Mocciaro Emanuele, Kidd Madison, Johnson Kevin, Bishop Elizabeth, Johnson Kathia, Zeng Ya Ping, Perrotta Cristiana, Micci Maria-Adelaide
Gene Expression Regulation Unit, San Raffaele Scientific Institute, Milan, Italy.
Department of Biomedical and Clinical Sciences, Università degli Studi di Milano, Milan, Italy.
PLoS One. 2025 May 13;20(5):e0323191. doi: 10.1371/journal.pone.0323191. eCollection 2025.
Traumatic brain injury (TBI) is one of the primary causes of long-term brain disabilities among military personnel and civilians, regardless of gender. A plethora of secondary events are triggered by a primary brain insult, increasing the complexity of TBI. One of the most affected brain regions is the hippocampus, where neurogenesis occurs throughout life due to the presence of neural stem cells (NSC). Preclinical models have been extensively used to better understand TBI and develop effective treatments. Among these, rapid stretch injury has been used to mimic the effect of mechanical stress produced by a TBI on neurons and glia in vitro. In this study, we aimed to determine the impact of rapid stretch on the viability, proliferation, and differentiation of NSC isolated from rat hippocampus (Hipp-NSC) and to determine the role of the stretch-activated ion channel Piezo-1 in modulating their response to mechanical stress. We found that while rapid stretch (30 and 50 PSI) reduced Hipp-NSC viability (measured as a function of LDH release), it did not change their proliferation and differentiation potentials. Interestingly, rapid stretch in the presence of a selective Piezo-1 inhibitor, GsMTx4, or Piezo1 targeting siRNA, directed Hipp-NSC differentiation toward a neurogenic lineage. Additionally, we found that inhibiting Piezo1 with the addition of a rapid stretch injury increased the expression of miRNAs known to regulate neurogenesis. This work uses a novel approach for studying the effect of mechanical stress on NSC in vitro and points to the critical role the stretch-activated ion channel Piezo-1 has in modulating the impact of TBI on hippocampal neurogenesis.
创伤性脑损伤（TBI）是军事人员和平民中长期脑残疾的主要原因之一，不分性别。原发性脑损伤会引发大量继发性事件，增加了TBI的复杂性。受影响最严重的脑区之一是海马体，由于神经干细胞（NSC）的存在，海马体终生都会发生神经发生。临床前模型已被广泛用于更好地理解TBI并开发有效的治疗方法。其中，快速拉伸损伤已被用于在体外模拟TBI产生的机械应力对神经元和神经胶质细胞的影响。在本研究中，我们旨在确定快速拉伸对从大鼠海马体分离的神经干细胞（Hipp-NSC）的活力、增殖和分化的影响，并确定拉伸激活离子通道Piezo-1在调节其对机械应力反应中的作用。我们发现，虽然快速拉伸（30和50 PSI）降低了Hipp-NSC的活力（以乳酸脱氢酶释放量衡量），但并未改变其增殖和分化潜能。有趣的是，在存在选择性Piezo-1抑制剂GsMTx4或靶向Piezo1的小干扰RNA的情况下进行快速拉伸，可引导Hipp-NSC向神经源性谱系分化。此外，我们发现，在快速拉伸损伤的基础上抑制Piezo1会增加已知调节神经发生的微小RNA的表达。这项工作采用了一种新颖的方法来研究体外机械应力对神经干细胞的影响，并指出拉伸激活离子通道Piezo-1在调节TBI对海马体神经发生的影响中起着关键作用。
