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Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

View ORCID ProfileBence Daniel, Julia A. Belk, Stefanie L. Meier, Andy Y. Chen, Katalin Sandor, Yanyan Qi, Hugo Kitano, Joshua R. Wheeler, Deshka S. Foster, Michael Januszyk, Michael T. Longaker, Howard Y. Chang, Ansuman T. Satpathy
doi: https://doi.org/10.1101/2021.06.24.449850
Bence Daniel
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
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  • ORCID record for Bence Daniel
  • For correspondence: bdaniel8@stanford.edu satpathy@stanford.edu howchang@stanford.edu
Julia A. Belk
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
2Department of Computer Science, Stanford University, Stanford, CA 94305, USA
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Stefanie L. Meier
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
9Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA
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Andy Y. Chen
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
8Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
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Katalin Sandor
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Yanyan Qi
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Hugo Kitano
2Department of Computer Science, Stanford University, Stanford, CA 94305, USA
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Joshua R. Wheeler
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
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Deshka S. Foster
5Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA
6Department of Surgery, Stanford University School of Medicine, Stanford CA 94305, USA
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Michael Januszyk
5Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA
6Department of Surgery, Stanford University School of Medicine, Stanford CA 94305, USA
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Michael T. Longaker
5Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA
6Department of Surgery, Stanford University School of Medicine, Stanford CA 94305, USA
7Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA
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Howard Y. Chang
3Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA
4Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: bdaniel8@stanford.edu satpathy@stanford.edu howchang@stanford.edu
Ansuman T. Satpathy
1Department of Pathology, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: bdaniel8@stanford.edu satpathy@stanford.edu howchang@stanford.edu
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Summary

Cell cycle (CC) is a fundamental biological process with robust, cyclical gene expression programs to facilitate cell division. In the immune system, a productive immune response requires the expansion of pathogen-responsive cell types, but whether CC also confers unique gene expression programs that inform the subsequent immunological response remains unclear. Here we demonstrate that single macrophages adopt different plasticity states in CC, which is a major source of heterogeneity in response to polarizing cytokines. Specifically, macrophage plasticity to interferon gamma (IFNG) is substantially reduced, while interleukin 4 (IL-4) can induce S-G2/M-biased gene expression. Additionally, IL-4 polarization shifts the CC-phase distribution of the population towards G2/M phase, providing a mechanism for reduced IFNG-induced repolarization. Finally, we show that macrophages express tissue remodeling genes in the S-G2/M-phases of CC, that can be also detected in vivo during muscle regeneration. Therefore, macrophage inflammatory and regenerative responses are gated by CC in a cyclical phase-dependent manner.

  • Single-cell chromatin maps reveal heterogeneous macrophage polarization states

  • Cell cycle coincides with heterogeneity and alters macrophage plasticity to polarizing cytokines

  • Macrophage polarization is a cell cycle phase-dependent immunological process

  • S-G2/M-biased gene expression is linked to tissue remodeling and detected in proliferating macrophages during muscle regeneration

Competing Interest Statement

J.A.B. is a consultant for Immunai. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Arsenal Biosciences. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio and Cartography Biosciences, and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted June 25, 2021.
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Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state
Bence Daniel, Julia A. Belk, Stefanie L. Meier, Andy Y. Chen, Katalin Sandor, Yanyan Qi, Hugo Kitano, Joshua R. Wheeler, Deshka S. Foster, Michael Januszyk, Michael T. Longaker, Howard Y. Chang, Ansuman T. Satpathy
bioRxiv 2021.06.24.449850; doi: https://doi.org/10.1101/2021.06.24.449850
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Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state
Bence Daniel, Julia A. Belk, Stefanie L. Meier, Andy Y. Chen, Katalin Sandor, Yanyan Qi, Hugo Kitano, Joshua R. Wheeler, Deshka S. Foster, Michael Januszyk, Michael T. Longaker, Howard Y. Chang, Ansuman T. Satpathy
bioRxiv 2021.06.24.449850; doi: https://doi.org/10.1101/2021.06.24.449850

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