Generation of regionally specified neural progenitors and functional neurons from human embryonic stem cells under defined conditions.
To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.
Department of Experimental Medical Science, Lund University, SE-221 84 Lund, Sweden.
Agnete
A
Kirkeby
Shane
S
Grealish
Daniel A
DA
Wolf
Jenny
J
Nelander
James
J
Wood
Martin
M
Lundblad
Olle
O
Lindvall
Malin
M
Parmar
D000375:Aging / Q000473:pathology; D000818:Animals; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism; D055724:Electrophysiological Phenomena / Q000187:drug effects; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D009043:Motor Activity / Q000187:drug effects; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D054259:Neural Tube / Q000187:drug effects / Q000196:embryology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D013687:Telencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects / Q000235:genetics
D047428:Protein Kinase Inhibitors; D038362:Glycogen Synthase Kinase 3; D004298:Dopamine