Feng Guo-Dong, He Bao-Rong, Lu Fan, Liu Lin-Hong, Zhang Lingling, Chen Bo, He Zu-Ping, Hao Ding-Jun, Yang Hao
Clinical Stem Cell Research Center, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200217, China.
Mol Neurobiol. 2014 Dec;50(3):997-1012. doi: 10.1007/s12035-014-8649-1. Epub 2014 Feb 9.
Our recent studies demonstrated that mature astrocytes from spinal cord can be reprogrammed in vitro and in vivo to generate neural stem/progenitor cells (NSPCs) following treatment with conditioned medium collected from mechanically injured astrocytes. However, little is known regarding the molecular mechanisms underlying the reprogramming of astrocytes. Here, we show that fibroblast growth factor 4 (FGF4) exerts a critical role in synergistically converting astrocytes into NSPCs that can express multiple neural stem cell markers (nestin and CD133) and are capable of both self-renewal and differentiation into neurons and glia. Lack of FGF4 signals fails to elicit the dedifferentiation of astrocytes towards NSPCs, displaying a substantially lower efficiency in the reprogramming of astrocytes and a slower transition through fate-determined state. These astrocyte-derived NSPCs displayed relatively poor self-renewal and multipotency. More importantly, further investigation suggested that FGF4 is a key molecule necessary for activating PI3K/Akt/p21 signaling cascades, as well as their downstream effectors responsible for directing cell reprogramming towards NSPCs. Collectively, these findings provide a molecular basis for astrocyte dedifferentiation into NSPCs after central nervous system (CNS) injury and imply that FGF4 may be a clinically applicable molecule for in situ neural repair in the CNS disorders.
我们最近的研究表明，脊髓中的成熟星形胶质细胞在体外和体内都可以通过用从机械损伤的星形胶质细胞收集的条件培养基处理来重新编程，以产生神经干/祖细胞（NSPCs）。然而，关于星形胶质细胞重编程的分子机制知之甚少。在这里，我们表明成纤维细胞生长因子4（FGF4）在协同将星形胶质细胞转化为NSPCs的过程中发挥关键作用，这些NSPCs可以表达多种神经干细胞标志物（巢蛋白和CD133），并且能够自我更新并分化为神经元和神经胶质细胞。缺乏FGF4信号无法引发星形胶质细胞向NSPCs的去分化，在星形胶质细胞重编程中显示出显著较低的效率，并且通过命运决定状态的转变较慢。这些星形胶质细胞衍生的NSPCs表现出相对较差的自我更新和多能性。更重要的是，进一步的研究表明FGF4是激活PI3K/Akt/p21信号级联及其负责将细胞重编程导向NSPCs的下游效应器所必需的关键分子。总的来说，这些发现为中枢神经系统（CNS）损伤后星形胶质细胞去分化为NSPCs提供了分子基础，并暗示FGF4可能是一种可用于中枢神经系统疾病原位神经修复的临床适用分子。
