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The role of specialized cell cycles during erythroid lineage development: insights from single-cell RNA sequencing

  • Progress in Hematology
  • The path from stem cells to red blood cells
  • Published:
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Abstract

Early erythroid progenitors known as CFU-e undergo multiple self-renewal cell cycles. The CFU-e developmental stage ends with the onset of erythroid terminal differentiation (ETD). The transition from CFU-e to ETD is a critical cell fate decision that determines erythropoietic rate. Here we review recent insights into the regulation of this transition, garnered from flow cytometric and single-cell RNA sequencing studies. We find that the CFU-e/ETD transition is a rapid S phase-dependent transcriptional switch. It takes place during an S phase that is much shorter than in preceding or subsequent cycles, as a result of globally faster replication forks. Furthermore, it is preceded by cycles in which G1 becomes gradually shorter. These dramatic cell cycle and S phase remodeling events are directly linked to regulation of the CFU-e/ETD switch. Moreover, regulators of erythropoietic rate exert their effects by modulating cell cycle duration and S phase speed. Glucocorticoids increase erythropoietic rate by inducing the CDK inhibitor p57KIP2, which slows replication forks, inhibiting the CFU-e/ETD switch. Conversely, erythropoietin promotes induction of ETD by shortening the cycle. S phase shortening was reported during cell fate decisions in non-erythroid lineages, suggesting a fundamentally new developmental role for cell cycle speed.

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Acknowledgements

MS would like to thank her students, postdoctoral fellows, trainees and colleagues whose work is discussed in this article, and to thank Yung Hwang, Aishwarya Swaminathan and Ashley Winward for reading the manuscript. This work is supported by NIH Grants R01DK130498, R01DK120639 and R01HL141402.

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  1. Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, 01605, USA

    Merav Socolovsky

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Socolovsky, M. The role of specialized cell cycles during erythroid lineage development: insights from single-cell RNA sequencing. Int J Hematol 116, 163–173 (2022). https://doi.org/10.1007/s12185-022-03406-9

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