Abstract
Spinal cord injury (SCI) makes a major contribution to disability and deaths worldwide. Reactive astrogliosis, a typical feature after SCI, which undergoes varying molecular and morphological changes, is ubiquitous but poorly understood. Reactive astrogliosis contributes to glial scar formation that impedes axonal regeneration. Brain-derived neurotrophic factor (BDNF), a well-established neurotrophic factor, exerts neuroprotective and growth-promoting effects on a variety of neuronal populations after injury. In the present study, by using LPS-induced in vitro injury model of astroglial cultures, we observed a high expression of interleukin (IL)-6, IL-1β, and BDNF in LPS-stimulated normal human astrocytes (NHAs). BDNF significantly promoted NHA proliferation. Further, online tools were employed to screen the candidate miRNAs which might directly target BDNF to inhibit its expression. Amongst the candidate miRNAs, miR-211 expression was down-regulated by LPS stimulation in a dose-dependent manner. Through direct targetting, miR-211 inhibited BDNF expression. Ectopic miR-211 expression significantly suppressed NHA proliferation, as well as LPS-induced activation of PI3K/Akt pathway. In contrast, inhibition of miR-211 expression significantly promoted NHA proliferation and LPS-induced activation of PI3K/Akt pathway. Taken together, miR-211/BDNF axis regulates LPS-induced NHA proliferation through PI3K/AKT pathway; miR-211/BDNF might serve as a promising target in the strategy against reactive astrocyte proliferation after SCI.
Highlights
Spinal cord injury (SCI) makes a major contribution to disability and deaths worldwide with an annual incidence of 15–40 cases per million of the population and limited treatment options [1-3]
In response to LPS stimulation, the contents of IL-1β, IL-6, and Brain-derived neurotrophic factor (BDNF) were promoted; BDNF promoted the proliferation of normal human astrocyte (NHA) upon LPS stimulation
Reactive astrogliosis is characterized by the proliferation and hypertrophy of astrocytes, which eventually leads to scar formation via the effects of neurotrophic factors such as BDNF [33], or activation of signaling pathways such as STAT3, transforming growth factors-β (TGF-β/Smad) and PI3K [12,32,34-37]
Summary
Spinal cord injury (SCI) makes a major contribution to disability and deaths worldwide with an annual incidence of 15–40 cases per million of the population and limited treatment options [1-3]. The loss of sensation and paralysis caused by SCI is irreversible, partially because injured axons encounter a series of inhibitory microenvironments which are non-permissive for growth [4-6]. A typical feature after SCI, which undergoes varying molecular and morphological changes [7,8], is ubiquitous but poorly understood. Reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades [7,9]. Astrogliosis is a defense response of the central nervous system (CNS) to minimize primary damage and repair injured tissues, but it generates harmful effects by forming potent barriers to axon regeneration [10]. Reactive astrocytes participate in the process of glial scar formation [11] which could further inhibit axonal regeneration [12] and block nerve injury repair. Investigation of the mechanisms of reactive astrogliosis is beneficial to develop strategies for protection against SCI
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