Traumatic Brain Injury Activation of the Adult Subventricular Zone Neurogenic Niche

Abstract

Traumatic brain injury (TBI) is common in both civilian and military life, placing a large burden on survivors and society. However, with the recognition of neural stem cells in adult mammals, including humans, came the possibility to harness these cells for repair of damaged brain, whereas previously this was thought to be impossible. In this review, we focus on the rodent adult subventricular zone (SVZ), an important neurogenic niche within the mature brain in which neural stem cells continue to reside. We review how the SVZ is perturbed following various animal TBI models with regards to cell proliferation, emigration, survival, and differentiation, and we review specific molecules involved in these processes. Together, this information suggests next steps in attempting to translate knowledge from TBI animal models into human therapies for TBI.

Keywords: adult neurogenesis; proliferation; regeneration; stem cells; traumatic brain injury (TBI).

Figure 1

Altered SVZ proliferation is variable across species and experiments. (A) Increased SVZ proliferation and/or neurogenesis in rat after mechanical injury to brain. Data from multiple studies. 1 - (Tzeng and Wu, 1999), 2 - (Goodus et al., 2015), 3 - (Gotts and Chesselet, 2005), 4 - (Szele and Chesselet, ; Sun et al., , ; Bye et al., 2011), 5 - (Weinstein et al., 1996) 6, 7 - (Bye et al., ; Grande et al., 2013), 8 - (Acosta et al., 2013, 2014). For both (A,B), baseline was set at a value of 10 and percent changes from this are shown. (B) SVZ proliferation or neurogenesis in mouse after mechanical injury across multiple studies. Individual studies shown with colored lines (Jankovski et al., ; Goings et al., ; Ramaswamy et al., ; Theus et al., ; Radomski et al., ; Saha et al., ; Sullivan et al., ; Mierzwa et al., ; Thomsen et al., 2014). The Saha et al., study was the most complete including time points at 3 days, 1, 2, 3, 4, 5, 6, 7, and 8 weeks post-lesion. (C). Cortical injury via aspiration. The injury excludes the corpus callosum (arrowhead) but is close to the subventricular zone (arrow). Aspiration lesions of the cerebral cortex were made in the same location both in mouse and rat (Szele and Chesselet, ; Goings et al., 2002, 2004).

Figure 2

SVZ neural stem cells differentiate into neuroblasts, that migrate tangentially through the rostral migratory stream to the olfactory bulb, where they migrate radially and differentiate into interneurons. In response to injury, these cells migrate from the SVZ/RMS to the injury site in an attempt to regenerate the damaged tissue (Saha et al., 2012).

Figure 3

Changes in cortical microenvironment assist progenitor migration after lesion. CD31 immunostaining of control intact cortex (A) and lesioned cortex at different times after injury (B–D). Double immunofluorescence confocal micrograph of Dcx (green) and CD31 (red) at day 7 (E–G) and day 15 (H). Similarly, double-immunostaining of astrocytes (blue) and neural progenitors (green) after 7 days of lesion (I,J). (K,L asterisk) Migration of progenitors (green) without any association. GFP immunostaining of brain sections 8 days after lentivirus injection (dpi) into the SVZ/RMS (M). In the cortex, GFP+ cells (green) co-express Dcx (red) (boxed in N). GFP+ cells remain within the RMS in control brains (O). GFP+ progenitors also showed association with either blood vessels (P–R) or astrocytes (S–U). Scale bars: (A–D) 250 μm, (E,H) 50 μm, (F,G) 16 μm, (I,J,P–U) 20 μm, (K,L) 30 μm, (N) 80 μm, (N inset) 40 μm, (M,O) 100 μm, (M inset) 50 μm (Saha et al., 2013).