title: Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells.
abstract: Mouse and human central nervous system progenitor cells can be propagated extensively ex vivo as stem cell lines. For the rat, however, in vitro expansion has proven to be problematic owing to proliferation arrest and differentiation. Here, we analyse the establishment, in adherent culture, of undifferentiated tripotent neural stem (NS) cell lines derived from rat foetal brain and spinal cord. Rat NS cells invariably undergo growth arrest and apparent differentiation after several passages; however, conditioned medium from proliferating cultures can overcome this block, enabling continuous propagation of undifferentiated rat NS cells. We found that dormancy is induced by autocrine production of bone morphogenetic proteins (BMPs). Accordingly, the BMP antagonist noggin can replace conditioned medium to sustain continuous self-renewal. Noggin can also induce dormant cells to re-enter the cell cycle, upon which they reacquire neurogenic potential. We further show that fibroblast growth factor 2 (FGF2) is required to suppress terminal astrocytic differentiation and maintain stem cell potency during dormancy. These findings highlight an extrinsic regulatory network, comprising BMPs, BMP antagonists and FGF2 signals, that governs the proliferation, dormancy and differentiation of rat NS cells and which can be manipulated to enable long-term clonogenic self-renewal.
authors.affiliation: Wellcome Trust Centre for Stem Cell Research and Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB21QR, UK.
authors.forename: Yirui
authors.initials: Y
authors.lastname: Sun
authors.forename: Jin
authors.initials: J
authors.lastname: Hu
authors.forename: Liangfu
authors.initials: L
authors.lastname: Zhou
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.forename: Austin
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology; D017077:Culture Media, Conditioned; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D051785:Smad Proteins / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology; D000099176:Noggin Protein
chemical_list: D000943:Antigens, Differentiation; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D016222:Fibroblast Growth Factor 2; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; D064231:Nestin; D055748:SOXB1 Transcription Factors; D051785:Smad Proteins; D000099176:Noggin Protein; C577484:NES protein, human; C577485:Nes protein, mouse; C577486:Nes protein, rat; C527784:Sox2 protein, rat