Journal
JOURNAL OF CELL SCIENCE
Volume 124, Issue 11, Pages 1867-1877Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/jcs.085506
Keywords
BMP; FGF; Dormancy; Neural stem cell
Categories
Funding
- European Commission
- National Natural Science Foundation of China [81000518]
- China Postdoctoral Science Foundation [201003237]
- Shanghai Pujiang Program [09PJ1408300]
- Science and Technology Commission of Shanghai Municipality [10JC1402300]
- Scientific Research Foundation for the Returned Overseas Chinese Scholars, Ministry of Education of China
- GlaxoSmithKline
- Medical Research Council [G0800784, G0800784B, G1100526] Funding Source: researchfish
- The Brain Tumour Charity [8/105] Funding Source: researchfish
- MRC [G0800784] Funding Source: UKRI
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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.
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