Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.
Overexpression of alpha-1 antitrypsin in mesenchymal stromal cells improves their intrinsic biological properties and therapeutic effects in nonobese diabetic mice.
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间充质基质细胞中α-1抗胰蛋白酶的过表达改善了其内在生物学特性和对非肥胖糖尿病小鼠的治疗效果。
DOI：
10.1002/sctm.20-0122
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发表时间：
2021-03
影响因子：
6
通讯作者：
Wang H
中科院分区：
文献类型：
--
作者：
Song L;Gou W;Wang J;Wei H;Lee J;Strange C;Wang H
自身免疫介导的损伤所导致的胰岛/β细胞功能障碍和死亡是1型糖尿病（T1D）的主要特征。间充质干细胞（MSCs）已用于动物模型和临床试验中1型糖尿病的治疗。基于α - 1抗胰蛋白酶（AAT）的抗炎作用，我们用pHAGE CMV - a1aT - UBC - GFP - W慢病毒载体感染人骨髓来源的间充质干细胞，从而产生了人AAT工程化间充质干细胞（hAAT - MSCs）。我们比较了空病毒处理的间充质干细胞（hMSC）和hAAT - MSCs的集落形成、分化和迁移能力，并测试了它们在预防非肥胖糖尿病（NOD）小鼠1型糖尿病发病中的保护作用。与hMSCs相比，hAAT - MSCs显示出更强的自我更新能力、更好的迁移能力和多向分化能力。此外，对84个间充质干细胞相关基因的聚合酶链反应阵列分析表明，与hMSCs相比，hAAT - MSCs中有23个基因上调，3个基因下调。上调的基因包括那些对间充质干细胞的干性（即Wnt家族成员3A[WNT3A]、激酶插入结构域受体[KDR]）、迁移（细胞间黏附分子1[ICAM - 1]、血管细胞黏附蛋白1[VICAM - 1]、基质金属蛋白酶 - 2[MMP2]）和存活（胰岛素样生长因子1[IGF - 1]）至关重要的基因。通路分析表明，改变的基因与生长因子活性、细胞迁移的正向调节和转录的正向调节有关。在体内，与接受溶媒或hMSCs的NOD小鼠相比，单次静脉输注hAAT - MSCs显著限制了胰岛的炎症浸润，并延缓了糖尿病的发病。综上所述，间充质干细胞中hAAT的过表达改善了用于1型糖尿病细胞治疗所需的间充质干细胞的内在生物学特性。
人α - 1抗胰蛋白酶工程化间充质干细胞（hAAT - MSCs）通过延缓1型糖尿病的发病，为细胞治疗引入了一种更有效的替代方法。通过在人骨髓来源的间充质干细胞中进行慢病毒感染来产生hAAT - MSCs，可使非肥胖糖尿病小鼠的自我更新、迁移能力显著提高，基因上调，同时限制胰岛细胞的炎症浸润。
Islet/β cell dysfunction and death caused by autoimmune‐mediated injuries are major features of type 1 diabetes (T1D). Mesenchymal stromal cells (MSCs) have been used for the treatment of T1D in animal models and clinical trials. Based on the anti‐inflammatory effects of alpha‐1 antitrypsin (AAT), we generated human AAT engineered MSCs (hAAT‐MSCs) by infecting human bone marrow‐derived MSCs with the pHAGE CMV‐a1aT‐UBC‐GFP‐W lentiviral vector. We compared the colony forming, differentiation, and migration capacity of empty virus‐treated MSCs (hMSC) and hAAT‐MSCs and tested their protective effects in the prevention of onset of T1D in nonobese diabetic (NOD) mice. hAAT‐MSCs showed increased self‐renewal, better migration and multilineage differentiation abilities compared to hMSCs. In addition, polymerase chain reaction array for 84 MSC‐related genes showed that 23 genes were upregulated, and 3 genes were downregulated in hAAT‐MSCs compared to hMSCs. Upregulated genes include those critical for the stemness (ie, Wnt family member 3A [WNT3A], kinase insert domain receptor [KDR]), migration (intercellular adhesion molecule 1 [ICAM‐1], vascular cell adhesion protein 1 [VICAM‐1], matrix metalloproteinase‐2 [MMP2]), and survival (insulin‐like growth factor 1 [IGF‐1]) of MSCs. Pathway analysis showed that changed genes were related to growth factor activity, positive regulation of cell migration, and positive regulation of transcription. In vivo, a single intravenous infusion of hAAT‐MSCs significantly limited inflammatory infiltration into islets and delayed diabetes onset in the NOD mice compared with those receiving vehicle or hMSCs. Taken together, overexpression of hAAT in MSCs improved intrinsic biological properties of MSCs needed for cellular therapy for the treatment of T1D. Human alpha‐1 antitrypsin‐engineered mesenchymal stromal cell (hAAT‐MSCs) introduces a more effective alternative to cellular therapy by delaying the onset of type 1 diabetes. The generation of hAAT‐MSCs through lentiviral infection in human bone marrow‐derived MSCs produces a significant increase of self‐renewal, migration, and upregulation of genes while limiting inflammatory infiltration into islet cells in the nonobese diabetic mice.
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影响因子：
7.5
作者：
Antebi B;Rodriguez LA 2nd;Walker KP 3rd;Asher AM;Kamucheka RM;Alvarado L;Mohammadipoor A;Cancio LC
通讯作者：
Cancio LC
DOI：
10.4049/jimmunol.0900803
发表时间：
2009-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Fiorina P;Jurewicz M;Augello A;Vergani A;Dada S;La Rosa S;Selig M;Godwin J;Law K;Placidi C;Smith RN;Capella C;Rodig S;Adra CN;Atkinson M;Sayegh MH;Abdi R
通讯作者：
Abdi R
影响因子：
4
作者：
Ciria M;García NA;Ontoria-Oviedo I;González-King H;Carrero R;De La Pompa JL;Montero JA;Sepúlveda P
通讯作者：
Sepúlveda P
DOI：
10.1080/15412550802092936
发表时间：
2008-06-01
影响因子：
2.2
作者：
Aldonyte, Ruta;Hutchinson, Edgar Tarun;Zhang, Jianliang
通讯作者：
Zhang, Jianliang
影响因子：
2.6
作者：
Bartholomew, A;Sturgeon, C;Hoffman, R
通讯作者：
Hoffman, R