Turinetto Valentina, Vitale Emanuela, Giachino Claudia
Department of Clinical and Biological Sciences, University of Turin, 10043 Orbassano, Turin, Italy.
Int J Mol Sci. 2016 Jul 19;17(7):1164. doi: 10.3390/ijms17071164.
Regenerative medicine is extensively interested in developing cell therapies using mesenchymal stem cells (MSCs), with applications to several aging-associated diseases. For successful therapies, a substantial number of cells are needed, requiring extensive ex vivo cell expansion. However, MSC proliferation is limited and it is quite likely that long-term culture evokes continuous changes in MSCs. Therefore, a substantial proportion of cells may undergo senescence. In the present review, we will first present the phenotypic characterization of senescent human MSCs (hMSCs) and their possible consequent functional alterations. The accumulation of oxidative stress and dysregulation of key differentiation regulatory factors determine decreased differentiation potential of senescent hMSCs. Senescent hMSCs also show a marked impairment in their migratory and homing ability. Finally, many factors present in the secretome of senescent hMSCs are able to exacerbate the inflammatory response at a systemic level, decreasing the immune modulation activity of hMSCs and promoting either proliferation or migration of cancer cells. Considering the deleterious effects that these changes could evoke, it would appear of primary importance to monitor the occurrence of senescent phenotype in clinically expanded hMSCs and to evaluate possible ways to prevent in vitro MSC senescence. An updated critical presentation of the possible strategies for in vitro senescence monitoring and prevention constitutes the second part of this review. Understanding the mechanisms that drive toward hMSC growth arrest and evaluating how to counteract these for preserving a functional stem cell pool is of fundamental importance for the development of efficient cell-based therapeutic approaches.
再生医学对利用间充质干细胞（MSCs）开发细胞疗法有着广泛的兴趣，这些疗法可应用于多种与衰老相关的疾病。为了实现成功的治疗，需要大量的细胞，这就需要在体外进行大量的细胞扩增。然而，MSCs的增殖是有限的，长期培养很可能会引起MSCs的持续变化。因此，相当一部分细胞可能会发生衰老。在本综述中，我们将首先介绍衰老的人MSCs（hMSCs）的表型特征及其可能随之而来的功能改变。氧化应激的积累和关键分化调节因子的失调决定了衰老hMSCs分化潜能的降低。衰老的hMSCs在迁移和归巢能力方面也表现出明显的损伤。最后，衰老hMSCs分泌组中的许多因子能够在全身水平上加剧炎症反应，降低hMSCs的免疫调节活性，并促进癌细胞的增殖或迁移。考虑到这些变化可能引发的有害影响，监测临床扩增的hMSCs中衰老表型的出现并评估预防体外MSCs衰老的可能方法似乎至关重要。对体外衰老监测和预防的可能策略进行最新的批判性介绍构成了本综述的第二部分。了解导致hMSC生长停滞的机制，并评估如何应对这些机制以保存功能性干细胞库，对于开发有效的基于细胞的治疗方法至关重要。
