PDF(Pubmed)
Abstract：
BACKGROUND: Traumatic Brain Injury (TBI) represents one of the main causes of brain damage in young people and the elderly population with a very high rate of psycho-physical disability and death. TBI is characterized by extensive cell death, tissue damage and neuro-inflammation with a symptomatology that varies depending on the severity of the trauma from memory loss to a state of irreversible coma and death. Recently, preclinical studies on mouse models have demonstrated that the post-traumatic adult Neural Stem/Progenitor cells response could represent an excellent model to shed light on the neuro-reparative role of adult neurogenesis following damage. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 plays a pivotal role in modulating the quiescence/activation balance of adult Neural Stem Cells (aNSCs) and in restraining the proliferation progression of progenitor cells. Based on these considerations, the aim of this work is to evaluate how the conditional ablation of p21Waf1/Cip1 in the aNSCS can alter the adult hippocampal neurogenesis in physiological and post-traumatic conditions.
METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche.
RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality.
CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.
METHODS: We designed a novel conditional p21Waf1/Cip1 knock-out mouse model, in which the deletion of p21Waf1/Cip1 (referred as p21) is temporally controlled and occurs in Nestin-positive aNSCs, following administration of Tamoxifen. This mouse model (referred as p21 cKO mice) was subjected to Controlled Cortical Impact to analyze how the deletion of p21 could influence the post-traumatic neurogenic response within the hippocampal niche.
RESULTS: The data demonstrates that the conditional deletion of p21 in the aNSCs induces a strong increase in activation of aNSCs as well as proliferation and differentiation of neural progenitors in the adult dentate gyrus of the hippocampus, resulting in an enhancement of neurogenesis and the hippocampal-dependent working memory. However, following traumatic brain injury, the increased neurogenic response of aNSCs in p21 cKO mice leads to a fast depletion of the aNSCs pool, followed by declined neurogenesis and impaired hippocampal functionality.
CONCLUSIONS: These data demonstrate for the first time a fundamental role of p21 in modulating the post-traumatic hippocampal neurogenic response, by the regulation of the proliferative and differentiative steps of aNSCs/progenitor populations after brain damage.
摘要：
背景：创伤性脑损伤（TBI）是年轻人和老年人群的脑损伤的主要原因之一，其心理残疾和死亡率很高。TBI的特点是广泛的细胞死亡，组织损伤和神经炎症，其症状根据从记忆丧失到不可逆转的昏迷和死亡状态的创伤的严重程度而变化。最近,对小鼠模型的临床前研究表明，创伤后成人神经干/祖细胞反应可以代表一个极好的模型，以阐明成人神经发生在损伤后的神经修复作用。细胞周期蛋白依赖性激酶抑制剂p21Waf1/Cip1在调节成年神经干细胞（aNSC）的静止/活化平衡和抑制祖细胞的增殖进程中起关键作用。基于这些考虑,这项工作的目的是评估aNSCS中p21Waf1/Cip1的条件消融如何在生理和创伤后条件下改变成人海马神经发生。
方法：我们设计了一种新颖的条件p21Waf1/Cip1敲除小鼠模型，其中p21Waf1/Cip1（称为p21）的缺失是受时间控制的，并且发生在Nestin阳性的aNSC中，服用他莫昔芬后。对该小鼠模型(称为p21cKO小鼠)进行受控皮质冲击,以分析p21的缺失如何影响海马小生境内的创伤后神经源性反应。
结果：数据表明，aNSCs中p21的条件性缺失诱导了海马成年齿状回中aNSCs的活化以及神经祖细胞的增殖和分化的强烈增加，导致神经发生和海马依赖性工作记忆的增强。然而,创伤性脑损伤后，p21cKO小鼠中神经源性反应的增加导致神经源性反应的快速消耗。其次是神经发生下降和海马功能受损。
结论：这些数据首次证明了p21在调节创伤后海马神经源性反应中的基本作用，通过调节脑损伤后aNSC/祖细胞群的增殖和分化步骤。
方法：我们设计了一种新颖的条件p21Waf1/Cip1敲除小鼠模型，其中p21Waf1/Cip1（称为p21）的缺失是受时间控制的，并且发生在Nestin阳性的aNSC中，服用他莫昔芬后。对该小鼠模型(称为p21cKO小鼠)进行受控皮质冲击,以分析p21的缺失如何影响海马小生境内的创伤后神经源性反应。
结果：数据表明，aNSCs中p21的条件性缺失诱导了海马成年齿状回中aNSCs的活化以及神经祖细胞的增殖和分化的强烈增加，导致神经发生和海马依赖性工作记忆的增强。然而,创伤性脑损伤后，p21cKO小鼠中神经源性反应的增加导致神经源性反应的快速消耗。其次是神经发生下降和海马功能受损。
结论：这些数据首次证明了p21在调节创伤后海马神经源性反应中的基本作用，通过调节脑损伤后aNSC/祖细胞群的增殖和分化步骤。
