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A cytoprotective role for the heme oxygenase‐1/CO pathway during neural differentiation of human mesenchymal stem cells
Author(s) -
Barbagallo Ignazio,
Tibullo Daniele,
Di Rosa Michelino,
Giallongo Cesarina,
Palumbo Giuseppe A.,
Raciti Giuseppina,
Campisi Agata,
Vanella Angelo,
Green Colin J.,
Motterlini Roberto
Publication year - 2008
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21660
Subject(s) - heme oxygenase , hemin , mesenchymal stem cell , biliverdin , microbiology and biotechnology , cytoprotection , cellular differentiation , heme , chemistry , neural stem cell , viability assay , stem cell , biology , apoptosis , biochemistry , enzyme , gene
The inducible protein heme oxygenase‐1 (HO‐1) catalyzes the oxidation of heme to carbon monoxide (CO) and biliverdin, which play a concerted action in cytoprotection against oxidative stress and in the modulation of cell proliferation and differentiation. Here we report that both HO‐1 expression and activity can be highly increased in undifferentiated human mesenchymal stem cells (MSCs) treated with hemin, a known HO‐1 inducer. However, HO‐1 mRNA and protein expression gradually decrease when MSCs undergo neural differentiation in vitro, making them extremely susceptible to glutamate‐mediated cytotoxicity. A time course for HO‐1 revealed that this protein is markedly down‐regulated after 2 days and returns to control levels 6 days after differentiation. Treatment with glutamate (250 μM) after 2 days of neural differentiation resulted in a more pronounced lactate dehydrogenase release, a marker of cell injury, compared with undifferentiated cells. Notably, cells pretreated with hemin (50 μM) or compounds that release small amounts of CO (10 μM CORM‐3 and CORM‐A1) rendered cells more resistant to glutamate‐induced toxicity; this effect was evident in both undifferentiated and differentiated MSCs. Our findings indicate that MSCs become more vulnerable to oxidative injury during the early stages of differentiation via mechanisms that involve a temporary inhibition of HO‐1 expression. Thus, overexpression of HO‐1 and CO‐releasing molecules could provide a possible therapeutic strategy to improve cell viability during neural differentiation in applications that use stem cell technology. © 2008 Wiley‐Liss, Inc.