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Page 4 of 11 Almurshidi et al. Neuroimmunol Neuroinflammation 2019;6:11 I http://dx.doi.org/10.20517/2347-8659.2019.19

POTENTIAL ROLES OF MIRNAS IN SCI
miRNAs in astrogliosis
Astrogliosis or astrocytosis refers to the response of astrocytes in response to SCI. Astrogliosis occurs
in the area close to the SCI and is a part of a complex multicellular response to SCI. Astrogliosis is
[27]
characterized by functional, molecular, and morphological changes in astrocytes . These changes usually
[28]
occur within a few hours following the initial injury and evolve with time . The process of astrogliosis is
beneficial in the acute stages where it triggers the repair of the spine-blood barrier, cell regeneration, and
prevention of inflammation. However, astrogliosis becomes detrimental in the later stages (4 to 6 weeks)
following SCI when astrocytes change from hypertrophic to hyperplastic, producing glial scar with
[29]
expression of chondroitin sulfate proteoglycans .

Under specific pathological conditions, molecular signaling mechanisms associated with miRNAs affects
the process of astrocyte proliferation and astrogliosis. For example, the addition of anti-miR-125b is linked
with reduced glial cell proliferation and overall regulation of cell growth [30,31] . Similarly, overexpression of
[32]
miR-145 following SCI has been shown to increase astrogliosis in astrocytes close to the injured area .
There was focus of another study, which sought to determine the regulating mechanism of miR-21 in
[33]
regard to glial scars and astrocytic hypertrophy . More specifically, these investigators carried out tests
involving overexpression of miR-21 in mouse astrocytes and concluded that overexpression of miR-21
in astrocytes attenuated hypertrophic response to SCI but expression of the miR-21 sponge augmented
hypertrophic phenotype, even in chronic phase of SCI. Other researchers have studied the role of miR-21
in the hypertrophy-hyperplasia shift. According to recent research, miR-21 suppresses the expression of
the glial fibrillary acidic protein (GFAP) and vimentin (VIM) under the influence of bone morphogenic
protein (BMP) receptors . Activation of different BMP receptors results in differential expression of miR-21
[34]
in astrocytes and controls astrogliosis [35,36] . BMP receptor type 1a (BMPR1a) and BMPR1b exert opposite
effects on reactive astrocytic hypertrophy. BMPR1b plays a role in glial scar progression in the chronic
stages following SCI. These receptors exert opposite effects on expression of miR-21 in astrocytes.
Activation of BMPT1a causes overexpression of miR-21 with a dramatic reduction in GFAP levels, limiting
the detrimental effects of BMPR1b signaling on glial scar formation following SCI.

miRNAs in apoptosis
Some researchers studied the action of miRNAs in the context of apoptosis. For example, overexpression of
[37]
miR-96-5p inhibits apoptosis but promotes migration and proliferation in MDA-MB-231 and MCF-7 cells .
In this study, these investigators overexpressed miR-96-5p by transfecting MDA-MB-231 and MCF-7 cells
with a miR-96-5p mimic. Treatment and incubation of these cells were done for two days after which
cells were double stained with Annexin V/propidium iodide. Flow cytometry was then used to quantify the
apoptotic cells. The conceivable molecular events leading to induction of apoptosis in SCI are shown [Figure 2].
Upregulation of miR-96 may suppress programmed cell death protein 4 (PDCD4) and subsequently
decrease apoptosis. It is known that reduction of miR-21 promotes apoptosis by inhibiting the expression
of phosphatase and tensin homolog (PTEN) and PDCD4 . Down regulation of the pro-apoptotic
[38]
factors PTEN and PDCD4 can increase expression of the cell survival factor Akt or protein kinase B,
leading to a reduction in apoptosis in SCI. Studies indicated that specific miRNAs (e.g., miR-21, miR-7-1)
could significantly enhance efficacy of promising therapeutic agents (e.g., estrogen receptor agonists) for
functional protection of spinal cord motoneurons and this combination therapeutic strategy could be used
in the future to attenuate apoptosis of motoneurons in SCI [39,40] .

miRNAs in axon regeneration and remodeling
It has been demonstrated that exercise, which promotes spinal cord plasticity, results in the down
[41]
regulation of miR-199a-3p and upregulation of miR-21 . Alteration in expression of these miRNAs
modulates the mechanistic target of rapamycin (mTOR) and PTEN, which are postulated to underlie