Effect of brain‐derived neurotrophic factor in neural differentiation of mouse embryonic stem cells and neural precursor cells

Abstract

SUMMARY Embryonic stem (ES) cells, which have pluripotency in differentiation,have been considered as an excellent source for cell replacement therapy of damaged tissues. Although neurotrophic factors induce neural differentiation in neural precursor cells, their actions in ES cells are not clear. This study was designated to examine the effect of brain-derived neurotrophic factor (BDNF) on neural differentiation in mouse ES cells. Undifferentiated mouse ES cells were maintained at suspension culture in the presence of leukemia inhibitory factor (LIF), and neural precursor cells were isolated from the subventricular zone (SVZ) of the 2-3 day old mice brain. Ott-4 was expressed in undifferentiated ES cells and neural precursor cells, of which expression was markedly decreased by induction of differentiation.RT-PCR analysis showed that neural differentiation of ES cells induced expression of various neural markers, and that BDNF increased their expression.Western blot analysis demonstrated that BDNF induced expression of synaptophysin, a neuronal marker, and inhibited expression of glial fibrillary acidic protein, a glial marker. Undifferentiated ES cells expressed TrkA, TrkB and TrkC, of which expressions were increased during differentiation. Neural differentiation increased their expression, and BDNF further increased them. The treatment of BDNF during differentiation decreased expression of Notchl. These results indicated that BDNF induces neural differentiation and inhibits glial differentiation in ES cells as well as neuronal precursor cells.

Stably BDNF-GFP expressing embryonic stem cells exhibit a BDNF release-dependent enhancement of neuronal differentiation

“…As described previously for MSCs or adult NSCs overexpressing untagged BDNF (Lim et al, 2011;Ma et al, 2012), or as revealed by application of BDNF to EBs (Kang et al, 2001) or to NSCs (Silva et al, 2009), neuronal differentiation of our BDNF-GFPoverexpressing ESCs was strongly enhanced (Figs 4,5). Given that this enhancement was critically dependent on the extracellular availability of BDNF (see inhibition by TrkB-Fc receptor bodies; Fig.…”

“…Furthermore, BDNF is known to support differentiation of embryonic, mesenchymal and neural stem cells into neurons in vitro and in vivo (Kang et al, 2001;Ortega and Alcántara, 2010;Trzaska and Rameshwar, 2011). For example, studies using embryonic and adult neuronal precursor cells from mouse striatum revealed a BDNF-mediated increase in neuron number and neurite outgrowth that was independent from increased cell division and increased survival (Ahmed et al, 1995).…”

Engineered 3D vascular and neuronal networks in a microfluidic platform

“…These results suggest that paracrine signaling via BDNF, but to a lesser extent BMP-2, secreted by ECs likely contributed to neurite elongation and activation of Ca 2+ oscillations. BDNF is a key growth factor that accelerates neuronal differentiation 39 by activation of MAPK/ERK and PI3K/Akt signaling pathways 40 . We, therefore, hypothesize that in co-culture with ECs, BDNF and potentially BMP-2 secreted by ECs and present in the culture medium upregulated neuronal differentiation and survival of neurons through autocrine signaling in co-culture system.…”

PSA-NCAM positive neural progenitors stably expressing BDNF promote functional recovery in a mouse model of spinal cord injury

“…Our data provide evidence for BDNF-induced NPC differentiation into both favored lineages in vivo, leading to cell replacement of damaged neurons and oligodendrocytes. We and others have already shown that BDNF enhances neuronal differentiation, as it is known to support differentiation of embryonic, mesenchymal, and NSCs into neurons in vitro and in vivo [ 8 – 10 , 19 ]. Furthermore, BDNF is important for oligodendroglial proliferation, differentiation, and myelination [ 11 – 13 ].…”