title: Differential responses of human neural and hematopoietic stem cells to ethanol exposure.
abstract: The mechanisms underlying fetal developmental defects caused by maternal ethanol (EtOH) consumption remain unclear. The symptoms of fetal alcohol syndrome (FAS) include neurological and immunological dysfunctions that are linked to cell reduction in these systems. Neural (NSC) and hematopoietic stem cells (HSC) may be targets for the cytotoxic effects of EtOH. Furthermore, protein kinase C (PKC) signal transduction systems of these stem cells may be involved in EtOH-induced cell death. Purified CD34+ human fetal liver hematopoietic stem cells (HSC) and CD133+/nestin+ human neural stem cells (NSC) were exposed to 0.1-10 mM EtOH. A range of indices of cell damage indicated that these doses of EtOH were deleterious to NSC, but had no observable effects on HSC. Furthermore, the colony-forming ability of NSC was completely inhibited by 5 mM EtOH treatment, whereas HSC were unaffected by even 20 mM EtOH. These results suggest that NSC are much more sensitive to EtOH than HSC. Classic and novel PKC isozyme protein expressions in the membrane fraction of cells were differentially affected by EtOH exposure across the two stem cell types. Concentrations of EtOH capable of inducing NSC, but not HSC, death also changed apoptosis-associated PKC isozyme expression in the membrane of NSC, but not HSC. Therefore, PKC expression may mediate the susceptibility of NSC to EtOH-induced cytotoxicity via cell signal transduction pathways. The toxic effect of EtOH on NSC may lead to the decreased neural cell number observed in FAS patients. The comparable immunity of HSC to the deleterious effects of EtOH exposure indicates that the susceptibility of NSC is not simply due to their being stem cells and also may explain the relative lack of hematopoietic problems associated with FAS.
authors.affiliation: Department of Pediatrics, Wayne State University School of Medicine, and Children's Research Center of Michigan, Detroit, MI 48201, USA. hsiao-nan.hao@crcm.med.wayne.edu
authors.forename: Hsiao-Nan
authors.initials: HN
authors.lastname: Hao
authors.forename: Graham C
authors.initials: GC
authors.lastname: Parker
authors.forename: Jane
authors.initials: J
authors.lastname: Zhao
authors.forename: Kaveh
authors.initials: K
authors.lastname: Barami
authors.forename: William D
authors.initials: WD
authors.lastname: Lyman
mesh_terms: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000096:biosynthesis; D017209:Apoptosis; D006690:Bisbenzimidazole / Q000494:pharmacology; D039481:CD11b Antigen / Q000096:biosynthesis; D016923:Cell Death; D002455:Cell Division; D002470:Cell Survival; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004396:Coloring Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000494:pharmacology* / Q000633:toxicity; D006023:Glycoproteins / Q000096:biosynthesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000096:biosynthesis; D009419:Nerve Tissue Proteins; D064231:Nestin; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides; D010641:Phenotype; D020033:Protein Isoforms; D011493:Protein Kinase C / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D013997:Time Factors
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D018952:Antigens, CD34; D039481:CD11b Antigen; D002492:Central Nervous System Depressants; D004396:Coloring Agents; D006023:Glycoproteins; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; D064231:Nestin; C000606023:PROM1 protein, human; D010455:Peptides; D020033:Protein Isoforms; D012333:RNA, Messenger; D000431:Ethanol; D011493:Protein Kinase C; D006690:Bisbenzimidazole