Data underlying the research of adipogenic dedifferentiation enhances survival of human umbilical cord-derived mesenchymal stem cells under oxidative stress

Mesenchymal stem cells (MSCs) serve as ideal candidates for a broad range of cell-based therapies. However, cell aging caused by long-term in vitro expansion and poor survival after in vivo delivery greatly limits their success in preclinical and clinical applications. Dedifferentiation represents a potential strategy for enhancing the retention and function of MSCs in hostile environments. In this study, we evaluated the cell phenotype, proliferation, and differentiation potential, as well as the anti-oxidative stress ability of human umbilical cord-derived MSCs (hMSCs) manipulated with adipogenic priming and subsequent dedifferentiation. After an in vitro differentiation and dedifferentiation procedure, the resultant dedifferentiated hMSCs (De-hMSCs) displayed properties similar to their original counterparts, including morphology, immunophenotype and mesodermal potential (Figure 1&S1). Upon re-induction, De-hMSCs exhibited a significantly higher adipogenic differentiation capability than unmanipulated hMSCs (Figure 2). The proliferative ability of De-hMSCs increased transiently in comparison to uncommitted hMSCs (Figure 3). Importantly, De-hMSCs showed a significantly enhanced ability to resist tert-butyl hydroperoxide (t-BHP) induced apoptosis compared to undifferentiated hMSCs (Figure 4). Mechanisms involving bcl-2 family proteins and autophagy may contribute to the demonstrated advantages of dedifferentiation-reprogrammed hMSCs (Figure 5&6). These results indicate that adipogenic dedifferentiation promotes adipogenesis and cell persistence, as well as preserves the stemness of human umbilical cord-derived MSCs that have been committed to the adipocytic lineage. As a unique stem cell population, dedifferentiated MSCs may represent an attractive and promising candidate for MSC-based therapy.

间充质干细胞（Mesenchymal stem cells, MSCs）是众多细胞治疗手段的理想候选细胞。然而，长期体外扩增引发的细胞衰老以及体内递送后存活率低下的问题，极大限制了其在临床前与临床研究中的应用成效。去分化（dedifferentiation）策略有望提升间充质干细胞在恶劣微环境中的留存能力与功能活性。本研究针对经成脂预诱导及后续去分化处理的人脐带源间充质干细胞（human umbilical cord-derived MSCs, hMSCs），对其细胞表型、增殖能力、分化潜能以及抗氧化应激能力进行了评估。经体外诱导分化与去分化流程后，所得去分化hMSCs（De-hMSCs）的各项特性与原始未处理细胞高度相似，包括形态学特征、免疫表型及中胚层分化潜能（图1及补充图S1）。再次诱导后，De-hMSCs的成脂分化能力显著高于未处理的hMSCs（图2）。与未定向分化的hMSCs相比，De-hMSCs的增殖能力呈现短暂性提升（图3）。尤为重要的是，与未分化的hMSCs相比，De-hMSCs抵抗叔丁基过氧化氢（tert-butyl hydroperoxide, t-BHP）诱导细胞凋亡的能力显著增强（图4）。涉及Bcl-2家族蛋白与细胞自噬的相关机制，可能是去分化重编程hMSCs具备上述优势的分子基础（图5及图6）。上述结果表明，成脂去分化不仅可促进成脂分化与细胞存活持久性，还能维持定向成脂谱系的人脐带源间充质干细胞的干细胞干性。作为一类独特的干细胞群体，去分化间充质干细胞有望成为基于间充质干细胞治疗的极具吸引力与应用前景的候选细胞。