Noggin enhances dopamine neuron production from human embryonic stem cells and improves behavioral outcome after transplantation into Parkinsonian rats.
Symptoms of Parkinson's disease have been improved by transplantation of fetal dopamine neurons recovered from aborted fetal tissue, but tissue recovery is difficult. Human embryonic stem cells may provide unlimited cells for transplantation if they can be converted to dopamine neurons and survive transplantation into brain. We have found that the bone morphogenic protein antagonist Noggin increased the number of dopamine neurons generated in vitro from human and mouse embryonic stem cells differentiated on mouse PA6 stromal cells. Noggin effects were seen with either early (for mouse, days 0-7, and for human, days 0-9) or continuous treatment. After transplant into cyclosporin-immunosuppressed rats, human dopamine neurons improved apomorphine circling in direct relation to the number of surviving dopamine neurons, which was fivefold greater after Noggin treatment than with control human embryonic stem cell transplants differentiated only on PA6 cells. We conclude that Noggin promotes dopamine neuron differentiation and survival from human and mouse embryonic stem cells. Disclosure of potential conflicts of interest is found at the end of this article.
Chiba
Shunmei
S
Department of Medicine, Division of Clinical Pharmacology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.
Lee
Young Mook
YM
Zhou
Wenbo
W
Freed
Curt R
CR
D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000637:transplantation; D055879:Gene Knock-In Techniques; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000166:cytology* / Q000378:metabolism / Q000637:transplantation; D010302:Parkinson Disease, Secondary / Q000473:pathology / Q000523:psychology / Q000628:therapy*; D051381:Rats; D055748:SOXB1 Transcription Factors / Q000235:genetics; D013239:Stereotyped Behavior; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D000099176:Noggin Protein
D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D016572:Cyclosporine; D004298:Dopamine; D007166:Immunosuppressive Agents; D055748:SOXB1 Transcription Factors; D000099176:Noggin Protein; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse; C098693:Sox1 protein, mouse