Intranigral Transplantation of Epigenetically Induced BDNF-Secreting Human Mesenchymal Stem Cells: Implications for Cell-Based Therapies in Parkinson's Disease

Abstract

It is thought that the ability of human mesenchymal stem cells (hMSC) to deliver neurotrophic factors might be potentially useful for the treatment of neurodegenerative disorders. The aim of the present study was to characterize signals and/or molecules that regulate brain-derived neurotrophic factor (BDNF) protein expression/delivery in hMSC cultures and evaluate the effect of epigenetically generated BDNF-secreting hMSC on the intact and lesioned substantia nigra (SN). We tested 4 different culture media and found that the presence of fetal bovine serum (FBS) decreased the expression of BDNF, whereas exogenous addition of epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF) to serum-free medium was required to induce BDNF release (125 ± 12 pg/day/10⁶ cells). These cells were called hM(N)SC. Although the induction medium inhibited the expression of alpha smooth muscle actin (ASMA), an hMSC marker, and increased the nestin-positive subpopulation of hMSC cultures, the ability to express BDNF was restricted to the nestin-negative subpopulation. One week after transplantation into the SN, the human cells integrated into the surrounding tissue, and some showed a dopaminergic phenotype. We also observed the activation of Trk receptors for neurotrophic factors around the implant site, including the BDNF receptor TrkB. When we transplanted these cells into the unilateral lesioned SN induced by striatal injection of 6-hydroxydopamine (6-OHDA), a significant hypertrophy of nigral tyrosine hydroxylase (TH)(+) cells, an increase of striatal TH-staining and stabilization of amphetamine-induced motor symptoms were observed. Therefore, hMSC cultures exposed to the described induction medium might be highly useful as a vehicle for neurotrophic delivery to the brain and specifically are strong candidates for future therapeutic application in Parkinson's disease.

The TrkB-Positive Dopaminergic Neurons are Less Sensitive to MPTP Insult in the Substantia Nigra of Adult C57/BL Mice

“…This study has thus suggested that TrkB-containing dopaminergic neurons are less sensitive to MPTP insult in the substantia nigra of adult C57/BL mice, and BDNF-TrkB signaling may play more important role in protecting the dopamine neurons from degeneration and show therapeutic application potential in alleviating the progression of Parkinson's disease [11,41,50]. Cell numbers (mean ± SEM., n = 5) present positive neurons counted in the substantia nigra pars compacta from five serial sections (30 lm thickness) of each midbrain with interval of four sections ** Significance at P \ 0.01 versus control Accumulating studies have shown that neurotrophins promote survival, transmitter production and release in the dopaminergic cells or brain neurons [1,3,32,38].…”

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

“…Moreover, stem cells genetically engineered to produce, for example, neurotrophins, which are then differentiated into neurons, can be used to deliver growth factors into a degenerating brain area to overcome cell death of grafted cells and to possibly enhance integration into the existing niches. Interestingly, mesenchymal stem cells (MSCs) can be epigenetically modified to endogenously express modest levels of BDNF (Somoza et al, 2010). Furthermore, it has been shown that, in a co-culture system with hippocampal neurons, MSCs induce glial-dependent neuronal survival, presumably through the secretion of BDNF (Mauri et al, 2012).…”

Hypoxic and ischemic effects on gene and protein expression levels of paracrine factors by human olfactory mucosa mesenchymal-like stem cells

“…1 These MSCs secrete the paracrine factors, vascular endothelial growth factor (VEGF), nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and matrix metalloproteinase-2 (MMP-2), which play an important role in the biological functions of MSCs. [2][3][4][5][6][7] It is important to understand the way in which the synthesis and secretion of these factors are controlled. This will help us better utilize MSCs in clinical situations.…”