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Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing

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Listed:
  • Salah Mahmoudi

    (Stanford University)

  • Elena Mancini

    (Stanford University)

  • Lucy Xu

    (Stanford University
    Stanford University)

  • Alessandra Moore

    (Stanford University
    Stanford University)

  • Fereshteh Jahanbani

    (Stanford University)

  • Katja Hebestreit

    (Stanford University)

  • Rajini Srinivasan

    (Stanford University
    Stanford University)

  • Xiyan Li

    (Stanford University)

  • Keerthana Devarajan

    (Stanford University)

  • Laurie Prélot

    (Stanford University)

  • Cheen Euong Ang

    (Stanford University
    Stanford University
    Stanford University)

  • Yohei Shibuya

    (Stanford University
    Stanford University)

  • Bérénice A. Benayoun

    (Stanford University
    University of Southern California)

  • Anne Lynn S. Chang

    (Stanford University)

  • Marius Wernig

    (Stanford University
    Stanford University)

  • Joanna Wysocka

    (Stanford University
    Stanford University)

  • Michael T. Longaker

    (Stanford University
    Stanford University)

  • Michael P. Snyder

    (Stanford University)

  • Anne Brunet

    (Stanford University
    Stanford University)

Abstract

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing2,3. They are also the most widely used cell type for reprogramming to induced pluripotent stem (iPS) cells, a process that has implications for regenerative medicine and rejuvenation strategies4. Here we show that fibroblast cultures from old mice secrete inflammatory cytokines and exhibit increased variability in the efficiency of iPS cell reprogramming between mice. Variability between individuals is emerging as a feature of old age5–8, but the underlying mechanisms remain unknown. To identify drivers of this variability, we performed multi-omics profiling of fibroblast cultures from young and old mice that have different reprogramming efficiencies. This approach revealed that fibroblast cultures from old mice contain ‘activated fibroblasts’ that secrete inflammatory cytokines, and that the proportion of activated fibroblasts in a culture correlates with the reprogramming efficiency of that culture. Experiments in which conditioned medium was swapped between cultures showed that extrinsic factors secreted by activated fibroblasts underlie part of the variability between mice in reprogramming efficiency, and we have identified inflammatory cytokines, including TNF, as key contributors. Notably, old mice also exhibited variability in wound healing rate in vivo. Single-cell RNA-sequencing analysis identified distinct subpopulations of fibroblasts with different cytokine expression and signalling in the wounds of old mice with slow versus fast healing rates. Hence, a shift in fibroblast composition, and the ratio of inflammatory cytokines that they secrete, may drive the variability between mice in reprogramming in vitro and influence wound healing rate in vivo. This variability may reflect distinct stochastic ageing trajectories between individuals, and could help in developing personalized strategies to improve iPS cell generation and wound healing in elderly individuals.

Suggested Citation

  • Salah Mahmoudi & Elena Mancini & Lucy Xu & Alessandra Moore & Fereshteh Jahanbani & Katja Hebestreit & Rajini Srinivasan & Xiyan Li & Keerthana Devarajan & Laurie Prélot & Cheen Euong Ang & Yohei Shib, 2019. "Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing," Nature, Nature, vol. 574(7779), pages 553-558, October.
  • Handle: RePEc:nat:nature:v:574:y:2019:i:7779:d:10.1038_s41586-019-1658-5
    DOI: 10.1038/s41586-019-1658-5
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    Citations

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    Cited by:

    1. Vera Vorstandlechner & Maria Laggner & Dragan Copic & Katharina Klas & Martin Direder & Yiyan Chen & Bahar Golabi & Werner Haslik & Christine Radtke & Erwin Tschachler & Konrad Hötzenecker & Hendrik J, 2021. "The serine proteases dipeptidyl-peptidase 4 and urokinase are key molecules in human and mouse scar formation," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    2. Shruthi Kalgudde Gopal & Ruoxuan Dai & Ania Maria Stefanska & Meshal Ansari & Jiakuan Zhao & Pushkar Ramesh & Johannes W. Bagnoli & Donovan Correa-Gallegos & Yue Lin & Simon Christ & Ilias Angelidis &, 2023. "Wound infiltrating adipocytes are not myofibroblasts," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Meiling Zheng & Zhi Hu & Xiaole Mei & Lianlian Ouyang & Yang Song & Wenhui Zhou & Yi Kong & Ruifang Wu & Shijia Rao & Hai Long & Wei Shi & Hui Jing & Shuang Lu & Haijing Wu & Sujie Jia & Qianjin Lu & , 2022. "Single-cell sequencing shows cellular heterogeneity of cutaneous lesions in lupus erythematosus," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Francesco Panariello & Onelia Gagliano & Camilla Luni & Antonio Grimaldi & Silvia Angiolillo & Wei Qin & Anna Manfredi & Patrizia Annunziata & Shaked Slovin & Lorenzo Vaccaro & Sara Riccardo & Valenti, 2023. "Cellular population dynamics shape the route to human pluripotency," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    5. Maria A. Missinato & Sean Murphy & Michaela Lynott & Michael S. Yu & Anaïs Kervadec & Yu-Ling Chang & Suraj Kannan & Mafalda Loreti & Christopher Lee & Prashila Amatya & Hiroshi Tanaka & Chun-Teng Hua, 2023. "Conserved transcription factors promote cell fate stability and restrict reprogramming potential in differentiated cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    6. Steven Andrew Baker & Shirley Kwok & Gerald J Berry & Thomas J Montine, 2021. "Angiotensin-converting enzyme 2 (ACE2) expression increases with age in patients requiring mechanical ventilation," PLOS ONE, Public Library of Science, vol. 16(2), pages 1-17, February.
    7. Urban Lendahl & Lars Muhl & Christer Betsholtz, 2022. "Identification, discrimination and heterogeneity of fibroblasts," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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