LOTUS Inhibits Neuronal Apoptosis and Promotes Tract Regeneration in Contusive Spinal Cord Injury Model Mice

Abstract

Nogo receptor-1 (NgR1) signaling is involved in the limitation of axonal regeneration following spinal cord injury (SCI) through collapsing the growth cone and inhibiting neurite outgrowth. Lateral olfactory tract usher substance (LOTUS), a NgR antagonist, suppresses these pathological conditions. A previous report demonstrated the positive effects of LOTUS expression on motor function through raphespinal tract regeneration using pan-neuronally LOTUS-overexpressing transgenic mice. However, this report used a hemi-section model, which does not represent the majority of clinical SCI cases, and lacked a detailed histological analysis of other descending tracts. To determine the true therapeutic effects of LOTUS, we used a more clinically relevant contusive SCI model in female transgenic mice. Definitive tracing analyses revealed that LOTUS promoted the extensive regeneration of the reticulospinal tract across the lesion site and suppressed axonal dieback of corticospinal tract (CST). A significant increase in raphespinal tract fibers was seen from the subacute to the chronic phase after the injury, strongly suggesting that LOTUS promoted translesional elongation of this tract. Furthermore, histological analyses revealed that LOTUS had a neuroprotective effect on the injured spinal cord through suppressing cellular apoptosis during the acute phase. These neuroprotective and regenerative effects contributed to significant motor functional recovery and restoration of the motor evoked potential (MEP). Therefore, LOTUS application could prove beneficial in the treatment of SCI by promoting axonal regeneration of some descending fibers, reducing axonal dieback of CST fibers and encouraging motor function recovery.

In vivo monitoring of remnant undifferentiated neural cells following human induced pluripotent stem cell-derived neural stem/progenitor cells transplantation

“…Protein isolation and Western blotting assay were performed as described previously . Detailed methods are presented in SI Materials and Methods.…”

A robust culture system to generate neural progenitors with gliogenic competence from clinically relevant induced pluripotent stem cells for treatment of spinal cord injury

“…We generated an SCI animal model by inducing contusive SCI with moderate severity at the 10th thoracic vertebrae level in adult female immunodeficient mice. 14,30,58 5.0 × 10 5 ffiPSC-gNS/PCs were transplanted into the center of the lesion 9 days after the SCI. First, to investigate any configuration changes of the injured spinal cord, we examined the cross-sectional area of the injured spinal cord by H&E staining 12 weeks after transplantation ( Figure S3A).…”

Rhein lysinate improves motor function in rats with spinal cord injury via inhibiting p38 MAPK pathway

“…Neuronal apoptosis is an important component of secondary SCI and spinal nerve cell death after SCI is caused by apoptosis . Studies in different SCI models have confirmed that neuronal apoptosis is widespread in secondary SCI . Apoptosis, also known as programmed cell death, is an intrinsic natural physiological process that maintains the stability of various tissues in the human body by eliminating metabolites of dead cells .…”

“…[3][4][5] Studies in different SCI models have confirmed that neuronal apoptosis is widespread in secondary SCI. 6,7 Apoptosis, also known as programmed cell death, is an intrinsic natural physiological process that maintains the stability of various tissues in the human body by eliminating metabolites of dead cells. 7 The mechanism of apoptosis in nerve cells is very complicated.…”

“…6,7 Apoptosis, also known as programmed cell death, is an intrinsic natural physiological process that maintains the stability of various tissues in the human body by eliminating metabolites of dead cells. 7 The mechanism of apoptosis in nerve cells is very complicated. 8 It is suggested that various posttraumatic stimulation signals can induce apoptosis through different pathways.…”