Induction of neuron-specific enolase promoter and neuronal markers in differentiated mouse bone marrow stromal cells.
Mesenchymal stem cells in the adult bone marrow are differentiated to connective tissue, muscle, bone, cartilage, and fat cells. Recent studies in cultures, animal models, and humans demonstrated the plasticity of these cells and their capacity to express neuronal markers. However, questions were raised as to whether the neuronal phenotypes reflect transient changes or even fusion with neurons. In this study, we induced the differentiation of mouse stromal cells to neuron-like cells and observed the activation of the tissue-specific promoter of neuron-specific enolase (NSE). We used transgenic (Tg) mice that carry the antiapoptotic human bcl-2 gene, expressed only in neurons under the NSE promoter. Some previous studies have indicated that the transgene induces neuroprotection in various animal models of neurodegenerative diseases. We found that following induction, the mouse stromal cells demonstrate neuronal phenotype and express the neuronal marker, NeuN (neural nuclei protein). However, most of the stromal cells derived from the Tg mice, but not the wild type, also expressed human Bcl-2, as indicated by immunocytochemistry. Furthermore, these induced neuron-like cells were more resistant to cell death induced by dopamine. In conclusion, our experimental models showed that stromal cells might be induced to neuronal phenotypes and activate neuronal-specific promoters. Moreover, neurons targeted over expression of the human bcl-2 gene and provided high resistance against such apoptotic insults. This novel strategy reveals a new horizon in the improvement of gene therapy, based on stem cell transplantation in neurodegenerative diseases.
Levy
Yossef S
YS
Felsenstein Medical Research Center, and the Department of Neurology, Rabin Medical Center-Beilinson Campus, Petach Tikva, The Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
Merims
Doron
D
Panet
Hanna
H
Barhum
Yael
Y
Melamed
Eldad
E
Offen
Daniel
D
D000818:Animals; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004298:Dopamine / Q000633:toxicity; D004351:Drug Resistance / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics; D019254:Genes, bcl-2 / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods / Q000639:trends; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000628:therapy; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation
D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; D010751:Phosphopyruvate Hydratase; D004298:Dopamine