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

Salah Mahmoudi, Elena Mancini, Lucy Xu, Alessandra Moore, 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 and Anne Brunet ()
Additional contact information
Salah Mahmoudi: Stanford University
Elena Mancini: Stanford University
Lucy Xu: Stanford University
Alessandra Moore: Stanford University
Fereshteh Jahanbani: Stanford University
Katja Hebestreit: Stanford University
Rajini Srinivasan: Stanford University
Xiyan Li: Stanford University
Keerthana Devarajan: Stanford University
Laurie Prélot: Stanford University
Cheen Euong Ang: Stanford University
Yohei Shibuya: Stanford University
Bérénice A. Benayoun: Stanford University
Anne Lynn S. Chang: Stanford University
Marius Wernig: Stanford University
Joanna Wysocka: Stanford University
Michael T. Longaker: Stanford University
Michael P. Snyder: Stanford University
Anne Brunet: Stanford University

Nature, 2019, vol. 574, issue 7779, 553-558

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41586-019-1658-5

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