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the development of the glial scar that becomes an impediment to axonal regeneration after SCI. Conditional
deletion of astrocytic BMPR1A in mice has adverse effects on recovery after SCI via impairing astrocytic
[26]
hypertrophy, reducing axonal density, and fostering inflammation . In contrast, conditional deletion
of astrocytic BMPR1B has more beneficial effects by increasing the number of hypertrophied astrocytes,
[26]
attenuation of the glial scar, and diminishing lesion size in mice after SCI . In addition, expression of
BMPR1A, 1B, and 2 in OPCs that were transplanted into rat spinal cord predominantly promoted their
[40]
differentiation into astrocytes . Similarly, culture of OPCs in the presence or absence of BMP2/4 and
noggin showed that BMP treatment increased their differentiation into astrocytes while noggin treatment
[40]
enhanced it .

ROLE OF BMP SIGNALING IN AXONAL GROWTH AND GLIAL CELL PROLIFERATIONS AFTER
SCI
Reactive astrogliosis (also known simply as astrogliosis or astrocytosis) and neuronal regrowth occur in
response to the loss of glial cells and neurons after SCI to partially promote healing of tissue damage and
attempt neuronal recovery [10,41] . Recent studies suggest that BMP signaling causes astrocytic proliferation
[42]
and neuronal growth after SCI [23,37,42] . Parikh et al. studied whether Smad1 activation could have a
beneficial effect on axonal regeneration in mice after SCI. BMP4 overexpression in dorsal motoneurons was
achieved by the intra-thecal administration of viral vectors overexpressing BMP4 in mice after SCI . The
[42]
results show activation of Smad1 in dorsal neurons, which is associated with improving axonal growth after
[42]
SCI . The administration of recombinant mouse noggin intra-thecally improved locomotive function
[37]
[23]
and increased axonal regrowth after SCI . Xiao et al. found that the levels of BMP2, 4, and 7 expression
were all increased in neurons, microglia, oligodendrocytes, and NSCs after SCI, which enhanced astrocytic
proliferation, while noggin treatment diminished astrocyte numbers.
ROLE OF BMP SIGNALING IN AUTOPHAGY AFTER SCI
Autophagy or “self-eating” is a central molecular mechanism that regulates tissue homeostasis in health
and disease . Autophagy is characterized by direct or indirect lysosomal degradation of damaged
[43]
mitochondria, misfolded proteins, and other cellular debris for recycling to maintain energy metabolism
[43]
in response to stressful stimuli . Macroautophagy is the major type of autophagy, which includes
sequential events of autophagosome formation, autophagosome-lysosome fusion, and autolysosomal
degradation of cargos . Autophagy flux is defined as the total dynamics of autophagy and thereby it is
[44]
the progression of cargo sequestration into autophagosomes, delivery to lysosomes, and degradation by
lysosomal enzymes . Autophagy flux is usually increased in mechanical injury such as mild traumatic
[45]
SCI or metabolic stress such as starvation, but autophagy flux is decreased due to suppression of autophagy
at an upstream (autophagosome formation) or downstream step (autolysosome formation) . Recent
[46]
studies suggest an impairment of autophagy flux after moderate to severe SCI, which leads to neuronal cell
death and adversely affects oligodendrocyte-mediated neuronal myelination and functional recovery [47,48] .
On the other hand, activating autophagy improves neurological recovery in rodent models of SCI due to
activation of autophagosome formation and/or enhancement of autophagy flux [49-51] . Although modulation
of autophagy plays a crucial role in the pathogenesis in SCI, there is limited knowledge on the role of
BMP signaling in the regulation of autophagy after SCI. BMP and activin membrane-bound inhibitor
[52]
(BAMBI) is a pseudo-receptor that lacks the kinase activity and inhibits the signaling of TGFβ family .
BAMBI has been found to be down regulated in rats after SCI, while intraspinal injection of the BAMBI
[52]
expressing vector after SCI promotes autophagy and improves locomotive function in rats . The BAMBI
overexpression causes activation of Beclin-1 and LC3B II, two proteins critical for inducing autophagy
and maintaining autophagy flux; on the other hand, it results in down regulation of autophagy inhibitor
proteins such as Bim and p62 . The role of BMP ligands and receptors in disruption of autophagy post-
[52]
SCI remains largely unknown; however, modulating BMP signaling to restore autophagy may provide a
new therapeutic avenue in treating SCI.