Close

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 Prelot, Cheen Euong Ang, Yohei Shibuya, Berenice A. Benayoun, Anne Lynn S. Chang, Marius Wernig, Joanna Wysocka, Michael T. Longaker, Michael P. Snyder, Anne Brunet

Preprint posted on 19 October 2018 https://www.biorxiv.org/content/early/2018/10/19/448431

Growing older and wiser: researchers reveal a subset of old fibroblasts that promote reprogramming more efficiently than their counterparts.

Selected by Shikha Nayar

Categories: cell biology, immunology

Context and Background

As we get older, our cells tend to produce elevated levels of pro-inflammatory cytokines. Over time, this leads to chronic inflammation, which is a hallmark of many chronic ailments such as cardiovascular diseases and fibrosis (Figure 1).1  Though reprogramming of mesenchymal cells has been effective in treating some chronic inflammatory conditions2, new findings such as presented in this study show that there exists a remarkable level of heterogeneity between aged fibroblasts, contributing to varying levels of efficiency in reprogramming. Understanding how this heterogeneity impacts reprogramming is key to being able to personalize treatments in patients with age-related diseases.

Figure 1 from Franceschi et al., 2018. The Seven pillars of ageing.

 

Key findings

The authors show a marked upregulation in pro-inflammatory cytokines, such as IL6 and TNFα, in plasma from old mice vs. young mice, also observed in conditioned media from cultured human fibroblasts. Strikingly, conditioned media of iPSC lines derived from old fibroblast cultures no longer contained increased levels of inflammatory cytokines, suggesting that reprogramming the cells also erased their pro-inflammatory state. A caveat that the authors then explore, is the increased variability of reprogramming efficiency of older cells. Through transcriptomic, chromatin and metabolomics profiling, they were able to conclude that an ‘activated’ fibroblast state is key to successful reprogramming. A few key features of these activated fibroblasts were their highly proliferative state, expression of the transcription factor EBF2 and secretion of ECM components (Figure 2d); yet the heterogeneity among old fibroblasts was identified in cell extrinsic rather than intrinsic factors. The authors concluded that secreted IL6 enhanced reprogramming efficiency, whereas TNFα reduced it; further, that blocking of TNFα reduced the variability in reprogramming efficiency between activated and non-activated old fibroblasts, and could be a key driver of diminishing plasticity in these cells.

 

Importance of this paper

This paper underscores the need to understand variability in reprogramming, and that both cell intrinsic and extrinsic factors should be examined to identify key drivers of this variability. Additionally, there have been an increasing number of studies showing that pro-inflammatory cytokines can have both damaging and protective roles in chronic inflammatory diseases. This study once again alludes to this dichotomy, and challenges us to be specific and careful when examining directionality of effect based on the disease in question.

 

Open questions

The authors allude to tissue heterogeneity as well as cellular heterogeneity; how might reprogramming cells in age-related diseases that affect different tissue types change? Would changes in systemic inflammatory milieu affect global reprogramming efficiency? Does this activated fibroblast subset also exist among “good” young fibroblasts? Additionally, would increased reprogramming efficiency of activated fibroblasts not only contribute to wound healing, but also to fibrosis? How would this be controlled? More investigation into these issues and why variability of reprogramming exists in patients with the same condition will help us target personalized approaches to managing chronic inflammatory conditions and wound healing.

 

References

  1. Franceschi, C., Garagnani, P., Parini, P., Giuliani, C. & Santoro, A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14, 576-590 (2018).
  1. Flavell, S J et al. “Fibroblasts as novel therapeutic targets in chronic inflammation” British journal of pharmacology153 Suppl 1, (2007): S241-6.

Tags: activated fibroblasts, ageing, reprogramming

Posted on: 30 November 2018

doi: https://doi.org/10.1242/prelights.6104

Read preprint (2 votes)

Have your say

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.

Sign up to customise the site to your preferences and to receive alerts

Register here

preLists in the cell biology category:

Fibroblasts

The advances in fibroblast biology preList explores the recent discoveries and preprints of the fibroblast world. Get ready to immerse yourself with this list created for fibroblasts aficionados and lovers, and beyond. Here, my goal is to include preprints of fibroblast biology, heterogeneity, fate, extracellular matrix, behavior, topography, single-cell atlases, spatial transcriptomics, and their matrix!

 



List by Osvaldo Contreras

EMBL Synthetic Morphogenesis: From Gene Circuits to Tissue Architecture (2021)

A list of preprints mentioned at the #EESmorphoG virtual meeting in 2021.

 



List by Alex Eve

FENS 2020

A collection of preprints presented during the virtual meeting of the Federation of European Neuroscience Societies (FENS) in 2020

 



List by Ana Dorrego-Rivas

Planar Cell Polarity – PCP

This preList contains preprints about the latest findings on Planar Cell Polarity (PCP) in various model organisms at the molecular, cellular and tissue levels.

 



List by Ana Dorrego-Rivas

BioMalPar XVI: Biology and Pathology of the Malaria Parasite

[under construction] Preprints presented at the (fully virtual) EMBL BioMalPar XVI, 17-18 May 2020 #emblmalaria

 



List by Dey Lab, Samantha Seah

1

Cell Polarity

Recent research from the field of cell polarity is summarized in this list of preprints. It comprises of studies focusing on various forms of cell polarity ranging from epithelial polarity, planar cell polarity to front-to-rear polarity.

 



List by Yamini Ravichandran

TAGC 2020

Preprints recently presented at the virtual Allied Genetics Conference, April 22-26, 2020. #TAGC20

 



List by Maiko Kitaoka et al.

3D Gastruloids

A curated list of preprints related to Gastruloids (in vitro models of early development obtained by 3D aggregation of embryonic cells). Updated until July 2021.

 



List by Paul Gerald L. Sanchez and Stefano Vianello

ECFG15 – Fungal biology

Preprints presented at 15th European Conference on Fungal Genetics 17-20 February 2020 Rome

 



List by Hiral Shah

ASCB EMBO Annual Meeting 2019

A collection of preprints presented at the 2019 ASCB EMBO Meeting in Washington, DC (December 7-11)

 



List by Madhuja Samaddar et al.

EMBL Seeing is Believing – Imaging the Molecular Processes of Life

Preprints discussed at the 2019 edition of Seeing is Believing, at EMBL Heidelberg from the 9th-12th October 2019

 



List by Dey Lab

Autophagy

Preprints on autophagy and lysosomal degradation and its role in neurodegeneration and disease. Includes molecular mechanisms, upstream signalling and regulation as well as studies on pharmaceutical interventions to upregulate the process.

 



List by Sandra Malmgren Hill

Lung Disease and Regeneration

This preprint list compiles highlights from the field of lung biology.

 



List by Rob Hynds

Cellular metabolism

A curated list of preprints related to cellular metabolism at Biorxiv by Pablo Ranea Robles from the Prelights community. Special interest on lipid metabolism, peroxisomes and mitochondria.

 



List by Pablo Ranea Robles

BSCB/BSDB Annual Meeting 2019

Preprints presented at the BSCB/BSDB Annual Meeting 2019

 



List by Dey Lab

MitoList

This list of preprints is focused on work expanding our knowledge on mitochondria in any organism, tissue or cell type, from the normal biology to the pathology.

 



List by Sandra Franco Iborra

Biophysical Society Annual Meeting 2019

Few of the preprints that were discussed in the recent BPS annual meeting at Baltimore, USA

 



List by Joseph Jose Thottacherry

ASCB/EMBO Annual Meeting 2018

This list relates to preprints that were discussed at the recent ASCB conference.

 



List by Dey Lab, Amanda Haage
Close