Insulin-like growth factor binding protein-6 released from human mesenchymal stem cells confers neuronal protection...

Human bone marrow‑derived mesenchymal stem cells (hMSCs) are a desirable cell source for cell‑based therapy to treat nervous system injuries due to their ability to differentiate into specific cell types. In addition to their multipotency, hMSCs render the tissue microenvironment more favorable for tissue repair by secreting various growth factors. Our previous study demonstrated that hMSCs secrete several growth factors, including several insulin‑like growth factor binding proteins (IGFBPs). Among these, IGFBP‑6 binds with high affinity and inhibits insulin growth factor‑2 (IGF‑2) to inhibit the growth of IGF‑2‑dependent tumors. However, the function of IGFBP‑6 in the nervous system remains to be fully elucidated. The present study investigated the protective effects of IGFBP‑6 secreted by hMSCs on H2O2‑injured primary cortical neuron cultures and lysolecithin‑injured organotypic spinal cord slice cultures. Treatment of the H2O2‑injured cortical neurons with conditioned media from hMSCs (hMSC‑CM) increased the phosphorylation of Akt, reduced cell death and mitochondrial translocation of Bax, and regulated extracellular levels of IGF‑1 and IGF‑2. MTT assay, western blot analysis and ELISA were used to detect the cell viability and protein expression levels, respectively. An inhibitory antibody against IGFBP‑6 eliminated this hMSC‑CM‑mediated neuroprotective effect in the injured cortical neuron cultures and spinal cord slice cultures. In addition, treatment with cyclolignan picropodophyllin, an inhibitor of IGF‑1 receptor (IGF‑1R), significantly inhibited neuronal protection by hMSC‑CM. These findings demonstrated that hMSC‑CM‑mediated neuroprotection was attributed to IGF‑1R‑mediated signaling, potentiated via the inhibition of IGF‑2 by IGFBP‑6. The results of the present study provide insight into the mechanism by which hMSC administration may promote recovery from nerve injury.