Effects and Mechanism of Action of Neonatal Versus Adult Astrocytes on Neural Stem Cell Proliferation After Traumatic Brain Injury

Abstract

Due to the limited capacity of brain tissue to self-regenerate after traumatic brain injury (TBI), the mobilization of endogenous neural stem cells (NSCs) is a popular research topic. In the clinic, the neurogenic abilities of adults versus neonates vary greatly, which is likely related to functional differences in NSCs. Recent studies have demonstrated that the molecules secreted from astrocytes play important roles in NSC fate determination. In this study, conditioned media (CM) derived from neonatal or adult rat astrocytes, which were unstimulated or stimulated by lipopolysaccharide (LPS), were prepared to treat NSCs. Our results revealed that neonatal rat astrocytes can significantly promote the proliferation of NSCs, compared with adult rat astrocytes, regardless of whether or not they were stimulated by LPS. Furthermore, we used mass spectrometry to detect the constituents of the CM from each group. We analyzed and screened for a protein, Tenascin-C (TNC), which was highly expressed in the neonatal group but poorly expressed in the adult group. We found that TNC can bind to the NSC surface epidermal growth factor receptor and promote proliferation through the PI3K-AKT pathway in vitro. Additionally, we confirmed in vivo that TNC can promote damage repair in a rat model of TBI, through enhancing the proliferation of endogenous NSCs. We believe that these findings provide a mechanistic understanding of why neonates show better neuroregenerative abilities than adults. This also provides a potential future therapeutic target, TNC, for injury repair after TBI. STEM CELLS

Human Cerebral Cortex Proteome of Fragile X-Associated Tremor/Ataxia Syndrome

“…The observed decrease of TNC protein in FXTAS is unexpected and highlights a distinction between the FXTAS proteome and those of other neurodegenerative diseases, in which increased TNC protein abundance often correlates with an inflammatory response and initiation of other neurodegenerative diseases (Xie et al, 2013;Wiemann et al, 2019). Increased TNC gene expression (increased mRNA abundance) has also been implicated in response to traumatic brain injury and subsequent activation of the inflammatory response pathway (Liu et al, 2018;Dai et al, 2019). However, TNC gene silencing after subarachnoid hemorrhage (SAH) was found to alleviate neuronal inflammation and apoptosis via phosphoinositide-3kinase (PI3K)/Akt/nuclear factor (NF)-κB pathway activation and has been highlighted as a potential therapeutic target to prevent neuronal cell death after injury (Shiba et al, 2014;Liu et al, 2018).…”

The neuroprotective function of 2-carba-cyclic phosphatidic acid: Implications for tenascin-C via astrocytes in traumatic brain injury

“…It is suggested that this suppression of inflammation by 2ccPA results in the suppression of neuro-apoptosis, reduction in the number of activated astrocytes, and downregulation of TN-C expression. In addition, TN-C has been reported to promote the proliferation of neural stem cells and damage repair in rat model of TBI (Dai et al, 2019). This finding provides a potential future therapeutic target, TN-C, for injury repair after TBI.…”

Niche Cells Crosstalk In Neuroinflammation After Traumatic Brain Injury

“…While NSPCs deficient for transcription factor E47, which is found to be downregulated by Id3, shows performance of differentiation again, in the absence of BMP-2 [106], indicating a balance in the differentiation course of NSCs. Neonatal AG also promote the proliferation of NSCs with secreted protein [107]. Represented with similar function, NPCs secrete factors like TGF-β2 to transform MG into protective type [102], who in turn to support the maintenance and growth.…”