Use of induced pluripotent stem cell derived neurons engineered to express BDNF for modulation of stressor related pathology

Abstract

Combined cell and gene-based therapeutic strategies offer potential in the treatment of neurodegenerative and psychiatric conditions that have been associated with structural brain disturbances. In the present investigation, we used a novel virus-free re-programming method to generate induced pluripotent stem cells (iPSCs), and then subsequently transformed these cells into neural cells which over-expressed brain derived neurotrophic factor (BDNF). Importantly, the infusion of iPSC derived neural cells (as a cell replacement and gene delivery tool) and BDNF (as a protective factor) influenced neuronal outcomes. Specifically, intracerebroventricular transplantation of iPSC-derived neural progenitors that over-expressed BDNF reversed the impact of immune (lipopolysaccharide) and chronic stressor challenges upon subventricular zone adult neurogenesis, and the iPSC-derived neural progenitor cells alone blunted the stressor-induced corticosterone response. Moreover, our findings indicate that mature dopamine producing neurons can be generated using iPSC procedures and appear to be viable when infused in vivo. Taken together, these data could have important implications for using gene-plus-cell replacement methods to modulate stressor related pathology.

IFN-γ differentially modulates memory-related processes under basal and chronic stressor conditions

“…Levels of norepinephrine (NE), serotonin (5-HT) and dopamine (DA), and their respective primary metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindole acetic acid (5-HIAA), and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were determined by HPLC within relevant brain punches according to previously reported methods ( Liu et al, 2014 ). Tissue punches were homogenized by ultrasonic disruption (Sonic Dismembrator Model 100, Fisher Scientific) in the homogenizing solution in which they were initially frozen (with DHBA as an internal standard).…”

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

“…In this study, mice which were exposed to a stressor regimen and received BDNF-secreting iPSC-derived neural progenitors via intracerebroventricular transplantation reversed the impact of stressor challenge by subventricular zone adult neurogenesis [112].…”

Induced pluripotent stem cells (iPSCs) as game‐changing tools in the treatment of neurodegenerative disease: Mirage or reality?

“…In another significant study, Cho, Hunter, Ye, Pongos, and Chan (2019b) generated transgenic HD monkey NPCs from their iPSCs and confirmed the efficacy of the combined use of the obtained NPCs and gene therapy in a transgenic HD mouse model. On the other hand, G. Liu et al (2014) found that the combination of iPSCs and trophic factors, in particular brain‐derived neurotrophic factor (BDNF), has the potential to stimulate neurogenesis and enhance preservation of neuronal structure and/or function, providing promising potential in disease‐modifying treatment of HD (G. Liu et al, 2014). According to other reports, iPSC‐derived NPCs transplantations diminished behavioral deficits and improved neuropathological variations in HD mouse models (Al‐Gharaibeh et al, 2017).…”