Department of Neuroscience Rita Levi-Montalcini, University of Turin, Turin, Italy.
Neuroscience Institute Cavalieri Ottolenghi (NICO), University of Turin, Regione Gonzole 10, IT-10043, Orbassano (Turin), Italy.
Nat Commun. 2022 Apr 28;13(1):2331. doi: 10.1038/s41467-022-30010-6.
In the developing mouse forebrain, temporally distinct waves of oligodendrocyte progenitor cells (OPCs) arise from different germinal zones and eventually populate either dorsal or ventral regions, where they present as transcriptionally and functionally equivalent cells. Despite that, developmental heterogeneity influences adult OPC responses upon demyelination. Here we show that accumulation of DNA damage due to ablation of citron-kinase or cisplatin treatment cell-autonomously disrupts OPC fate, resulting in cell death and senescence in the dorsal and ventral subsets, respectively. Such alternative fates are associated with distinct developmental origins of OPCs, and with a different activation of NRF2-mediated anti-oxidant responses. These data indicate that, upon injury, dorsal and ventral OPC subsets show functional and molecular diversity that can make them differentially vulnerable to pathological conditions associated with DNA damage.
在发育中的小鼠前脑中，从不同的生发区出现了时间上不同的少突胶质前体细胞（OPC）波，最终分布在背侧或腹侧区域，在那里它们表现为转录和功能等同的细胞。尽管如此，发育异质性还是会影响成年 OPC 在脱髓鞘后的反应。在这里，我们发现由于柠檬酸激酶缺失或顺铂处理导致的 DNA 损伤积累会自主破坏 OPC 的命运，导致背侧和腹侧亚群分别发生细胞死亡和衰老。这种替代命运与 OPC 的不同发育起源有关，并与 NRF2 介导的抗氧化反应的不同激活有关。这些数据表明，在损伤后，背侧和腹侧 OPC 亚群表现出功能和分子多样性，这使它们对与 DNA 损伤相关的病理状况具有不同的易感性。
