Abstract
Modulating endogenous regenerative processes may represent a suitable treatment for central nervous system (CNS) injuries, such as stroke or trauma. Neural stem/progenitor cells (NS/PCs), which naturally reside in the subventricular zone (SVZ) of the adult brain, proliferate and differentiate to other cell types, and therefore may compensate the negative consequences of ischemic injury. The fate of NS/PCs in the developing brain is largely influenced by Wingless/Integrated (Wnt) signaling; however, its role in the differentiation of adult NS/PCs under ischemic conditions is still enigmatic. In our previous study, we identified the Wnt/β-catenin signaling pathway as a factor promoting neurogenesis at the expense of gliogenesis in neonatal mice. In this study, we used adult transgenic mice in order to assess the impact of the canonical Wnt pathway modulation (inhibition or hyper-activation) on NS/PCs derived from the SVZ, and combined it with the middle cerebral artery occlusion (MCAO) to disclose the effect of focal cerebral ischemia (FCI). Based on the electrophysiological properties of cultured cells, we first identified three cell types that represented in vitro differentiated NS/PCs – astrocytes, neuron-like cells, and precursor cells. Following FCI, we detected fewer neuron-like cells after Wnt signaling inhibition. Furthermore, the immunohistochemical analysis revealed an overall higher expression of cell-type-specific proteins after FCI, indicating increased proliferation and differentiation rates of NS/PCs in the SVZ. Remarkably, Wnt signaling hyper-activation increased the abundance of proliferating and neuron-like cells, while Wnt pathway inhibition had the opposite effect. Finally, the expression profiling at the single cell level revealed an increased proportion of neural stem cells and neuroblasts after FCI. These observations indicate that Wnt signaling enhances NS/PCs-based regeneration in the adult mouse brain following FCI, and supports neuronal differentiation in the SVZ.
Highlights
Stroke is one of the leading causes of mortality worldwide, affecting a great number of people in developed countries and imposing a considerable economic burden on society (Woodruff et al, 2011; Rajsic et al, 2019)
This study is a logical continuation of our previous experiments performed on neonatal mice under physiological conditions, where we revealed that canonical Wnt signaling promotes neurogenesis at the expense of gliogenesis (Kriska et al, 2016)
To elucidate the effect of the Wnt/β-catenin pathway on the differentiation potential of Neural stem/progenitor cells (NS/PCs) in non-operated (CTRL) mice and mice after the induction of permanent focal cerebral ischemia (FCI) (MCAO), we compared either in vitro cultures treated with 4OHT to their respective controls (EtOH), or tissue specimens from mice with manipulated Wnt signaling (TAM), to control mice with intact Wnt signaling (CO)
Summary
Stroke is one of the leading causes of mortality worldwide, affecting a great number of people in developed countries and imposing a considerable economic burden on society (Woodruff et al, 2011; Rajsic et al, 2019). Ischemic stroke due to a blocked artery comprises more than 85% of all stroke cases (Woodruff et al, 2011); the most frequently affected vessel of the brain is the middle cerebral artery. Recent studies have attempted to treat or replace diminishing numbers of neural cells with the use of stem cells from various sources (Ruzicka et al, 2017), or by utilizing NS/PCs naturally residing in the adult brain (Groves et al, 2019) with the capability of differentiating to other cell types (Kriska et al, 2016; Butti et al, 2019; Vancamp et al, 2019)
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