Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle.
Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle.
复制标题
DOI：
10.1186/s13287-021-02174-3
复制
发表时间：
2021-02-12
影响因子：
7.5
通讯作者：
Ashraf M
中科院分区：
文献类型：
--
作者：
Xuan W;Khan M;Ashraf M
杜氏肌营养不良症（DMD）是由编码肌营养不良蛋白的基因突变引起的。肌营养不良蛋白的丧失会导致骨骼肌和心肌严重的进行性肌肉萎缩。人类诱导多能干细胞（hiPSCs）及其衍生物为治疗多种疾病提供了重要的机会。在这里，我们研究了具有肌肉分化特性的组蛋白去乙酰化酶抑制剂givinostat （Givi）是否可以将hipsc重编程为肌肉祖细胞（MPC）以治疗DMD。用CHIR99021和givinostat （Givi-MPC）或CHIR99021和成纤维细胞生长因子（fibroblast growth factor）作为对照，从hipsc中生成MPC。通过CCK-8、菌落和迁移试验研究其增殖和迁移能力。通过MPC体内移植观察其植入、病理变化和营养不良蛋白的恢复情况。从培养的MPC中收集条件培养基，分析细胞外囊泡（EVs）。与control-MPC相比，Givi-MPC表现出更强的增殖和迁移能力。Givi-MPC在氧化应激后产生的活性氧（ROS）较少，TNF-α刺激后il - 6的表达不明显。在心脏毒素（CTX）损伤的Mdx/SCID小鼠后肢移植后，与用对照mpc或人成肌细胞治疗的小鼠相比，Givi-MPC在治疗后的肌肉中表现出强劲的植入和恢复的肌营养不良蛋白。Givi-MPC显著限制炎症细胞浸润，减少肌肉坏死和纤维化。此外，gii - mpc在处理过的肌肉中植入干细胞池。此外，与来自人成肌细胞的EVs相比，从Givi-MPC释放的EVs富含几种与肌血管生成相关的mirna，包括miR-181a、miR-17、miR-210和miR-107以及miR-19b。结果表明，利用具有抗氧化、抗炎和肌肉基因促进特性的givinostat将hipsc重编程为MPC，可有效修复损伤肌肉并恢复损伤肌肉中的肌营养不良蛋白。在线版本包含补充材料，可在10.1186/s13287-021-02174-3获得。
Duchenne muscular dystrophy (DMD) is caused by mutations of the gene that encodes the protein dystrophin. A loss of dystrophin leads to severe and progressive muscle wasting in both skeletal and heart muscles. Human induced pluripotent stem cells (hiPSCs) and their derivatives offer important opportunities to treat a number of diseases. Here, we investigated whether givinostat (Givi), a histone deacetylase inhibitor, with muscle differentiation properties could reprogram hiPSCs into muscle progenitor cells (MPC) for DMD treatment. MPC were generated from hiPSCs by treatment with CHIR99021 and givinostat called Givi-MPC or with CHIR99021 and fibroblast growth factor as control-MPC. The proliferation and migration capacity were investigated by CCK-8, colony, and migration assays. Engraftment, pathological changes, and restoration of dystrophin were evaluated by in vivo transplantation of MPC. Conditioned medium from cultured MPC was collected and analyzed for extracellular vesicles (EVs). Givi-MPC exhibited superior proliferation and migration capacity compared to control-MPC. Givi-MPC produced less reactive oxygen species (ROS) after oxidative stress and insignificant expression of IL6 after TNF-α stimulation. Upon transplantation in cardiotoxin (CTX)-injured hind limb of Mdx/SCID mice, the Givi-MPC showed robust engraftment and restored dystrophin in the treated muscle than in those treated with control-MPC or human myoblasts. Givi-MPC significantly limited infiltration of inflammatory cells and reduced muscle necrosis and fibrosis. Additionally, Givi-MPC seeded the stem cell pool in the treated muscle. Moreover, EVs released from Givi-MPC were enriched in several miRNAs related to myoangiogenesis including miR-181a, miR-17, miR-210 and miR-107, and miR-19b compared with EVs from human myoblasts. It is concluded that hiPSCs reprogrammed into MPC by givinostat possessing anti-oxidative, anti-inflammatory, and muscle gene-promoting properties effectively repaired injured muscle and restored dystrophin in the injured muscle. The online version contains supplementary material available at 10.1186/s13287-021-02174-3.
登录
查看更多内容
影响因子：
2.5
作者：
Cachaço, AS;Pereira, CS;Thorsteinsdóttir, S
通讯作者：
Thorsteinsdóttir, S
影响因子：
3.4
作者：
Dayanidhi, Sudarshan;Lieber, Richard L.
通讯作者：
Lieber, Richard L.
影响因子：
10.5
作者：
Saccone V;Consalvi S;Giordani L;Mozzetta C;Barozzi I;Sandoná M;Ryan T;Rojas-Muñoz A;Madaro L;Fasanaro P;Borsellino G;De Bardi M;Frigè G;Termanini A;Sun X;Rossant J;Bruneau BG;Mercola M;Minucci S;Puri PL
通讯作者：
Puri PL
影响因子：
64.8
作者：
Sacco, Alessandra;Doyonnas, Regis;Kraft, Peggy;Vitorovic, Stefan;Blau, Helen M.
通讯作者：
Blau, Helen M.
影响因子：
2.7
作者：
Grabowska, Iwona;Mazur, Magdalena A.;Brzoska, Edyta
通讯作者：
Brzoska, Edyta