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MXD4/MAD4 Regulates Human Keratinocyte Precursor Fate
Julien Coutier1, Frédéric Auvré1, Gilles Lemaître1
1Laboratory of Genomic and Radiobiology of Keratinopoiesis, CEA/DRF/IBFJ/IRCM, Evry, France; Paris-Saclay University, Evry Val-d'Essonne University, Evry, France.
The Journal of Investigative Dermatology
|August 25, 2022
Summary
The transcription factor MXD4/MAD4 is highly expressed in quiescent human epidermal stem cells. Decreasing MXD4/MAD4 promotes keratinocyte precursor proliferation and function for skin bioengineering.
Area of Science:
- Dermatology
- Stem Cell Biology
- Molecular Biology
Background:
- Understanding human epidermal precursor cell fate is crucial for skin repair and bioengineering.
- Optimizing keratinocyte (KC) precursor ex vivo expansion requires characterizing pathways balancing immaturity and differentiation.
Purpose of the Study:
- To investigate the role of the transcription factor MXD4/MAD4 in human epidermal keratinocyte stem/progenitor cells.
- To identify pathways regulating keratinocyte precursor immaturity versus differentiation for improved ex vivo expansion.
Main Methods:
- Quantitative analysis of MXD4/MAD4 expression in quiescent versus cycling KC progenitors.
- Short hairpin RNA (shRNA)-mediated knockdown of MXD4/MAD4 in holoclone KCs.
- Assessment of MYC expression, KC precursor proliferation, clonogenic potential, and 3D epidermis organoid generation.
Main Results:
- MXD4/MAD4 is expressed at higher levels in quiescent KC stem/progenitor cells than in cycling progenitors.
- Decreased MXD4/MAD4 expression in holoclone KCs leads to increased MYC expression.
- Modulation of MXD4/MAD4 enhances KC precursor proliferation, maintains clonogenic potential, and preserves functionality in 3D organoids.
Conclusions:
- MXD4/MAD4 is a key regulator of stemness in the human epidermis keratinocyte lineage.
- Targeting MXD4/MAD4 offers a novel strategy for enhancing ex vivo expansion of human KC precursors for therapeutic applications.
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