Journal
NATURE CELL BIOLOGY
Volume 14, Issue 3, Pages 287-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb2442
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Funding
- Fundacao para a Ciencia e Tecnologia [SFRH/BD/33208/2007]
- Swedish Foundation for Strategic Research
- Medical Research Council of the United Kingdom
- Leukaemia and Lymphoma Research
- EuroSyStem
- STEMEXPAND
- Fundação para a Ciência e a Tecnologia [SFRH/BD/33208/2007] Funding Source: FCT
- Cancer Research UK [12796] Funding Source: researchfish
- Medical Research Council [MC_U137973817] Funding Source: researchfish
- MRC [MC_U137973817] Funding Source: UKRI
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How the molecular programs of differentiated cells develop as cells transit from multipotency through lineage commitment remains unexplored. This reflects the inability to access cells undergoing commitment or located in the immediate vicinity of commitment boundaries. It remains unclear whether commitment constitutes a gradual process, or else represents a discrete transition. Analyses of in vitro self-renewing multipotent systems have revealed cellular heterogeneity with individual cells transiently exhibiting distinct biases for lineage commitment(1-6). Such systems can be used to molecularly interrogate early stages of lineage affiliation and infer rules of lineage commitment. In haematopoiesis, population-based studies have indicated that lineage choice is governed by global transcriptional noise, with self-renewing multipotent cells reversibly activating transcriptome-wide lineage-affiliated programs(7). We examine this hypothesis through functional and molecular analysis of individual blood cells captured from self-renewal cultures, during cytokine-driven differentiation and from primary stem and progenitor bone marrow compartments. We show dissociation between self-renewal potential and transcriptome-wide activation of lineage programs, and instead suggest that multipotent cells experience independent activation of individual regulators resulting in a low probability of transition to the committed state.
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