Farber Institute of Neurosciences, Department of Neuroscience, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Neurological Surgery, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Neurobiol Dis. 2015 Feb;74:229-39. doi: 10.1016/j.nbd.2014.11.016. Epub 2014 Dec 5.
Previous studies have established the subventricular (SVZ) and subgranular (SGZ) zones as sites of neurogenesis in the adult forebrain (Doetsch et al., 1999a; Doetsch, 2003a). Work from our laboratory further indicated that midline structures known as circumventricular organs (CVOs) also serve as adult neural stem cell (NSC) niches (Bennett et al., 2009, 2010). In the quiescent rat brain, NSC proliferation remains low in all of these sites. Therefore, we recently examined whether ischemic stroke injury (MCAO) or sustained intraventricular infusion of the mitogen bFGF could trigger an up-regulation in NSC proliferation, inducing neurogenesis and gliogenesis. Our data show that both stroke and bFGF induce a dramatic and long-lasting (14day) rise in the proliferation (BrdU+) of nestin+Sox2+GFAP+ NSCs capable of differentiating into Olig2+ glial progenitors, GFAP+nestin-astrocyte progenitors and Dcx+ neurons in the SVZ and CVOs. Moreover, because of the upsurge in NSC number, it was possible to detect for the first time several novel stem cell niches along the third (3V) and fourth (4V) ventricles. Importantly, a common feature of all brain niches was a rich vasculature with a blood-brain-barrier (BBB) that was highly permeable to systemically injected sodium fluorescein. These data indicate that stem cell niches are more extensive than once believed and exist at multiple sites along the entire ventricular system, consistent with the potential for widespread neurogenesis and gliogenesis in the adult brain, particularly after injury. We further suggest that because of their leaky BBB, stem cell niches are well-positioned to respond to systemic injury-related cues which may be important for stem-cell mediated brain repair.
先前的研究已经确定侧脑室下区（SVZ）和颗粒下区（SGZ）是成年前脑的神经发生部位（Doetsch 等人，1999a；Doetsch，2003a）。我们实验室的工作进一步表明，被称为室周器官（CVOs）的中线结构也作为成年神经干细胞（NSC）龛（Bennett 等人，2009 年，2010 年）。在静止的大鼠脑中，所有这些部位的 NSC 增殖仍然很低。因此，我们最近研究了缺血性中风损伤（MCAO）或持续的脑室内 bFGF 灌注是否可以触发 NSC 增殖的上调，诱导神经发生和神经胶质发生。我们的数据表明，中风和 bFGF 都导致 SVZ 和 CVOs 中的 nestin+Sox2+GFAP+ NSCs 的增殖（BrdU+）急剧而持久（14 天）上升，这些 NSCs 能够分化为 Olig2+神经胶质前体、GFAP+nestin-星形胶质细胞前体和 Dcx+神经元。此外，由于 NSC 数量的增加，有可能首次在第三脑室（3V）和第四脑室（4V）沿线检测到几个新的干细胞龛。重要的是，所有脑龛的共同特征是富含血管，具有高度渗透的血脑屏障（BBB），可用于系统注射的荧光素钠。这些数据表明，干细胞龛比以前认为的更广泛，存在于整个脑室系统的多个部位，与成年大脑中的广泛神经发生和神经胶质发生一致，特别是在受伤后。我们进一步提出，由于它们的血脑屏障渗漏，干细胞龛很容易对全身损伤相关信号做出反应，这对于干细胞介导的大脑修复可能很重要。
