PMID:21558414

Citation	Sun, Y, Hu, J, Zhou, L, Pollard, SM and Smith, A (2011) Interplay between FGF2 and BMP controls the self-renewal, dormancy and differentiation of rat neural stem cells. J. Cell. Sci. 124:1867-77
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.
Links	PubMed PMC3096055 Online version:10.1242/jcs.085506
Keywords	Animals; Antigens, Differentiation/metabolism; Bone Morphogenetic Proteins/antagonists & inhibitors; Bone Morphogenetic Proteins/pharmacology; Bone Morphogenetic Proteins/physiology; Carrier Proteins/pharmacology; Cell Differentiation; Cell Line; Cell Proliferation/drug effects; Cerebral Cortex/cytology; Culture Media, Conditioned; Fibroblast Growth Factor 2/pharmacology; Fibroblast Growth Factor 2/physiology; Humans; Intermediate Filament Proteins/metabolism; Mice; Nerve Tissue Proteins/metabolism; Neural Stem Cells/cytology; Neural Stem Cells/metabolism; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; SOXB1 Transcription Factors/metabolism; Smad Proteins/metabolism; Spinal Cord/cytology
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:A0A2U1		GO:2000737: negative regulation of stem cell differentiation	ECO:0000269:		P		FGF2 sustains stem cell character of dormant NS cells in presence of BMP4. Fig 7: Cells cultured with FGF2 and BMP4 retained Nestin and Sox2 expression (Transcription factors vital for ES cell line maintanence). Contrastingly,cells grown in presence of BMP4 and EGF without FGF2 show down-regulation of Sox2 expression and differentiation into GFP-positive astrocytes.	complete

References

See Help:References for how to manage references in GONUTS.