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Modulation of inflammatory responses after global ischemia by transplanted umbilical cord matrix stem cells.

ABSTRACT: Rat umbilical cord matrix (RUCM) cells are stem-cell-like cells and have been shown to reduce neuronal loss in the selectively vulnerable brain regions after cardiac arrest (CA). Here, we investigate whether this protection is mediated by the RUCM cells' modulation of the postischemia inflammation responses, which have long been implicated as a secondary mechanism of injury following ischemia. Brain sections were examined immunohistochemically for glial fibrillary acidic protein (GFAP), vimentin, and nestin as markers for astroglia and reactive astrogliosis, Ricinus Communis Agglutinin-1 (RCA-1) as a marker for microglia, and Ki67 as a marker for cell proliferation. Rats were randomly assigned to six experimental groups: (1) 8-minute CA without treatment, (2) 8-minute CA pre-treated with culture medium injection, (3) 8-minute CA pre-treated with RUCM cells, (4) sham-operated CA, (5) medium injection without CA, and (6) RUCM cell transplantation without CA. Groups 1-3 have significantly higher Ki67(+) cell counts and higher GFAP(+) immunoreactivity in the hippocampal Cornu Ammonis layer 1 (CA1) region compared to groups 4-6, irrespective of treatment. Groups 1 and 2 have highly elevated GFAP(+), vimentin(+), and nestin(+) immunoreactivity, indicating reactive astrogliosis. Strikingly, RUCM cell treatment nearly completely inhibited the appearance of vimentin(+) and greatly reduced nestin(+) reactive astrocytes. RUCM cell treatment also greatly reduced RCA-1 staining, which is found to strongly correlate with the neuronal loss in the CA1 region. Our study indicates that treatment with stem-cell-like RUCM cells modulates the inflammatory response to global ischemia and renders neuronal protection by preventing permanent damage to the selectively vulnerable astrocytes in the CA1 region. Disclosure of potential conflicts of interest is found at the end of this article.

SUBMITTER: Hirko AC

PROVIDER: S-EPMC2802492 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Modulation of inflammatory responses after global ischemia by transplanted umbilical cord matrix stem cells.

Hirko Aaron C AC Dallasen Renee R Jomura Sachiko S Xu Yan Y

Stem cells (Dayton, Ohio) 20080821 11

Rat umbilical cord matrix (RUCM) cells are stem-cell-like cells and have been shown to reduce neuronal loss in the selectively vulnerable brain regions after cardiac arrest (CA). Here, we investigate whether this protection is mediated by the RUCM cells' modulation of the postischemia inflammation responses, which have long been implicated as a secondary mechanism of injury following ischemia. Brain sections were examined immunohistochemically for glial fibrillary acidic protein (GFAP), vimentin ...[more]

PMID: 18719227

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Project description:Rat umbilical cord matrix stem cells (UCMSC) have been shown to exhibit a remarkable ability to control rat mammary adenocarcinoma (Mat B III) cell proliferation both in vivo and in vitro. To study the underlying mechanisms and genes involved in Mat B III growth attenuation, total RNA was extracted from the naive rat UCMSC alone and those cocultured with Mat B III in Transwell culture dishes. Gene expression profiles of naive rat UCMSC alone and those cocultured with Mat B III cells were investigated by microarray analysis using an Illumina RatRef-12 Expression BeadChip. The comparison of gene expression profiles between untreated and cocultured rat UCMSC identified five upregulated candidate genes (follistatin (FST), sulfatase1 (SULF-1), glucose phosphate isomerase (GPI), HtrA serine peptidase (HTRA1), and adipocyte differentiation-related protein (ADRP)) and two downregulated candidate genes (transforming growth factor, beta-induced, 68 kDa (TGF?I) and podoplanin (PDPN)) based upon the following screening criteria: (1) expression of the candidate genes should show at least a 1.5-fold change in rat UCMSC cocultured with Mat B III cells; (2) candidate genes encode secretory proteins; and (3) they encode cell growth-related proteins. Following confirmation of gene expression by real-time PCR, ADRP, SULF-1 and GPI were selected for further analysis. Addition of specific neutralizing antibodies against these three gene products or addition of gene-specific siRNA's individually in cocultures of 1:20 rat UCMSC:Mat B III cells significantly increased cell proliferation, implying that these gene products are produced under the cocultured condition and functionally attenuate cell growth. Immunoprecipitation followed by Western blot analysis demonstrated that these proteins are indeed secreted into the culture medium. Individual overexpression of these three genes in rat UCMSC significantly enhanced UCMSC-dependent inhibition of cell proliferation in coculture. These results suggest that ADRP, SULF-1 and GPI act as tumor suppressor genes, and these genes might be involved in rat UCMSC-dependent growth attenuation of rat mammary tumors.

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Modulation of inflammatory responses after global ischemia by transplanted umbilical cord matrix stem cells.

Publications

Modulation of inflammatory responses after global ischemia by transplanted umbilical cord matrix stem cells.

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