BDNF‐overexpressing human mesenchymal stem cells mediate increased neuronal protection in vitro

Abstract

The use of neurotrophic factors as therapeutic agents for neurodegenerative diseases is considered as an approach aimed at restoring and maintaining neuronal function in the peripheral and central nervous system. Since the neuroprotective effect is depending on chronic delivery of the neurotrophic factors a sustained application, e.g., via cell‐based delivery is necessary. Human mesenchymal stem cells (hMSCs) were lentivirally modified to overexpress brain‐derived neurotrophic factor (BDNF) and to express fluorescent marker genes for easy visualization. Since genetically modified cells should be site‐specifically retained (e.g., by encapsulation) in the patients to avoid adverse effects the cells were additionally differentiated to chondrocytes to hypothetically improve their vitality and survival in a delivery matrix. Different polycations for lentiviral transduction were investigated for their efficiency. The success of differentiation was determined by analysis of chondrocyte marker genes and the neuroprotective effect of BDNF‐overexpressing cells was exemplarily investigated on neurons of the peripheral auditory system. The genetically modified hMSCs overexpressed BDNF from under 1 to 125 ng ml−1 day−1 depending on the donor and transfection method. Using protamine sulfate the transfection efficacy was superior compared to the use of polybrene. The BDNF secreted by the MSCs was significantly neuroprotective in comparison to the relevant controls even though the produced mean concentrations were lower than the effective concentrations for recombinant industrially produced proteins described in literature. The presented system of BDNF‐overexpressing hMSCs is neuroprotective and is therefore considered as a promising method for sustained delivery of proteins in therapeutically relevant amounts to degenerating neuronal structures.

Effect of TO901317 on promoting the differentiation of human bone marrow mesenchymal stem cells into dopamine neurons on Parkinson's disease

“…BMSCs transplantation restrained multiple parameters of spinal neuroin ammation found in diabetic mice 47 . BMSCs can release neurotrophic factors, including GDNF and BDNF to protect neurons 48,49 .…”

Therapeutic effect of TO901317 on 6-OHDA-induced Parkinson rats in vitro and in vivo

“…Neural stem cells, embryonic stem cells, 43 . It is important that BMSCs can release neurotrophic factors, including GDNF and BDNF to protect neurons 44,45 .…”

Alginate-encapsulated brain-derived neurotrophic factor–overexpressing mesenchymal stem cells are a promising drug delivery system for protection of auditory neurons

“…MSC isolation and proliferation was performed as previously described. 47 When a cell confluency of about 80% was achieved, they were passaged or prepared for encapsulation.…”