Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets
Mesenchymal stem cells alleviate hypoxia-induced oxidative stress and enhance the pro-survival pathways in porcine islets
复制标题
间充质干细胞减轻缺氧诱导的氧化应激并增强猪胰岛的促生存途径
DOI：
10.1177/1535370219844472
复制
发表时间：
2019-05
期刊：
影响因子：
--
通讯作者：
Wei Wang
中科院分区：
文献类型：
--
作者：
Yixiong Tan;Wei Nie;Cheng Chen;Xuesong He;Yuzhi Xu;Xiaoqian Ma;Juan Zhang;Mengqun Tan;Pengfei Rong;Wei Wang
胰岛移植是治疗1型糖尿病（T1 DM）的一种有前途的方法。缺氧和氧化应激是造成移植胰岛损伤的主要原因。间充质干细胞（MSC）已被证明主要通过旁分泌增强细胞存活。然而，MSC对胰岛的保护作用的作用机制尚未完全阐明。在这项研究中，我们研究了人脐带来源的MSC（huc-MSC）是否可以抑制缺氧和ROS相关的细胞死亡的新生猪胰岛细胞簇（NICCs），并进一步确定潜在的分子机制。在常氧和低氧（1%O2）条件下培养NICCs，加入或不加入MSC条件培养基（MSC-CM）。AO/EB染色和Annexin V/PI流式细胞术检测NICCs凋亡情况。总的和线粒体的活性氧产生检测荧光测定。Western blot和ERK通路抑制剂PD 98059用于评估可能涉及的通路。结果表明，MSC-CM抑制缺氧诱导的NICCs氧化应激和细胞死亡。MSC-CM还在缺氧条件下激活了NICCs中的几种促存活途径。此外，MSC分泌的外泌体和IL-6部分再现了MSC-CM的多功能益处。该研究表明，huc-MSCs通过调节细胞氧化还原状态和细胞信号通路保护NICCs免受缺氧诱导的细胞死亡。这种增加的理解可能使间充质干细胞成为一个更有前途的辅助细胞疗法胰岛transplantation.Impact statementThe利用间充质干细胞（MSC）是一个有前途的方法，作为胰岛移植的辅助治疗。但是，无法将有希望的临床前结果转化为人类受试者的良好治疗效果，表明缺乏需要进一步研究的MSC-胰岛相互作用的关键知识。缺氧和氧化应激是导致胰岛移植物大量丢失的重要因素。然而，以前的研究主要集中在MSC保护的其他方面，如诱导血管重建，增加胰岛素分泌，减少胰岛细胞凋亡。在这项研究中，我们的目的是调查是否MSC可以保护胰岛细胞从缺氧损伤抑制活性氧的产生和潜在的潜在途径参与。我们还探讨了MSC衍生的外泌体和IL-6对缺氧损伤的胰岛的影响。我们的数据为开发MSC应用提供了新的分子靶点，这可能最终提高临床胰岛移植的效率。
Islet transplantation is a promising treatment for selected patients with type 1 diabetes mellitus (T1DM). Hypoxia and oxidative stress are major causes of damage to transplanted islets. Mesenchymal stem cells (MSCs) have been shown to enhance cell survival mainly through paracrine secretion. However, mechanisms of action underlying the protective effects of MSCs on islets have not been fully elucidated. In this study, we investigated whether human umbilical cord-derived MSCs (huc-MSCs) could inhibit hypoxia and ROS-related cell death of neonatal porcine islet cell clusters (NICCs) and further determined the underlying molecular mechanisms. NICCs were culturedin vitrounder normoxic and hypoxic (1% O2) conditions with or without MSC-conditioned medium (MSC-CM). Apoptosis of NICCs was evaluated by the AO/EB staining and Annexin V/PI flow cytometry analysis. Total and mitochondrial ROS production was detected by fluorometric assays. Western blot and the ERK pathway inhibitor, PD98059, were used to assess the possible pathways involved. The results showed that MSC-CM suppressed hypoxia-induced oxidative stress and cell death of NICCs. MSC-CM also activated several pro-survival pathways in NICCs under hypoxic conditions. Furthermore, MSC-secreted exosomes and IL-6 partially recapitulated the multifunctional benefits of MSC-CM. This study showed that huc-MSCs protected NICCs from hypoxia-induced cell death by regulating the cell redox state and cell signaling pathways. This increased understanding may enable MSCs to become a more promising adjuvant cell therapy for islet transplantation.Impact statementThe utilization of mesenchymal stem cells (MSCs) is a promising approach to serve as adjuvant therapy for islet transplantation. But the inability to translate promising preclinical results into sound therapeutic effects in human subjects indicates a lack of key knowledge of MSC-islet interactions that warrant further research. Hypoxia and oxidative stress are critical factors which lead to a tremendous loss of islet grafts. However, previous studies mainly focused on other aspects of MSC protection such as inducing revascularization, enhancing insulin secretion, and reducing islet apoptosis. In this study, we aim to investigate whether MSC can protect islet cells from hypoxic damage by inhibiting ROS production and the potential underlying pathways involved. We also explore the effects of MSC-derived exosomes and IL-6 on hypoxia-injured islets. Our data provide new molecular targets for developing MSC applications, and this may ultimately promote the efficiency of clinical islet transplantation.
登录
查看更多内容
影响因子：
3.9
作者：
Nie, Wei;Ma, Xiaoqian;Wang, Wei
通讯作者：
Wang, Wei
DOI：
10.1016/j.bbrc.2009.06.039
发表时间：
2009-08
影响因子：
3.1
作者：
G. Ryu;Min-Kyung Lee;Esder Lee;Seung-Hyun Ko;Y. Ahn;Ji‐Won Kim;K. Yoon;K. Song
通讯作者：
G. Ryu;Min-Kyung Lee;Esder Lee;Seung-Hyun Ko;Y. Ahn;Ji‐Won Kim;K. Yoon;K. Song
影响因子：
3.9
作者：
Han-Sin Lee;Sanghyun Song;Du Yeon Shin;Geunsoo Kim;Jong-Hyun Lee;C. Cho;Kyo-Won Lee;Hyojun Park-
通讯作者：
Han-Sin Lee;Sanghyun Song;Du Yeon Shin;Geunsoo Kim;Jong-Hyun Lee;C. Cho;Kyo-Won Lee;Hyojun Park-
影响因子：
6.2
作者：
R. Krishnan;Brian Buder;M. Alexander;C. Foster;J. Lakey
通讯作者：
R. Krishnan;Brian Buder;M. Alexander;C. Foster;J. Lakey
DOI：
10.1007/978-981-13-2050-7
发表时间：
2019
期刊：
Neural Interface: Frontiers and Applications
影响因子：
--
作者：
Wim E. Crusio-;John D Lambris;Xiaoxiang Zheng
通讯作者：
Wim E. Crusio-;John D Lambris;Xiaoxiang Zheng