Cited by 285Wound Healing and TreatmentsPluripotent Stem Cells ResearchGenetics, Aging, and Longevity in Model Organisms

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

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Mahmoudi, Salah, Mancini, Elena, Xu, Lucy, Moore, Alessandra, Jahanbani, Fereshteh, Hebestreit, Katja, Srinivasan, Rajini, Li, Xiyan, Devarajan, Keerthana, Prélot, Laurie, Ang, Cheen Euong, Shibuya, Yohei, Benayoun, Bérénice A., Chang, Anne Lynn S., Wernig, Marius, Wysocka, Joanna, Longaker, Michael T., Snyder, Michael P., Brunet, Anne·2019·Nature

DOI 10.1038/s41586-019-1658-5PMC PMC7253295

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Abstract

Age-associated chronic inflammation (inflammageing) is a central hallmark of ageing 1, but its influence on specific cells remains largely unknown. Fibroblasts are present in most tissues and contribute to wound healing 2,3. 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 strategies 4. 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 age 5-8, 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.

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Authors: Mahmoudi, S., Mancini, E., Xu, L., Moore, A., Jahanbani, F., Hebestreit, K., Srinivasan, R., Li, X., Devarajan, K., Prélot, L., Ang, C. E., Shibuya, Y., Benayoun, B. A., Chang, A. L. S., Wernig, M., Wysocka, J., Longaker, M. T., Snyder, M. P., & Brunet, A.
Affiliations: Stanford University (US)
Stanford Medicine (US)
Institute for Stem Cell Biology and Regenerative Medicine (US)
University of Southern California (US)
Corresponding author: Brunet, Anne
ORCID: Xu, Lucy
Moore, Alessandra
Jahanbani, Fereshteh
Hebestreit, Katja
Srinivasan, Rajini
Li, Xiyan
Devarajan, Keerthana
Prélot, Laurie
Ang, Cheen Euong
Shibuya, Yohei
Benayoun, Bérénice A.
Chang, Anne Lynn S.
Wernig, Marius
Wysocka, Joanna
Longaker, Michael T.
Snyder, Michael P.
Brunet, Anne
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2019-10-23
Volume: 574
Issue: 7779
Pages: 553-558
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-019-1658-5
PMC: PMC7253295
OpenAlex: W2981890739
Cited by: 285
References: 69
Citations by year: 2026: 15 · 2025: 48 · 2024: 43 · 2023: 56 · 2022: 36 · 2021: 53 · 2020: 34
FWCI: 21.47
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institutes of Health (1s10od025212-01)
National Institute on Aging (K99AG049934, R00AG049934, P01AG036695)
National Institute of General Medical Sciences (R01GM116892, P01GM099130)
National Institute of Diabetes and Digestive and Kidney Diseases (P30DK116074)
National Center for Research Resources (S10RR025518)
Topics: Health Sciences › Medicine › Surgery › Wound Healing and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords: fibroblast heterogeneity, inflammaging, induced pluripotent stem cells, wound healing, aged mice, inflammatory cytokines, TNF-α, fibroblast activation, interindividual variability, fibroblast subpopulations, conditioned medium
MeSH terms: Aging, Animals, Cell Line, Fibroblasts, Humans, Jews, Male, Mice, Inbred C57BL, Stochastic Processes, Time Factors, Wound Healing, Signal Transduction, Cytokines, Cellular Senescence, Culture Media, Conditioned, Sequence Analysis, RNA, Inflammation Mediators, Mice, Induced Pluripotent Stem Cells, Single-Cell Analysis, Cellular Reprogramming

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

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