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

Abstract

Mesenchymal stem cells (MSCs) have been used for cell-based therapies in regenerative medicine, with increasing importance in central and peripheral nervous system repair. However, MSCs grafting present disadvantages, such as, a high number of cells required for transplantation and low survival rate when transplanted into the central nervous system (CNS). In line with this, MSCs secretome which present on its composition a wide range of molecules (neurotrophins, cytokines) and microvesicles, can be a solution to surpass these problems. However, the effect of MSCs secretome in axonal elongation is poorly understood. In this study, we demonstrate that application of MSCs secretome to both rat cortical and hippocampal neurons induces an increase in axonal length. In addition, we show that this growth effect is axonal intrinsic with no contribution from the cell body. To further understand which are the molecules required for secretome-induced axonal outgrowth effect, we depleted brain-derived neurotrophic factor (BDNF) from the secretome. Our results show that in the absence of BDNF, secretome-induced axonal elongation effect is lost and that axons present a reduced axonal growth rate. Altogether, our results demonstrate that MSCs secretome is able to promote axonal outgrowth in CNS neurons and this effect is mediated by BDNF.

Comparison between the effect of human Wharton’s jelly–derived mesenchymal stem cells and levetiracetam on brain infarcts in rats

“…42,43 In the present study, rats treated with WJ-MSCs showed better results than rats treated with LEV. 42,43 In the present study, rats treated with WJ-MSCs showed better results than rats treated with LEV.…”

“…[57] MSCs administration after MCAO in rats resulted in reduction in infarction volume, improvement in behavioral and functional performance, and increase in GDNF and BDNF levels in the infarcted cerebral hemisphere. 42,43 In the present study, rats treated with WJ-MSCs showed better results than rats treated with LEV. This can be attributed to the contradictory effects of MSCs and LEV on the expression of the iNOS protein as the WJ-MSCs decreased its expression, while LEV increased it.…”

Cell Secretome: Basic Insights and Therapeutic Opportunities for CNS Disorders

“…Moreover, Salgado and coworkers [82] pointed out that the secretome from WJ-MSCs and HUCPVCs is also able to increase survival, proliferation, and differentiation of hippocampal neurons due to the presence of, for example, NGF and FGF [82,83]. Additionally, the BDNF present on these cell secretomes is mediating axonal growth [84]. Figure 2 highlights ASC secretome composition, referring to specific biofactors and their biologic effect on the nervous system.…”

Secretion, migration and adhesion as key processes in the therapeutic activity of mesenchymal stem cells

“…What is more, they correlate the nerve survival and outgrowth improvement with BDNF activity from co-culture experiments (Crigler et al, 2006). Further studies reveal that BDNF is a key factor secreted by MSCs from Wharton's Jelly of the umbilical cord (WJ-MSCs), which exclusively mediates axonal elongation in the rat cortical and hippocampal neurons (Martins et al, 2017).…”