Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Via Nizza 52, 10126 Torino, Italy.
Department of Translational Medicine, University of Piemonte Orientale, 28100 Novara, Italy.
Cells. 2022 Mar 27;11(7):1130. doi: 10.3390/cells11071130.
Keratinocyte stem cells play a fundamental role in homeostasis and repair of stratified epithelial tissues. Transplantation of cultured keratinocytes autografts provides a landmark example of successful cellular therapies by restoring durable integrity in stratified epithelia lost to devastating tissue conditions. Despite the overall success of such procedures, failures still occur in case of paucity of cultured stem cells in therapeutic grafts. Strategies aiming at a further amplification of stem cells during keratinocyte ex vivo expansion may thus extend the applicability of these treatments to subjects in which endogenous stem cells pools are depauperated by aging, trauma, or disease. Pharmacological targeting of stem cell signaling pathways is recently emerging as a powerful strategy for improving stem cell maintenance and/or amplification. Recent experimental data indicate that pharmacological inhibition of two prominent keratinocyte signaling pathways governed by apical mTOR and ROCK protein kinases favor stem cell maintenance and/or amplification ex vivo and may improve the effectiveness of stem cell-based therapeutic procedures. In this review, we highlight the pathophysiological roles of mTOR and ROCK in keratinocyte biology and evaluate existing pre-clinical data on the effects of their inhibition in epithelial stem cell expansion for transplantation purposes.
角朊细胞干细胞在维持和修复表皮组织中起着重要作用。培养的自体角朊细胞移植为成功的细胞治疗提供了一个标志性的例子，它通过恢复因破坏性组织条件而丧失的分层上皮组织的持久完整性。尽管这些手术总体上取得了成功，但在治疗性移植物中培养的干细胞数量不足的情况下，仍会出现失败。因此，旨在体外扩增角朊细胞干细胞的策略可以将这些治疗方法扩展到因衰老、创伤或疾病而使内源性干细胞池枯竭的患者。针对干细胞信号通路的药理学靶向最近已成为一种增强干细胞维持和/或扩增的强大策略。最近的实验数据表明，通过抑制两个主要的角朊细胞信号通路——顶端 mTOR 和 ROCK 蛋白激酶，有利于体外干细胞的维持和/或扩增，并可能提高基于干细胞的治疗程序的有效性。在这篇综述中，我们强调了 mTOR 和 ROCK 在角朊细胞生物学中的病理生理作用，并评估了它们在移植目的上皮干细胞扩增中抑制作用的现有临床前数据。
