美国辛辛那提儿童医院医疗中心Susanne I. Wells研究团队取得一项新突破。他们发现遗传性的DNA修复缺陷破坏了人类皮肤的结构和功能。2020年11月23日出版的《细胞-干细胞》杂志发表了这项成果。

为了研究表皮脆弱性，将以条件性范可尼贫血（FA）途径患者来源的多能干细胞（PSC）分化为表皮干细胞和祖细胞（ESPC）和PSC来源的表皮器官型筏（PSC-EOR）。FA PSC-EORs减少了细胞间连接，并增加了基底细胞区室的增殖。此外，在FA患者的皮肤中发现了桥粒和半桥粒的缺陷，这些缺陷在机械诱导的应力作用下转化为加速水疱。

总之，他们证明了关键DNA修复途径可以维持人类皮肤的结构和功能，并提供3D表皮模型，目前可以探索鳞状细胞癌（SCC）的预防方法。

据悉，SCC是一种全球公共卫生负担，起源于皮肤和粘膜的ESPC。为了了解遗传危险因素如何促成SCC，必须进行ESPC生物学研究。FA的儿童是FA DNA修复途径基因的种系功能丧失突变导致的极端SCC易感性的范例。

附：英文原文

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

Author: Sonya Ruiz-Torres, Marion G. Brusadelli, David P. Witte, Kathryn A. Wikenheiser-Brokamp, Sharon Sauter, Adam S. Nelson, Mathieu Sertorio, Timothy M. Chlon, Adam Lane, Parinda A. Mehta, Kasiani C. Myers, Mary C. Bedard, Bidisha Pal, Dorothy M. Supp, Paul F. Lambert, Kakajan Komurov, Melinda Butsch Kovacic, Stella M. Davies, Susanne I. Wells, Sonya Ruiz-Torres, Marion G. Brusadelli, David P. Witte, Kathryn A. Wikenheiser-Brokamp, Sharon Sauter, Adam S. Nelson, Mathieu Sertorio, Timothy M. Chlon, Adam Lane, Parinda A. Mehta, Kasiani C. Myers, Mary C. Bedard, Bidisha Pal, Dorothy M. Supp, Paul F. Lambert, Kakajan Komurov, Melinda Butsch Kovacic, Stella M. Davies, Susanne I. Wells

Issue&Volume: 2020-11-23

Abstract: Squamous cell carcinoma (SCC) is a global public health burden originating in epidermalstem and progenitor cells (ESPCs) of the skin and mucosa. To understand how geneticrisk factors contribute to SCC, studies of ESPC biology are imperative. Children withFanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germlineloss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities,patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway weredifferentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs).FA PSC-EORs harbored diminished cell-cell junctions and increased proliferation inthe basal cell compartment. Furthermore, desmosome and hemidesmosome defects wereidentified in the skin of FA patients, and these translated into accelerated blisteringfollowing mechanically induced stress. Together, we demonstrate that a critical DNArepair pathway maintains the structure and function of human skin and provide 3D epidermalmodels wherein SCC prevention can now be explored.

DOI: 10.1016/j.stem.2020.10.012

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30506-3