Abstract：
In response to central nervous system (CNS) injury, astrocytes go through a series of alterations, referred to as reactive astrogliosis, ranging from changes in gene expression and cell hypertrophy to permanent astrocyte borders around stromal cell scars in CNS lesions. The mechanisms underlying injury-induced reactive astrocytes in the adult CNS have been extensively studied. However, little is known about injury-induced reactive astrocytes during early postnatal development. Astrocytes in the mouse cortex are mainly produced through local proliferation during the first 2 weeks after birth. Here we show that Sox2, a transcription factor critical for stem cells and brain development, is expressed in the early postnatal astrocytes and its expression level was increased in reactive astrocytes after traumatic brain injury (TBI) at postnatal day (P) 7 in the cortex. Using a tamoxifen-induced hGFAP-CreERT2; Sox2flox/flox ; Rosa-tdT mouse model, we found that specific knockout of Sox2 in astrocytes greatly inhibited the proliferation of reactive astrocytes, the formation of glia limitans borders and subsequently promoted the tissue recovery after postnatal TBI at P7 in the cortex. In addition, we found that injury-induced glia limitans borders were still formed at P2 in the wild-type mouse cortex, and knockout of Sox2 in astrocytes inhibited the reactivity of both astrocytes and microglia. Together, these findings provide evidence that Sox2 is essential for the reactivity of astrocytes in response to the cortical TBI during the early postnatal period and suggest that Sox2-dependent astrocyte reactivity is a potential target for therapeutic treatment after TBI.
摘要：
为了应对中枢神经系统（CNS）损伤，星形胶质细胞经历了一系列的改变，被称为反应性星形胶质增生，从基因表达和细胞肥大的变化到中枢神经系统病变基质细胞疤痕周围的永久性星形胶质细胞边界。成人中枢神经系统中损伤诱导的反应性星形胶质细胞的潜在机制已得到广泛研究。然而,对出生后早期发育过程中损伤诱导的反应性星形胶质细胞知之甚少。小鼠皮质中的星形胶质细胞主要是在出生后的前2周内通过局部增殖产生的。在这里，我们发现Sox2是一种对干细胞和大脑发育至关重要的转录因子，在出生后第7天（P）在皮质中的创伤性脑损伤（TBI）后，在出生后早期星形胶质细胞中表达，其表达水平在反应性星形胶质细胞中增加。使用他莫昔芬诱导的hGFAP-CreERT2;Sox2flox/flox;Rosa-tdT小鼠模型，我们发现星形胶质细胞中Sox2的特异性敲除大大抑制了反应性星形胶质细胞的增殖,在出生后TBI后，在皮质P7处形成神经胶质为界，随后促进了组织恢复。此外,我们发现，在野生型小鼠皮层的P2处仍然形成损伤诱导的神经胶质细胞边界，星形胶质细胞中Sox2的敲除抑制了星形胶质细胞和小胶质细胞的反应性。一起,这些发现提供了证据,证明Sox2对于出生后早期星形胶质细胞对皮质TBI的反应性至关重要,并提示Sox2依赖性星形胶质细胞反应性是TBI后治疗性治疗的潜在靶点.
