Neurotrophic Actions of Bone Marrow Stromal Cells on Primary Culture of Dorsal Root Ganglion Tissues and Neurons

Abstract

Application of adult bone marrow stromal cells (BMSCs) provides therapeutic benefits to the treatment of neurological insults. The aim of this study was to explore the potential of nonhematopoietic BMSCs to produce soluble factors and stimulate signaling pathways in neurons that mediate trophic effects. A combination of enzyme-linked immunosorbent assay and two-dimensional gel electrophoresis coupled with mass spectrometry showed that the BMSCs released into the culture medium an array of soluble factors such as nerve growth factor, brain-derived neurotrophic factor, basic fibroblast growth factor, and ciliary neurotrophic factor, which have been shown to exhibit potent neurotrophic effects on neural cells. Immunochemistry, cell viability assay, and quantitative real-time RT-PCR collectively showed that neurite outgrowth and neurogenesis in cultured rat dorsal root ganglion (DRG) explants and neurons were enhanced after they were cocultured with rat BMSCs. Western blot analysis revealed that BMSC-conditioned medium activated phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase and/or phosphoinositide 3-kinase/serine/threonine kinase (PI3K/Akt) in primary culture of rat DRG neurons, which suggested that BMSCs trigger endogenous survival signaling pathways in neurons through their secreted soluble factors. Our data help to elucidate the mechanisms by which BMSCs function as a cell therapy agent in peripheral nerve regeneration.

The Secretome of Bone Marrow and Wharton Jelly Derived Mesenchymal Stem Cells Induces Differentiation and Neurite Outgrowth in SH-SY5Y Cells

“…Similar findings were also reported in in vitro [26–29] and in vivo [30–32] models of spinal cord injury. For instance, Führman et al [28] and Gu et al [29] reported that coculture of BMSCs with dorsal root ganglia (DRG) explants and neurons significantly enhanced neuronal cell survival and neurite outgrowth, through the secretion of NGF, BDNF, bFGF, and CNTF (ciliary neurotrophic factor), HGF, SDF-1 (stromal cell-derived factor 1), VEGF, EGF, NT-3 (neurotrophin-3), and NT-4 (neurotrophin 4) GFs, as well as IL-1 (interleukin-1), IL-6, and IL-8 (interleukin-8) cytokines.…”

“…For instance, Führman et al [28] and Gu et al [29] reported that coculture of BMSCs with dorsal root ganglia (DRG) explants and neurons significantly enhanced neuronal cell survival and neurite outgrowth, through the secretion of NGF, BDNF, bFGF, and CNTF (ciliary neurotrophic factor), HGF, SDF-1 (stromal cell-derived factor 1), VEGF, EGF, NT-3 (neurotrophin-3), and NT-4 (neurotrophin 4) GFs, as well as IL-1 (interleukin-1), IL-6, and IL-8 (interleukin-8) cytokines. This expression pattern is in accordance with data published by others upon BMSCs transplantation in animal models of SCI [30–32].…”

Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF

“…MSCs secretomes present a high range of molecules, such as cytokines and growth factors 11, 30–32 . BDNF is a neurotrophin that, together with TrkB, its cognate receptor, is present throughout CNS 33 .…”

Biological Features of Human Bone Marrow Stromal Cells (hBMSC) Cultured with Animal Protein-Free Medium—Safety and Efficacy of Clinical Use for Neurotransplantation

“…Actually, previous reports have shown that the BMSC produced NGF, BDNF, neurotrophin-3, and glial cell line-derived neurotrophic factor [39]. Furthermore, the BMSC-conditioned medium activates phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase and/or phosphoinositide 3-kinase/serine/threonine kinase (Akt) in primary culture of rat dorsal root ganglion neurons [40]. The BMSC markedly promote the neurite extension from the neurons in the organotypic slice of the spinal cord [41].…”