microRNA-21 Regulates Astrocytic Response Following Spinal Cord Injury

Abstract

Astrogliosis following spinal cord injury (SCI) involves an early hypertrophic response that serves to repair damaged blood brain barrier and a subsequent hyperplastic response that results in a dense scar that impedes axon regeneration. The mechanisms regulating these two phases of astrogliosis are beginning to be elucidated. In this study, we found that microRNA-21 (miR-21) increases in a time-dependent manner following SCI in mouse. Astrocytes adjacent to the lesion area express high levels of miR-21 whereas astrocytes in uninjured spinal cord express low levels of miR-21. To study the role of miR-21 in astrocytes after SCI, transgenic mice were generated that conditionally over-express either the primary miR-21 transcript in astrocytes or a miRNA sponge designed to inhibit miR-21 function. Over-expression of miR-21 in astrocytes attenuated the hypertrophic response to SCI. Conversely, expression of the miR-21 sponge augmented the hypertrophic phenotype, even in chronic stages of SCI recovery when astrocytes have normally become smaller in size with fine processes. Inhibition of miR-21 function in astrocytes also resulted in increased axon density within the lesion site. These findings demonstrate a novel role for miR-21 in regulating astrocytic hypertrophy and glial scar progression after SCI, and suggest miR-21 as a potential therapeutic target for manipulating gliosis and enhancing functional outcome.

TGF-β Family Signaling in Neural and Neuronal Differentiation, Development, and Function

“…These results indicate a specific role of BMPRIA in the initial injury response; however, Bmpr1a 2/2 mice show better recovery 5 weeks postinjury, suggesting that BMPRIB regulates glial scar progression (Sahni et al 2010). Further, miR-21, a posttranscriptional regulator of gene expression induced by BMP signaling, mediates the astrocytic response after spinal cord injury (Sahni et al 2010;Bhalala et al 2012). Thus, many members of the TGF-b family have important roles following CNS injury, although these processes have yet to be fully understood.…”

The glial scar in spinal cord injury and repair

“…reported that miR-21 regulates astrocytic hypertrophy and glial scar progression after SCi, which implicates epigenetic regulation as a potential therapeutic target for manipulating glial scar formation and improving functional performance [82] .…”

“…in addition, a study of PKC disruption by the inhibitor Gö6976 has linked an increase in the regeneration of dorsal column axons with the inactivation of CSPGs after dorsal spinal cord hemisection [81] . More interestingly, Bhalala et al recentlyreported that miR-21 regulates astrocytic hypertrophy and glial scar progression after SCi, which implicates epigenetic regulation as a potential therapeutic target for manipulating glial scar formation and improving functional performance [82] . …”

Unraveling molecular determinants of manual therapy: an approach to integrative therapeutics for the treatment of fibromyalgia and CFS/ME

“…While both miRs are increased in spinal cord after spinal cord injury, the second also increases in the prefontal cortex of the brain in a model of carrageenan induced facial inflammatory pain. Importantly the increase of miR-223 coincides with the peak of mechanical hyperalgesia, suggesting a role of this miR in the process [94][95][96]. Regarding deregulation of miR-21 and its connexion to pain mechanisms we should point out that Simeoli (EVs), including exosomes, loaded with miR-21 upon capsaicin activation of TRPV1 receptors.…”