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RNA-sequencing analysis gene expression changes of astrocytes treated with TGF- β1 in response to oxygen-glucose deprivation/reperfusion

ABSTRACT: Astrocytes are abundant glial cells in the central nervous system (CNS) that play important roles in cerebral ischemia-reperfusion injury. Following brain ischemia, astrocytes can trigger endogenous neuroprotective mechanisms such as neurogenesis, regulation of inflammation, transfer of mitochondria, and defense against oxidative stress. Transforming growth factor beta 1 (TGF-β1) is known as an injury-related cytokine, particularly associated with neurogenesis, neuronal migration, inflammatory reactions, and astrocyte scar formation in response to brain injury. TGF-β1 is closely related to ischemia-reperfusion brain injury and plays a significant role as both effectors and targets of I/R brain injury. Upregulation of endogenous TGF-β1 in neurons may contribute to preventing apoptosis after ischemic insult. TGF-β1 exerts dynamic effects in tissues through autocrine and paracrine signaling pathways as a secretory factor. The current study suggests that the multiple functions exerted by astrocytes might potentially be mediated by TGF-β1 signaling, raising the idea that astrocytes could be a potential therapeutic target for neuroprotection as sources or targets of TGF-β1. However, few studies are currently available on the effects of TGF-β1 on astrocytes after ischemia-reperfusion brain injury. Although current research shows that transforming growth factor-beta acts as a neuroprotective agent in cerebral ischemia, its specific mechanism is still not completely clear. In this study, RNA sequencing analysis was performed to investigate the potential mechanism of astrocytes pretreated with TGF-β1. Our study found that TGF-β1 mediates the upregulation of DUSP4 in astrocytes, which plays a neuroprotective role after ischemia-reperfusion injury. Overexpression of TGF-β1 inhibits the activation of astrocytes, accompanied by decreased levels of inflammatory factors and reactive oxygen species (ROS), while promoting the transfer of mitochondria between astrocytes and neurons. This enhanced neuron survival and axonal regeneration after injury. Hence, this study provides further insights into strategies for inhibiting neurological impairment and suggests a potential therapeutic target after ischemia-reperfusion injury.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE253273 | GEO | 2025/01/08

REPOSITORIES: GEO

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Project description:Background Transforming growth factor β1 (TGF-β1) has a neuroprotective function in traumatic brain injury (TBI) through its anti-inflammatory and immunomodulatory properties. In our previous study, we found that TGF-β1 played a critical role in inhibiting apoptosis and increasing neuronal activity in murine cortical neurons following trauma. However, the precise mechanisms underlying the neuroprotective actions of TGF-β1 on the cortex require further investigation. Methods Thus, in this study, we were aimed to investigate the regulatory function of TGF-β1 on neuronal autophagy and apoptosis using an in vitro primary cortical neuron trauma-injury model. Results To establish the landscape of differentially expressed genes (DEGs) with or without TGF-β1 (10ng/ml) treatment for 24 hours, we performed RNA-sequencing. We observed significant enrichment of DEGs related to autophagy, apoptosis, and the lysosome pathway in trauma-injured cortical neurons. Additionally, transmission electron microscopy (TEM) confirmed the presence of autophagosomes as well as autophagolysosomes. Western blot analysis revealed upregulation of autophagy-related protein light chain 3 (LC3)-Ⅱ/LC3-Ⅰ, sequestosome 1 (SQSTM1)/p62, along with apoptosis-related protein Cleaved-caspase3 in trauma-injured primary cortical neurons. Furthermore, mechanically injured neurons showed an upregulation of lysosomal marker protein lysosomal marker protein (LAMP1) and lysosomal enzyme mature cathepsin D (mCTSD), but a decrease in the activity of CTSD enzyme. These results indicated that apoptosis was up-regulated in mechanically injured neurons at 24 hours, accompanied by lysosomal dysfunction and impaired autophagic flux. Notably, TGF-β1 significantly reversed these changes. Conclusions Therefore, our findings suggested that TGF-β1 exerted neuroprotective effects on mechanically injured neurons by reducing lysosomal dysfunction, decreasing the accumulation of autophagosomes and autophagolysosomes, and enhancing autophagic flux.

Project description:Background: Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Methods: Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Results: Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Conclusions: Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest. One group of pigs underwent cardiac arrest (CA) without subsequent cardiopulmonary resuscitation (CPR) and the brain of the animals was removed after 5, 20 or 30 min post CA for genome-wide expression study. Two groups of pigs underwent first CA for 12 min with a subsequent 8 min-long CPR and received either an infusion of saline or an infusion of saline with MB from one minute after the start of CPR until 50 min after return of spontaneous circulation (ROSC). In both latter groups the brains were removed for microarray analysis at the following time points: 30, 60, 180 min.

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RNA-sequencing analysis gene expression changes of astrocytes treated with TGF- β1 in response to oxygen-glucose deprivation/reperfusion

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