Human oligodendrocytes derived from embryonic stem cells: Effect of noggin on phenotypic differentiation in vitro and on myelination in vivo.
In attempts to produce mature oligodendrocytes from human embryonic stem (huES) cells, we searched conditions inducing transcription factors Olig1/2, as well as Nkx2.2 and Sox10, which are needed for maturation. This was obtained by retinoic acid treatment followed by noggin, an antagonist of bone morphogenetic proteins (BMPs). We found that retinoic acid induces BMPs in huES cells. Addition of noggin at a specific step was essential to form numerous mature oligodendrocytes with ramified branches and producing myelin basic protein (MBP). We describe a procedure converting huES cells into enriched populations of oligodendrocyte precursors that can be expanded and passaged repeatedly and subsequently differentiated into mature cells. Transplantation of such precursors showed that pretreatment by noggin markedly stimulates their capacity to myelinate in the brain of MBP-deficient shiverer mice in organotypic cultures and in living animals. Arrays of numerous long MBP+ fibers were generated over extended areas in the brain, with evidence of cell migration after transplantation and with formation of compact myelin sheaths.
Izrael
Michal
M
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
Zhang
Peilin
P
Kaufman
Rosalie
R
Shinder
Vera
V
Ella
Raya
R
Amit
Michal
M
Itskovitz-Eldor
Joseph
J
Chebath
Judith
J
Revel
Michel
M
D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line; D003711:Demyelinating Diseases / Q000601:surgery; D004347:Drug Interactions; D053595:Embryonic Stem Cells / Q000187:drug effects* / Q000502:physiology; D005333:Fetus; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008818:Mice, Neurologic Mutants; D046529:Microscopy, Electron, Transmission / Q000379:methods; D004676:Myelin Basic Protein / Q000378:metabolism* / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009687:Nuclear Proteins; D009836:Oligodendroglia / Q000502:physiology* / Q000648:ultrastructure; D038081:Organogenesis; D033581:Stem Cell Transplantation / Q000379:methods; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology; D000099176:Noggin Protein
D002352:Carrier Proteins; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D004676:Myelin Basic Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000099176:Noggin Protein; C000715631:NKX2-2 protein, human; C000715627:Nkx2-2 protein, mouse