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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation

Ken Inomata1, Takahiro Aoto, Nguyen Thanh Binh

  • 1Division of Stem Cell Medicine, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.

Cell
|June 16, 2009
PubMed

Insights

DNA damage causes hair graying by depleting melanocyte stem cells (MSCs). The DNA-damage response triggers MSC differentiation, not apoptosis, with ATM kinase acting as a crucial stemness checkpoint.

Area of Science:

  • Stem cell biology
  • Aging research
  • DNA damage response

Background:

  • Somatic stem cell depletion and DNA damage accumulation are linked to aging phenotypes.
  • Hair graying, a hallmark of aging, results from impaired melanocyte stem cell (MSC) maintenance.

Purpose of the Study:

  • To investigate the impact of irreparable DNA damage on MSC renewal.
  • To elucidate the mechanism by which DNA damage affects MSCs and hair graying.
  • To determine the role of Ataxia-telangiectasia mutated (ATM) kinase in MSC maintenance.

Main Methods:

  • Induction of irreparable DNA damage in mouse models using ionizing radiation.
  • Analysis of MSC behavior, differentiation, apoptosis, and senescence.
  • Assessment of hair graying phenotypes.
  • Genetic manipulation to study the role of ATM kinase deficiency.

Main Results:

  • Irreparable DNA damage abrogates MSC renewal in mice.
  • The DNA-damage response induces MSC differentiation into mature melanocytes, rather than apoptosis or senescence.
  • MSC depletion leads to irreversible hair graying.
  • ATM kinase deficiency sensitizes MSCs to ectopic differentiation, highlighting its role as a stemness checkpoint.

Conclusions:

  • Irreparable DNA damage triggers premature differentiation of MSCs, leading to their depletion and hair graying.
  • ATM kinase is essential for maintaining MSC quality and quantity by preventing ectopic differentiation, acting as a stemness checkpoint.

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