You are here

| ESCs/iPSCs

Inflammatory Factors from Aged Fibroblasts Affect Reprogramming and Wound Healing

Review of  “Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing” from Nature by Stuart P. Atkinson

The humble fibroblast, present in most tissues, generally takes a starring role during the generation of induced pluripotent stem cells (iPSCs); however, only a modest number of studies have sought to evaluate how the aging process affects fibroblasts and how this process impacts the reprogramming process [1-4]. Information regarding fibroblast aging may also have relevance in the field of wound treatments, as fibroblasts also play a vital role in the wound healing process [5, 6].  To remedy the general lack of knowledge in this area, researchers led by Anne Brunet (Stanford University, Stanford, CA, USA) recently undertook a systematic multilevel approach to evaluate how aging influences the reprogramming of mouse fibroblast [7].

As described in their recent study, Mahmoudi et al. discovered that cultured fibroblasts derived from old mice (28–29 months) contained significantly higher numbers of cells that secreted a range of inflammatory cytokines when compared to young mice (3 months). Furthermore, the proportion of activated fibroblasts correlated with the efficiency of iPSC generation from that specific culture of cells when using the expression of OCT4, SOX2, KLF4, and MYC for the reprogramming process. Experiments using fibroblast conditioned-medium confirmed the controlling role of secreted inflammatory factors from activated fibroblasts in reprogramming, and the authors identified interleukin-6, interleukin-1β, and tumor necrosis factor as crucially important factors.

The authors then shifted their focus to wound healing, noting that old mice exhibited variability in their wound healing rate in vivo, suggesting that, as for reprogramming, an ever-growing subpopulation of fibroblasts in aging mice may be at fault. Indeed, single-cell RNA-sequencing analysis identified fibroblasts with different cytokine expression and signaling profiles in the wounds of old mice with slow healing rates, when compared to old mice displaying quicker healing rates.

Overall, the authors point to the alteration of fibroblast composition and the increased secretion of inflammatory cytokines during the aging process as a critical driver of reprogramming variability in vitro and wound healing rate in vivo. Can we use this information to improve both iPSC generation from older donors and wound healing in the elderly?

For the answers to these pressing questions, and more, stay tuned to the Stem Cells Portal!

References

  1. Lapasset L, Milhavet O, Prieur A, et al., Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state. Genes & Development 2011;25:2248-2253.
  2. Li H, Collado M, Villasante A, et al., The Ink4/Arf locus is a barrier for iPS cell reprogramming. Nature 2009;460:1136-1139.
  3. Mosteiro L, Pantoja C, Alcazar N, et al., Tissue damage and senescence provide critical signals for cellular reprogramming in vivo. Science 2016;354:aaf4445.
  4. Ravaioli F, Bacalini MG, Franceschi C, et al., Age-Related Epigenetic Derangement upon Reprogramming and Differentiation of Cells from the Elderly. Genes 2018;9.
  5. Eming SA, Martin P, and Tomic-Canic M, Wound repair and regeneration: Mechanisms, signaling, and translation. Science Translational Medicine 2014;6:265sr6.
  6. Lynch MD and Watt FM, Fibroblast heterogeneity: implications for human disease. Journal of Clinical Investigation 2018;128:26-35.
  7. Mahmoudi S, Mancini E, Xu L, et al., Heterogeneity in old fibroblasts is linked to variability in reprogramming and wound healing. Nature 2019;574:553-558.