05 and **P < 0.01 versus control. Scale bars: 50 μm.