Neurogenic Niche Conversion Strategy Induces Migration and Functional Neuronal Differentiation of Neural Precursor Cells Following Brain Injury

Abstract

Glial scars formed after brain injuries provide permissive cues for endogenous neural precursor/stem cells (eNP/ SCs) to undergo astrogenesis rather than neurogenesis. Following brain injury, eNP/SCs from the subventricular zone leave their niche, migrate to the injured cortex, and differentiate into reactive astrocytes that contribute to glial scar formation. In vivo neuronal reprogramming, directly converting non-neuronal cells such as reactive astrocytes or NG2 glia into neurons, has greatly improved brain injury repair strategies. However, reprogramming carries a high risk of future clinical applications such as tumorigenicity, involving virus. In this study, we constructed a neural matrix to alter the adverse niche at the injured cortex, enabling eNP/SCs to differentiate into functional neurons. We found that the neural matrix functioned as a ''glial trap'' that largely concentrated and limited reactive astrocytes to the core of the lesion area, thus altering the adverse niche. The eNP/SCs migrated toward the injured cortex and differentiated into functional neurons. In addition, regenerated neurites extended across the boundary of the injured cortex. Mice treated with the neural matrix demonstrated significant behavioral recovery. For the first time, we induced eNP/SC-derived functional neurons in the cortex after brain injury without the use of viruses, microRNAs, or small molecules. Our novel strategy of applying this ''glial trap'' to obtain functional neurons in the injured cortex may provide a safer and more natural therapeutic alternative to reprogramming in future clinical applications.

Hypoxic preconditioning ameliorated neuronal injury after middle cerebral artery occlusion by promoting neurogenesis

“…Studies have found that mesenchymal stem‐cell transplantation can repair neuronal injury by regulating CXCL12/CXCR4 signaling with the beneficial effects mainly achieved through the replacement of injured cells (Chau et al, 2018; Hu et al., 2019), immunomodulation (Chen et al., 2018), and neurotrophic actions (Abati, Bresolin, Comi, & Corti, 2019). However, exogenously transplanted stem cells have low survival rates possibly due to immune rejection, acute inflammation, and lack of neurotrophic signals (Wang et al., 2019).…”

“…However, exogenously transplanted stem cells have low survival rates possibly due to immune rejection, acute inflammation, and lack of neurotrophic signals (Wang et al, 2019).…”

Astrocyte and Oligodendrocyte Responses From the Subventricular Zone After Injury

“…Under normal physiological conditions, the SVZ can generate mature astrocytes (Sohn et al, 2015) and following injury, the number of astrocytes produced by the SVZ drastically increases. Lineage tracing with the Nestin-CreER T2 promoter has been used to directly identify SVZ-derived progenitors migrating to the injury site, with the Nestin-CreER T2 :R26R-YFP/RFP traced cells predominately expressing the astrocytic marker GFAP within the injured striatal parenchyma after middle cerebral artery occlusion (MCAO) (Li et al, 2010), in the cortex after injury (PBS filling brain cavity) (Wang et al, 2019), cortical stroke (Benner et al, 2013;Faiz et al, 2015) or stab-wound injury (Burns et al, 2009). These studies reveal that the SVZ produces a more predominant astrocytic component than previously appreciated.…”

Unique Astrocyte Cytoskeletal and Nuclear Morphology in a Three-Dimensional Tissue-Engineered Rostral Migratory Stream

“…Neural precursor cells (NPCs) in the SVZ of rodents can differentiate into neuroblasts and migrate through a pathway of aligned astrocytes known as the rostral migratory stream (RMS) to the olfactory bulb (OB), where they mature into functional granule, periglomerular, or glutamatergic interneurons and integrate into existing circuitry [3][4][5][6]. Following brain injury, SVZ neurogenesis is upregulated [7][8][9] and neuroblasts can divert from the SVZ-RMS-OB pathway, migrate toward injured brain regions, and mature into functional, phenotypically relevant neurons [10][11][12]. Further, experimentally enhancing the redirection of neuroblasts from the SVZ into injured regions can induce functional recovery following injury [10,[12][13][14][15][16][17][18][19][20][21][22].…”

“…Following brain injury, SVZ neurogenesis is upregulated [7][8][9] and neuroblasts can divert from the SVZ-RMS-OB pathway, migrate toward injured brain regions, and mature into functional, phenotypically relevant neurons [10][11][12]. Further, experimentally enhancing the redirection of neuroblasts from the SVZ into injured regions can induce functional recovery following injury [10,[12][13][14][15][16][17][18][19][20][21][22].…”