Controlling low rates of cell differentiation through noise and ultrahigh feedback

Science  20 Jun 2014:
Vol. 344, Issue 6190, pp. 1384-1389
DOI: 10.1126/science.1252079

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Cell fate control—a numbers game

Precursor cells in adult mammalian tissues differentiate at very low rates; for example, only 10% of fat cells are replaced per year. If all precursor cells responded to the same threshold of stimulus, these low rates would not be possible. Noise in the system (variability in the abundance of key proteins in different cells) could allow only a few cells to differentiate, but then such variability would allow dedifferentiation as well, which is not observed. Ahrends et al. used computational modeling and protein measurements in single cells to show that multiple feedback loops in the regulatory circuits, along with noise, can allow both stable and infrequent differentiation.

Science, this issue p. 1384


Mammalian tissue size is maintained by slow replacement of de-differentiating and dying cells. For adipocytes, key regulators of glucose and lipid metabolism, the renewal rate is only 10% per year. We used computational modeling, quantitative mass spectrometry, and single-cell microscopy to show that cell-to-cell variability, or noise, in protein abundance acts within a network of more than six positive feedbacks to permit pre-adipocytes to differentiate at very low rates. This reconciles two fundamental opposing requirements: High cell-to-cell signal variability is needed to generate very low differentiation rates, whereas low signal variability is needed to prevent differentiated cells from de-differentiating. Higher eukaryotes can thus control low rates of near irreversible cell fate decisions through a balancing act between noise and ultrahigh feedback connectivity.

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