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Page 58 Al-Sammarraie et al. Neuroimmunol Neuroinflammation 2021;8:53-63 I http://dx.doi.org/10.20517/2347-8659.2020.34
[34]
was observed in response to SCI, which contributed to glial scar formation in SCI tissue . On one hand,
glial scar provides protective mechanisms to limit the lesion size after SCI; on the other hand, it leads to
deleterious effects by the inhibition of axonal regeneration [34,35] . Recent studies suggest that BMP signaling
promotes differentiation of neuronal stem cells (NSCs) and oligodendrocyte precursor cells (OPCs) into
[36]
astrocytes predominantly [36-38] . Wang et al. studied the effect of the microenvironment created by reactive
astrocytes on the differentiation of OPCs after SCI in rats. They found that SCI increased the expression
of BMP4 in astrocytes isolated from the site of injury, and it further released BMP4 in their conditioning
media. They also found that in vitro culture of OPCs in astrocytes-derived conditioning media activated
Smad1, 5, and 8, which led to differentiation of a significant number of OPCs into astrocytes, while
inhibiting differentiation of oligodendrocytes .
[36]
In contrast, noggin treatment reduced astrocytic differentiation and increased oligodendrocytic
[37]
[36]
differentiation . Similarly, Xiao et al. conducted a study to test the effect of BMP signaling on the
differentiation of NSCs after SCI in mice. This study found that BMP2, 4, and 7 were expressed in intact
spinal cord and their expression was further increased after SCI in the following cell types: neurons,
NSCs, microglia, and oligodendrocytes, but not in astrocytes . They also found that the expression of
[37]
[37]
phosphorylated Smad1, 5, and 8 were increased after SCI in the above cell types, OPCs, and astrocytes .
Furthermore, they found that BMP4 was highly expressed in neutrospheres (free-floating clusters of neural
stem cells) cultured from the spinal cord and it promoted astrocytic differentiation from NSCs, while
inhibition of BMP signaling using noggin treatment reduced astrocytic differentiation . Setoguchi et al.
[38]
[37]
examined the effect of BMPs on the differentiation of transplanted NPCs in vitro and after SCI in mice.
This study found that BMP2 was expressed in the spinal cord before injury and was upregulated drastically
[38]
after . They also found that BMP2 and 7 promoted the differentiation of NPCs to astrocytes in vitro,
while the inhibition of BMP signaling using Smad6, Smad7, or noggin overexpressing NPCs resulted in
[38]
the differentiation of NPCs into neuronal cells and inhibited the differentiation of NPCs into astrocytes .
Similarly, transplanting the above-modified NPCs into a mice model of SCI resulted in improvement of the
motor scores with inhibition of astrocytic differentiation and promotion of neuronal and oligodendrocytic
[38]
differentiations in vivo . Together, these studies imply that targeting BMP signaling could be beneficial
for ameliorating astrocytic scar formation, and for enhancing oligodendrocytic differentiation for
remyelination after SCI.

[39]
In addition, North et al. showed that the conditional deletion of β1 integrin from ependymal stem cells
resulted in an increase in their differentiation into astrocytes, which could promote glial scar formation
after SCI and reduce BBB motor scores in SCI mice, which were found to be associated with increases in
[25]
canonical (Smad1/5/8) and non-canonical (p38) signaling. Furthermore, Song et al. found that BMP4
treatment of NSCs in culture promoted astrocytic differentiation via activation of Smad1/5/8, while
noggin treatment resulted in reduction of astrocytic differentiation and an increase in oligodendrocytic
differentiation in vitro. In contrast, Enzmann et al. showed that the intra-thecal transplantation of noggin
[16]
overexpressing NSCs or progenitor cells was unable to restrict astrocytic differentiation in rats after SCI,
suggesting additional regulatory mechanisms were controlling astrocytic differentiation.

Studies also showed that the expression of BMP receptors was increased after SCI, particularly affecting
astrocytic hypertrophy (an astrocyte grown bigger than its normal size to adapt to changes) and
differentiation. Astrocytes play both physiological and pathological roles after traumatic SCI, which triggers
an initial astroctytic hypertrophy and subsequently, an astrocytic hyperplasia. In astrocytic hypertrophy,
astrocytes are reactive with bigger bodies, thicker processes, and overexpression of their intermediate
filament proteins such as glial fibrillary acidic protein and vimentin to help repair the blood-brain barrier
and reduce the spread of inflammatory cells at the site of SCI. On the other hand, in astrocytic hyperplasia,
astrocytes increase their numbers around the injury site and produce much finer processes to contribute to