From basic biology to engineered therapies: the keratinocyte stem cell playbook

Area of Science:

• Dermatology and Regenerative Medicine
• Stem Cell Biology
• Tissue Engineering

Background:

• Keratinocyte stem cells (KSCs) are crucial for skin renewal, barrier function, and repair.
• KSC homeostasis relies on complex intrinsic and extrinsic regulatory programs.
• Understanding these programs is key to advancing regenerative therapies.

Purpose of the Study:

• To synthesize current knowledge on KSC homeostasis and fate regulation.
• To review methods for isolating and expanding human keratinocytes ex vivo.
• To highlight clinical applications and emerging uses of KSCs.

Main Methods:

• Review of existing literature on KSC biology, culture techniques, and clinical applications.
• Framework integrating three interdependent 'fate locks': identity, cell-cycle, and mechanotransduction.
• Analysis of niche-derived cues and intrinsic timers influencing keratinocyte fate.

Main Results:

• KSC fate is governed by interconnected molecular pathways including the identity switch, cell-cycle lock, and mechanotransduction lock.
• Niche signals and intrinsic timers synergistically control keratinocyte self-renewal and differentiation.
• Significant progress has been made in xeno-free KSC expansion using defined media and biomimetic surfaces.

Conclusions:

• A unified framework clarifies KSC homeostasis, essential for understanding epidermal regeneration.
• Advances in KSC culture support the development of novel wound healing therapies.
• KSC-derived products show promise beyond skin repair, including immunomodulation and tissue regeneration.