Partial Ablation of Non-Myogenic Progenitor Cells as a Therapeutic Approach to Duchenne Muscular Dystrophy.
Partial Ablation of Non-Myogenic Progenitor Cells as a Therapeutic Approach to Duchenne Muscular Dystrophy.
复制标题
DOI：
10.3390/biom11101519
复制
发表时间：
2021-10-15
期刊：
影响因子：
5.5
通讯作者：
Kolonin MG
中科院分区：
文献类型：
--
作者：
Gao Z;Lu A;Daquinag AC;Yu Y;Huard M;Tseng C;Gao X;Huard J;Kolonin MG
由肌营养不良蛋白缺失引起的杜氏肌营养不良症 (DMD) 仍然无法治愈。 DMD 引起的肌肉再生减少与分化为肌成纤维细胞的纤维脂肪祖细胞 (FAP) 的积累有关，并导致胶原组织的堆积，从而加重 DMD 的发病机制。表达血小板衍生生长因子受体 (PDGFR) 的间充质基质细胞 (MSC) 在 DMD 进展期间在肌肉中被激活，并产生促进 DMD 进展的 FAP。在这里，我们假设 DMD 中的肌肉功能障碍可以通过 MSC 衍生的 FAP 的遗传或药理学耗竭来延迟。在本文中，我们在肌营养不良蛋白缺陷的 mdx 小鼠中检验了这一假设。为了减少纤维/脂肪浸润并增强肌肉祖细胞 (MPC)，我们使用了一种模型，通过在 Pdgfrb 启动子下表达的自杀转基因病毒胸苷激酶 (TK) 对增殖的 MSC 进行诱导性基因消融。我们还测试了来自脂肪组织的间充质干细胞（脂肪基质细胞 (ASC)）是否有助于 FAP 并可作为 DMD 的靶点。使用针对 ASC 的猎杀肽 D-CAN 进行药物消融。通过这些方法消除 MSC 可以提高耐力（根据跑步机跑步测量）以及握力，而不会显着影响纤维化。尽管还需要更多的研究，但我们的结果表明，在 DMD 小鼠模型中，致病性 MSC 的消耗可以减轻肌肉损伤并延缓肌肉功能的丧失。
Duchenne muscular dystrophy (DMD), caused by the loss of dystrophin, remains incurable. Reduction in muscle regeneration with DMD is associated with the accumulation of fibroadipogenic progenitors (FAPs) differentiating into myofibroblasts and leading to a buildup of the collagenous tissue aggravating DMD pathogenesis. Mesenchymal stromal cells (MSCs) expressing platelet-derived growth factor receptors (PDGFRs) are activated in muscle during DMD progression and give rise to FAPs promoting DMD progression. Here, we hypothesized that muscle dysfunction in DMD could be delayed via genetic or pharmacologic depletion of MSC-derived FAPs. In this paper, we test this hypothesis in dystrophin-deficient mdx mice. To reduce fibro/adipose infiltration and potentiate muscle progenitor cells (MPCs), we used a model for inducible genetic ablation of proliferating MSCs via a suicide transgene, viral thymidine kinase (TK), expressed under the Pdgfrb promoter. We also tested if MSCs from fat tissue, the adipose stromal cells (ASCs), contribute to FAPs and could be targeted in DMD. Pharmacological ablation was performed with a hunter-killer peptide D-CAN targeting ASCs. MSC depletion with these approaches resulted in increased endurance, measured based on treadmill running, as well as grip strength, without significantly affecting fibrosis. Although more research is needed, our results suggest that depletion of pathogenic MSCs mitigates muscle damage and delays the loss of muscle function in mouse models of DMD.
登录
查看更多内容
影响因子：
23.9
作者：
Caplan AI;Correa D
通讯作者：
Correa D
DOI：
10.1158/1078-0432.ccr-11-1916
发表时间：
2012-02-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Klopp AH;Zhang Y;Solley T;Amaya-Manzanares F;Marini F;Andreeff M;Debeb B;Woodward W;Schmandt R;Broaddus R;Lu K;Kolonin MG
通讯作者：
Kolonin MG
影响因子：
50.3
作者：
Cooke VG;LeBleu VS;Keskin D;Khan Z;O'Connell JT;Teng Y;Duncan MB;Xie L;Maeda G;Vong S;Sugimoto H;Rocha RM;Damascena A;Brentani RR;Kalluri R
通讯作者：
Kalluri R
影响因子：
2.8
作者：
Isaac, Christian;Wright, Adam;Usas, Arvydas;Li, Hongshuai;Tang, Ying;Mu, Xiaodong;Greco, Nicholas;Dong, Qing;Vo, Nam;Kang, James;Wang, Bing;Huard, Johnny
通讯作者：
Huard, Johnny
影响因子：
12.4
作者：
Daquinag, Alexes C.;Tseng, Chieh;Kolonin, Mikhail G.
通讯作者：
Kolonin, Mikhail G.