Enhanced viability and function of mesenchymal stromal cell spheroids is mediated via autophagy induction

作者：Shobha Regmi, Pawan Kumar Raut, Shiva Pathak, Prakash Shrestha, Pil‐Hoon Park, Jee‐Heon Jeong · 发表于：Autophagy · 年份：2020 · DOI：10.1080/15548627.2020.1850608 · 被引用次数：89 · 研究领域：Mesenchymal stem cell research、Autophagy in Disease and Therapy、Heme Oxygenase-1 and Carbon Monoxide

Mesenchymal stromal cells (MSCs) have received attention as promising therapeutic agents for the treatment of various diseases. However, poor post-transplantation viability is a major hurdle in MSC-based therapy, despite encouraging results in many inflammatory disorders. Recently, three dimensional (3D)-cultured MSCs (MSC3D) were shown to have higher cell survival and enhanced anti-inflammatory effects, although the underlying mechanisms have not yet been elucidated. In this study, we investigated the molecular mechanisms by which MSC3D gain the potential for enhanced cell viability. Herein, we found that macroautophagy/autophagy was highly induced and ROS production was suppressed in MSC3D as compared to 2D-cultured MSCs (MSC2D). Interestingly, inhibition of autophagy induction caused decreased cell viability and increased apoptotic activity in MSC3D. Furthermore, modulation of ROS production was closely related to the survival and apoptosis of MSC3D. We also observed that HMOX1 (heme oxygenase 1) was significantly up-regulated in MSC3D. In addition, gene silencing of HMOX1 caused upregulation of ROS production and suppression of the genes related to autophagy. Moreover, inhibition of HIF1A (hypoxia inducible factor 1 subunit alpha) caused suppression of HMOX1 expression in MSC3D, indicating that the HIF1A-HMOX1 axis plays a crucial role in the modulation of ROS production and autophagy induction in MSC3D. Finally, the critical role of autophagy induction on improved therap...