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Isolating Intestinal Stem Cells from Adult Drosophila Midguts by FACS to Study Stem Cell Behavior During Aging
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Loss of DCAF8 impairs hematopoietic stem cell function with cellular senescence via the DOCK11-CDC42 axis

Pengfei Xu1, Xiuli Zhang1,2, Donghe Li1

  • 1Shanghai Institute of Hematology, State Key Laboratory for Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Blood
|July 11, 2025
PubMed

Insights

Aging hematopoietic stem cells (HSCs) show reduced function due to declining DCAF8 levels. Loss of DCAF8 impairs HSC self-renewal by increasing DOCK11 and CDC42 activity, leading to senescence and DNA damage.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Gerontology

Background:

  • Hematopoietic stem cells (HSCs) are crucial for lifelong blood system maintenance.
  • Functional decline in HSCs contributes to aging and hematological disorders.
  • Understanding HSC regulation is key for anti-aging interventions.

Purpose of the Study:

  • Investigate the role of DCAF8 in HSC function and aging.
  • Elucidate the molecular mechanisms underlying DCAF8-mediated HSC regulation.
  • Identify potential therapeutic targets for age-related HSC dysfunction.

Main Methods:

  • Analysis of DCAF8 expression in HSCs across age groups.
  • Phenotypic characterization of DCAF8-deficient HSCs in mice.
  • Investigation of DCAF8's interaction with DOCK11 and CDC42 pathways.
  • Genetic manipulation (knockout) to assess rescue effects.

Main Results:

  • DCAF8 expression declines progressively in HSCs with age.
  • DCAF8 deficiency impairs HSC self-renewal, increases senescence, and elevates DNA damage.
  • DCAF8 targets DOCK11 for degradation, regulating the DOCK11-CDC42 axis.
  • Loss of DCAF8 leads to DOCK11 accumulation and increased CDC42 activity, disrupting HSC polarity.
  • DOCK11 knockout rescues Dcaf8-/- HSC defects.

Conclusions:

  • DCAF8 plays a vital role in maintaining HSC function and preventing senescence.
  • The DCAF8-DOCK11-CDC42 pathway is critical for HSC polarity and self-renewal.
  • Targeting this pathway may offer therapeutic strategies against HSC aging and related diseases.

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