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Assessment of the Immunomodulatory Properties of Human Mesenchymal Stem Cells MSCs
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ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells

Si Wang1,2,3,4, Boqiang Hu5,6, Zhichao Ding1,3

  • 11National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 100101 Beijing, China.

Cell Discovery
|February 10, 2018
PubMed

Insights

Cellular aging involves organelle dysfunction. Researchers found that downregulating transcription factor ATF6 accelerates human mesenchymal stem cell aging by disrupting organelle homeostasis, revealing a key gene network.

Area of Science:

  • Cellular and Molecular Biology
  • Aging Research
  • Stem Cell Biology

Background:

  • Loss of organelle homeostasis is a key feature of cellular aging.
  • The specific gene expression mechanisms underlying this process remain largely unknown.

Purpose of the Study:

  • To investigate the role of transcription factor ATF6 in human mesenchymal stem cell (hMSC) aging.
  • To identify ATF6-regulated genes involved in maintaining organelle homeostasis.

Main Methods:

  • CRISPR/Cas9-mediated gene inactivation of ATF6 in hMSCs.
  • Transcriptomic analysis (RNA sequencing) to identify ATF6-regulated genes.
  • Comparison of ATF6 function in hMSCs, human embryonic stem cells, and human adipocytes.

Main Results:

  • ATF6 inactivation in hMSCs, but not other cell types, induced premature cellular aging and endomembrane dysfunction.
  • Identified cell type-specific ATF6-regulated genes crucial for organelle homeostasis.
  • Characterized FOS as a constitutive ATF6-responsive gene; its downregulation contributes to hMSC aging.

Conclusions:

  • ATF6 plays a critical, cell type-specific role in regulating organelle homeostasis and preventing premature aging in hMSCs.
  • Discovered a novel ATF6-dependent gene network governing membrane organelle regulation.
  • Provides new mechanistic insights into stem cell aging and age-related decline.

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