4.7 Article

Inherited DNA Repair Defects Disrupt the Structure and Function of Human Skin

期刊

CELL STEM CELL
卷 28, 期 3, 页码 424-+

出版社

CELL PRESS
DOI: 10.1016/j.stem.2020.10.012

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资金

  1. Environmental Carcinogenesis and Mutagenesis Training Program [T32ES007250-26]
  2. NCI [R01 CA223790, R01 CA228113]
  3. Fanconi Anemia Research Fund
  4. Center for Clinical and Translational Science and Training [1UL1TR001425-01]
  5. NIAMS [F31AR070008]
  6. NHLBI [R01HL108102]

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The study found that genetic mutations in Fanconi anemia (FA) patients can affect cell structure and function, accelerating the process of cancer development. This provides a new direction for exploring SCC prevention.
Squamous cell carcinoma (SCC) is a global public health burden originating in epidermal stem and progenitor cells (ESPCs) of the skin and mucosa. To understand how genetic risk factors contribute to SCC, studies of ESPC biology are imperative. Children with Fanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germline loss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities, patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway were differentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs). FA PSC-EORs harbored diminished cell-cell junctions and increased proliferation in the basal cell compartment. Furthermore, desmosome and hemidesmosome defects were identified in the skin of FA patients, and these translated into accelerated blistering following mechanically induced stress. Together, we demonstrate that a critical DNA repair pathway maintains the structure and function of human skin and provide 3D epidermal models wherein SCC prevention can now be explored.

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