Insulin-like Growth Factor-1 Receptor Dictates Beneficial Effects of Treadmill Training by Regulating Survival and Migration of Neural Stem Cell Grafts in the Injured Spinal Cord

Abstract

Survival and migration of transplanted neural stem cells (NSCs) are prerequisites for therapeutic benefits in spinal cord injury. We have shown that survival of NSC grafts declines after transplantation into the injured spinal cord, and that combining treadmill training (TMT) enhances NSC survival via insulin-like growth factor-1 (IGF-1). Here, we aimed to obtain genetic evidence that IGF-1 signaling in the transplanted NSCs determines the beneficial effects of TMT. We transplanted NSCs heterozygous (+/−) for Igf1r, the gene encoding IGF-1 receptor, into the mouse spinal cord after injury, with or without combining TMT. We analyzed the influence of genotype and TMT on locomotor recovery and survival and migration of NSC grafts. In vitro experiments were performed to examine the potential roles of IGF-1 signaling in the migratory ability of NSCs. Mice receiving +/− NSC grafts showed impaired locomotor recovery compared with those receiving wild-type (+/+) NSCs. Locomotor improvement by TMT was more pronounced with +/+ grafts. Deficiency of one allele of Igf1r significantly reduced survival and migration of the transplanted NSCs. Although TMT did not significantly influence NSC survival, it substantially enhanced the extent of migration for only +/+ NSCs. Cultured neurospheres exhibited dynamic motility with cytoplasmic protrusions, which was regulated by IGF-1 signaling. IGF-1 signaling in transplanted NSCs may be essential in regulating their survival and migration. Furthermore, TMT may promote NSC graft-mediated locomotor recovery via activation of IGF-1 signaling in transplanted NSCs. Dynamic NSC motility via IGF-1 signaling may be the cellular basis for the TMT-induced enhancement of migration.

Neural Stem Cell Transplantation Improves Locomotor Function in Spinal Cord Transection Rats Associated with Nerve Regeneration and IGF-1 R Expression

“…In one study, it was shown that increasing the concentration of IGF-1 in the cerebrospinal fluid, along with treadmill training, could markedly attenuate reactive nitrogen or oxygen species, which are detrimental to NSC survival after transplantation. Moreover, Hwang and colleagues found that mice receiving IGF-1R +/- NSC grafts showed reduced locomotor recovery compared with those receiving wild-type (IGF-1R +/+ ) NSCs, illustrating that IGF-1 R plays an important role locomotor recovery 52 . In our study, we found the level of IGF-1 R in the rostral segment was increased significantly after transplanting NSCs in the site of the SCT.…”

Efficient One-Step Induction of Human Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs) Produces MSC-Derived Neurospheres (MSC-NS) with Unique Transcriptional Profile and Enhanced Neurogenic and Angiogenic Secretomes

“…Serum-free suspension culture with EGF-and bFGF-containing medium led to a significant increase in neurogenic and stemness gene expression (probably neurogenic genes predominate) in UC-MSCs, resulting in neurosphere formation which closely resembles neural progenitor cells with self-renewal and multipotency capacity. IGF all have been implicated in neural stem cell maintenance and proliferation [36][37][38][39][40][41], and thus they can be seen as at least partially neurogenic cytokines. Therefore, our short neural induction protocol not only produced cell phenotypically resembling neurospheres but also led to a quick upregulation and expression of neurogenic and angiogenic cytokines.…”

Exercise Ameliorates Spinal Cord Injury by Changing DNA Methylation

“…The exercise schedule was started 1 week after injury, and treadmill exercise was performed twice per day (morning and afternoon for 15 min per session) and 5 days per week for 12 weeks after injury ( Figure 1 ). Treadmill exercise was conducted at a running speed of 5 m/min at the beginning, and the speed was gradually increased to 12 m/min as the walking capabilities of the rats allowed until the end of the training as previously described [ 26 , 27 ].…”