Essential role of p21Waf1/Cip1 in the modulation of post-traumatic hippocampal Neural Stem Cells response

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.

1. Introduction

Traumatic Brain Injury (TBI) represents one of the leading causes of death worldwide, as well as being a serious social, economic and health problem globally. It is the main cause of coma, plays a key role in disabilities due to traumatic events and is the most frequent cause of brain damage in children and young adults [1, 2]. In Europe, head trauma is responsible for more years of disability than any other cause [3] while in the United States approximately 80 thousand people every year are victims of brain damage [4, 5]. Following TBI, primary brain lesions are observed when tissues and blood vessels are stretched and compressed [6, 7]; these primary injuries are followed by secondary damages, a complex set of cellular processes and biochemical cascades that occur from a few minutes to several days following the trauma and can cause a drastic worsening of the patient’s general condition with a high probability of death in more cases serious [8, 9].

The hippocampus is one of the brain region most vulnerable to cell death and synaptic dysfunction after TBI, with consequent impairment in learning and memory processes [10, 11]. In this regard, the post-traumatic increase of proliferation of neural stem/progenitor cells observed in the hippocampal dentate gyrus could represent a pivotal compensatory and regenerative mechanism after TBI-induced neuronal death. [12, 13]. However, the extent of the proliferative rate as well as the ability of newly generated neurons to integrate into existing circuits and contribute to functional recovery remain poorly understood. The cyclin-dependent kinase inhibitor p21Waf1/Cip1 is a key regulator of cell cycle progression and has been shown to control the quiescence/activation balance of adult neural stem cells. This study investigates the role of p21 in modulating the hippocampal neurogenic response after traumatic brain injury using a novel conditional knockout mouse model.