One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.
One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.
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DOI：
10.1016/j.stemcr.2021.03.001
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发表时间：
2021-04-13
影响因子：
5.9
通讯作者：
Kuhlmann T
中科院分区：
文献类型：
--
作者：
Chanoumidou K;Hernández-Rodríguez B;Windener F;Thomas C;Stehling M;Mozafari S;Albrecht S;Ottoboni L;Antel J;Kim KP;Velychko S;Cui QL;Xu YKT;Martino G;Winkler J;Schöler HR;Baron-Van Evercooren A;Boespflug-Tanguy O;Vaquerizas JM;Ehrlich M;Kuhlmann T
对人类少突胶质细胞的有限获取损害了对髓鞘疾病中少突胶质细胞病理学的更好理解。在这里，我们描述了一种方法，将人成纤维细胞直接转化为少突胶质细胞样细胞（dc-hiOL），这使得评估髓鞘再生促进化合物和疾病建模。SOX 10、OLIG 2和NKX6.2在人成纤维细胞中的异位表达导致O 4+细胞的快速生成，其在16天内进一步分化为MBP+成熟少突胶质细胞样细胞。dc-hiOL在体外经历染色质重塑以表达少突胶质细胞标记物、包鞘轴突和纳米纤维，对髓鞘形成化合物治疗作出响应，并在体外重演与PLP 1突变相关的Pelizaeus-Merzbacher脑白质营养不良相关的少突胶质细胞病理。此外，DNA甲基化组分析提供了证据，表明CpG甲基化模式在源自年轻和老年供体的成纤维细胞的dc-hiOL之间显著不同，表明源细胞的“年龄”得以维持。总之，dc-hiOL代表了一种可重复的技术，可以有助于髓鞘疾病领域的个性化医疗。SOX 10、OLIG 2和NKX6.2在16天内直接将人成纤维细胞转化为dc-hiOL dc-hiOL表达关键的少突胶质细胞标记dc-hiOL保留供体细胞的表观遗传年龄来自PMD患者的dc-hiOL显示成熟缺陷和对细胞死亡的脆弱性在这篇文章中，Kuhlmann及其同事的研究表明，人类成纤维细胞可以直接转化为少突胶质细胞样细胞在S 0X 10、0 LIG 2和NKX6.2过表达后，表达dc-hiOL。dc-hiOL经历染色质重塑以激活少突胶质细胞相关基因，在体外进行鞘化，并维持供体细胞的表观遗传年龄。证明了dc-hiOL在早髓鞘形成化合物筛选和疾病建模研究中的适用性。
Limited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.2 in human fibroblasts results in rapid generation of O4+ cells, which further differentiate into MBP+ mature oligodendrocyte-like cells within 16 days. dc-hiOLs undergo chromatin remodeling to express oligodendrocyte markers, ensheath axons, and nanofibers in vitro, respond to promyelination compound treatment, and recapitulate in vitro oligodendroglial pathologies associated with Pelizaeus-Merzbacher leukodystrophy related to PLP1 mutations. Furthermore, DNA methylome analysis provides evidence that the CpG methylation pattern significantly differs between dc-hiOLs derived from fibroblasts of young and old donors, indicating the maintenance of the source cells’ “age.” In summary, dc-hiOLs represent a reproducible technology that could contribute to personalized medicine in the field of myelin diseases. SOX10, OLIG2, and NKX6.2 directly convert human fibroblasts into dc-hiOLs in 16 days dc-hiOLs express key oligodendrocyte markers dc-hiOLs preserve the epigenetic age of donor cells dc-hiOLs from PMD patients show maturation deficit and vulnerability to cell death In this article, Kuhlmann and colleagues show that human fibroblasts can be directly converted into oligodendrocyte-like cells (dc-hiOLs) upon overexpression of SOX10, OLIG2, and NKX6.2. dc-hiOLs undergo chromatin remodeling to activate oligodendrocyte-related genes, perform ensheathment in vitro, and maintain the epigenetic age of donor cells. The applicability of dc-hiOLs in promyelination compound screening and disease-modeling studies is demonstrated.
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影响因子：
4.6
作者：
Popp B;Krumbiegel M;Grosch J;Sommer A;Uebe S;Kohl Z;Plötz S;Farrell M;Trautmann U;Kraus C;Ekici AB;Asadollahi R;Regensburger M;Günther K;Rauch A;Edenhofer F;Winkler J;Winner B;Reis A
通讯作者：
Reis A
DOI：
10.1242/dev.098418
发表时间：
2014-01
期刊：
Development (Cambridge, England)
影响因子：
--
作者：
Hoffmann SA;Hos D;Küspert M;Lang RA;Lovell-Badge R;Wegner M;Reiprich S
通讯作者：
Reiprich S
影响因子：
12.7
作者：
van der Knaap MS;Bugiani M
通讯作者：
Bugiani M
影响因子：
9.8
作者：
Nevin, Zachary S.;Factor, Daniel C.;Tesar, Paul J.
通讯作者：
Tesar, Paul J.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK