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TISSUE-SPECIFIC STEM CELLS

Modulation of Inflammatory Responses After Global Ischemia by Transplanted Umbilical Cord Matrix Stem Cells

Departments of ^aAnesthesiology,
^bPharmacology, and
^cStructural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

Key Words. Umbilical cord matrix stem cells • Stroke • Reactive astrocytosis • Microglia • Vimentin • Nestin • Stem cells

Correspondence: Correspondence: Yan Xu, Ph.D., University of Pittsburgh School of Medicine, 2048 Biomedical Science Tower 3, 3501 Fifth Avenue, Pittsburgh, Pennsylvania 15260, USA. Telephone: (412) 648-9922; Fax: (412) 648-8998; e-mail: xuy{at}anes.upmc.edu

Received on January 24, 2008; accepted for publication on August 5, 2008.

First published online in STEM CELLS EXPRESS  August 21, 2008.

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.