Format

Send to

Choose Destination
Nature. 2019 Oct;574(7779):553-558. doi: 10.1038/s41586-019-1658-5. Epub 2019 Oct 23.

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

Author information

1
Department of Genetics, Stanford University, Stanford, CA, USA.
2
Department of Biology, Stanford University, Stanford, CA, USA.
3
Department of Surgery, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA, USA.
4
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA, USA.
5
Department of Chemical and Systems Biology, Stanford University, Stanford, CA, USA.
6
Department of Bioengineering, Stanford University, Stanford, CA, USA.
7
Department of Pathology, Stanford University, Stanford, CA, USA.
8
Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA, USA.
9
Department of Dermatology, Stanford University, Stanford, CA, USA.
10
Department of Genetics, Stanford University, Stanford, CA, USA. anne.brunet@stanford.edu.
11
Glenn Laboratories for the Biology of Aging, Stanford University, Stanford, CA, USA. anne.brunet@stanford.edu.

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.

PMID:
31645721
DOI:
10.1038/s41586-019-1658-5
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Nature Publishing Group
Loading ...
Support Center