Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation.
Bone marrow stromal cells (MSCs) have the capability under specific conditions of differentiating into various cell types such as osteocytes, chondrocytes, and adipocytes. Here we demonstrate a highly efficient and specific induction of cells with neuronal characteristics, without glial differentiation, from both rat and human MSCs using gene transfection with Notch intracellular domain (NICD) and subsequent treatment with bFGF, forskolin, and ciliary neurotrophic factor. MSCs expressed markers related to neural stem cells after transfection with NICD, and subsequent trophic factor administration induced neuronal cells. Some of them showed voltage-gated fast sodium and delayed rectifier potassium currents and action potentials compatible with characteristics of functional neurons. Further treatment of the induced neuronal cells with glial cell line-derived neurotrophic factor (GDNF) increased the proportion of tyrosine hydroxylase-positive and dopamine-producing cells. Transplantation of these GDNF-treated cells showed improvement in apomorphine-induced rotational behavior and adjusting step and paw-reaching tests following intrastriatal implantation in a 6-hydroxy dopamine rat model of Parkinson disease. This study shows that a population of neuronal cells can be specifically generated from MSCs and that induced cells may allow for a neuroreconstructive approach.
Dezawa
Mari
M
Department of Anatomy and Neurobiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. dezawa@anat2.med.kyoto-u.ac.jp
Kanno
Hiroshi
H
Hoshino
Mikio
M
Cho
Hirotomi
H
Matsumoto
Naoya
N
Itokazu
Yutaka
Y
Tajima
Nobuyoshi
N
Yamada
Hitoshi
H
Sawada
Hajime
H
Ishikawa
Hiroto
H
Mimura
Toshirou
T
Kitada
Masaaki
M
Suzuki
Yoshihisa
Y
Ide
Chizuka
C
D000818:Animals; D015415:Biomarkers; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017690:Cell Transplantation; D002478:Cells, Cultured; D020934:Ciliary Neurotrophic Factor / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010300:Parkinson Disease / Q000378:metabolism; D010641:Phenotype; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D051880:Receptors, Notch; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014182:Transplantation, Autologous; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014793:Visual Cortex / Q000166:cytology / Q000378:metabolism
D015415:Biomarkers; D020934:Ciliary Neurotrophic Factor; C495039:GDNF protein, human; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008565:Membrane Proteins; D009414:Nerve Growth Factors; D051880:Receptors, Notch; D014157:Transcription Factors; D016222:Fibroblast Growth Factor 2; D005576:Colforsin; D014446:Tyrosine 3-Monooxygenase