Journal
DEVELOPMENT
Volume 144, Issue 17, Pages 3042-3053Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.153239
Keywords
Human embryonic stem cells; Micropatterning; BMP4 pathway; Differentiation mechanisms
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Funding
- Rice University
- National Science Foundation [MCB-1553228]
- Cancer Prevention and Research Institute of Texas [RR 140073]
- John S. Dunn Foundation
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1553228] Funding Source: National Science Foundation
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Paracrine signals maintain developmental states and create cell fate patterns in vivo and influence differentiation outcomes in human embryonic stem cells (hESCs) in vitro. Systematic investigation of morphogen signaling is hampered by the difficulty of disentangling endogenous signaling from experimentally applied ligands. Here, we grow hESCs in micropatterned colonies of 1-8 cells ('mu Colonies') to quantitatively investigate paracrine signaling and the response to external stimuli. We examine BMP4-mediated differentiation in mu Colonies and standard culture conditions and find that in aeColonies, above a threshold concentration, BMP4 gives rise to only a single cell fate, contrary to its role as a morphogen in other developmental systems. Under standard culture conditions BMP4 acts as a morphogen but this requires secondary signals and particular cell densities. We find that a 'community effect' enforces a common fate within aeColonies, both in the state of pluripotency and when cells are differentiated, and that this effect allows a more precise response to external signals. Using live cell imaging to correlate signaling histories with cell fates, we demonstrate that interactions between neighbors result in sustained, homogenous signaling necessary for differentiation.
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