Limited Ca2+ and PKA-pathway dependent neurogenic differentiation of human adult mesenchymal stem cells as compared to fetal neuronal stem cells.
The ability of mesenchymal stem cells to generate functional neurons in culture is still a matter of controversy. In order to assess this issue, we performed a functional comparison between neuronal differentiation of human MSCs and fetal-derived neural stem cells (NSCs) based on morphological, immunocytochemical, and electrophysiological criteria. Furthermore, possible biochemical mechanisms involved in this process were presented. NF200 immunostaining was used to quantify the yield of differentiated cells after exposure to cAMP. The addition of a PKA inhibitor and Ca(2+) blockers to the differentiation medium significantly reduced the yield of differentiated cells. Activation of CREB was also observed on MSCs during maturation. Na(+)-, K(+)-, and Ca(2+)-voltage-dependent currents were recorded from MSCs-derived cells. In contrast, significantly larger Na(+) currents, firing activity, and spontaneous synaptic currents were recorded from NSCs. Our results indicate that the initial neuronal differentiation of MSCs is induced by cAMP and seems to be dependent upon Ca(2+) and the PKA pathway. However, compared to fetal neural stem cells, adult mesenchymal counterparts are limited in their neurogenic potential. Despite the similar yield of neuronal cells, NSCs achieved a more mature functional state. Description of the underlying mechanisms that govern MSCs' differentiation toward a stable neuronal phenotype and their limitations provides a unique opportunity to enhance our understanding of stem cell plasticity.
Lepski
Guilherme
G
Department of Neurosurgery, Eberhard-Karls-Univesity, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany. guilherme.lepski@med.uni-tuebingen.de
Jannes
Cinthia Elim
CE
Maciaczyk
Jaroslaw
J
Papazoglou
Anna
A
Mehlhorn
Alexander T
AT
Kaiser
Stefan
S
Teixeira
Manoel Jacobsen
MJ
Marie
Suely K N
SK
Bischofberger
Josef
J
Nikkhah
Guido
G
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000200:Action Potentials / Q000502:physiology; D000328:Adult; D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D018929:Cell Culture Techniques; D000242:Cyclic AMP / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D055724:Electrophysiological Phenomena / Q000502:physiology; D053686:Fetal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D055815:Young Adult
D000943:Antigens, Differentiation; D019208:Brain-Derived Neurotrophic Factor; C115163:CREB1 protein, human; D002121:Calcium Channel Blockers; D017362:Cyclic AMP Response Element-Binding Protein; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C094363:protein kinase inhibitor (6-22)-amide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D015056:1-Methyl-3-isobutylxanthine