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Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals

Salah Mahmoudi, Elena Mancini, Alessandra Moore, Lucy Xu, Fereshteh Jahanbani, Katja Hebestreit, Rajini Srinivasan, Xiyan Li, Keerthana Devarajan, Laurie Prélot, Cheen Euong Ang, Yohei Shibuya, Bérénice A. Benayoun, Anne Lynn S. Chang, Marius Wernig, Joanna Wysocka, Michael T. Longaker, Michael P. Snyder, Anne Brunet
doi: https://doi.org/10.1101/448431
Salah Mahmoudi
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Elena Mancini
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Alessandra Moore
2Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA
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Lucy Xu
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
3Department of Biology, Stanford University, Stanford, CA 94305, USA
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Fereshteh Jahanbani
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Katja Hebestreit
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Rajini Srinivasan
4Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA
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Xiyan Li
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Keerthana Devarajan
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Laurie Prélot
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Cheen Euong Ang
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
6Department of Bioengineering, Stanford University, Stanford, CA 94305, USA
7Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Yohei Shibuya
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
7Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Bérénice A. Benayoun
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
8Current affiliation: Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA
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Anne Lynn S. Chang
9Department of Dermatology, Stanford University, Stanford, CA 94305, USA
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Marius Wernig
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
7Department of Pathology, Stanford University, Stanford, CA 94305, USA
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Joanna Wysocka
3Department of Biology, Stanford University, Stanford, CA 94305, USA
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
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Michael T. Longaker
2Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA
5Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA
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Michael P. Snyder
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
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Anne Brunet
1Department of Genetics, Stanford University, 300 Pasteur Drive, Stanford, CA 94305, USA
10Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA 94305, USA
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  • For correspondence: anne.brunet@stanford.edu
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Abstract

Age-associated chronic inflammation (inflammaging) has emerged as a central hallmark of aging1-3, but its impact on specific cells is still largely unknown. Fibroblasts are present in all tissues and contribute to wound healing4-6. They are also the cell type that is mostly used for induced pluripotent stem cell (iPSC) reprogramming7 – a process that has implications for regenerative medicine and rejuvenation strategies8-17. Here we show that primary fibroblasts from old mice secrete inflammatory cytokines and that there is an increased variability in reprogramming efficiency between fibroblast cultures from old individuals. Individual-to-individual variability is emerging as a key feature of old age18-21, which could reflect distinct aging trajectories, but the underlying causes remain unknown. To identify drivers of this variability, we perform a multi-omic assessment of young and old fibroblast cultures with different reprogramming efficiency. This approach, coupled with single cell transcriptomics, reveals that old fibroblast cultures are heterogeneous and show a greater proportion of ‘activated fibroblasts’ that secrete inflammatory cytokines, which correlates with reprogramming efficiency. We experimentally validate that activated fibroblasts express inflammatory cytokines in vivo and that their presence is linked to enhanced reprogramming efficiency in culture. Conditioned-media swapping experiments show that extrinsic factors secreted by activated fibroblasts are more critical than intrinsic factors for the individual-to-individual variability in reprogramming efficiency, and we identify TNFα as a key inflammatory cytokine underlying this variability. Interestingly, old mice also exhibit variability in wound healing efficiency in vivo and old wounds show an increased subpopulation of activated fibroblasts with a unique TNFα signature. Our study shows that a switch in fibroblast composition, and the ratio of inflammatory cytokines they secrete, drives variability in reprogramming in vitro and may influence wound healing in vivo. These findings could help identify personalized strategies to improve iPSC generation and wound healing in older individuals.

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Posted October 19, 2018.
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Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals
Salah Mahmoudi, Elena Mancini, Alessandra Moore, Lucy Xu, Fereshteh Jahanbani, Katja Hebestreit, Rajini Srinivasan, Xiyan Li, Keerthana Devarajan, Laurie Prélot, Cheen Euong Ang, Yohei Shibuya, Bérénice A. Benayoun, Anne Lynn S. Chang, Marius Wernig, Joanna Wysocka, Michael T. Longaker, Michael P. Snyder, Anne Brunet
bioRxiv 448431; doi: https://doi.org/10.1101/448431
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Old fibroblasts secrete inflammatory cytokines that drive variability in reprogramming efficiency and may affect wound healing between old individuals
Salah Mahmoudi, Elena Mancini, Alessandra Moore, Lucy Xu, Fereshteh Jahanbani, Katja Hebestreit, Rajini Srinivasan, Xiyan Li, Keerthana Devarajan, Laurie Prélot, Cheen Euong Ang, Yohei Shibuya, Bérénice A. Benayoun, Anne Lynn S. Chang, Marius Wernig, Joanna Wysocka, Michael T. Longaker, Michael P. Snyder, Anne Brunet
bioRxiv 448431; doi: https://doi.org/10.1101/448431

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