Human neural stem cells genetically modified to overexpress brain‐derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model

Abstract

Intracerebral hemorrhage (ICH) is a lethal stroke type; mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, so an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and promote functional recovery in rat ICH model, and others have shown that intracerebral infusion of brain-derived neurotrophic factor (BDNF) results in improved structural and functional outcome from cerebral ischemia. We postulated that human NSCs overexpressing BDNF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs and increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by injection of bacterial collagenase into striatum. The HB1.F3.BDNF (F3.BDNF) human NSC line produces sixfold higher amounts of BDNFF over the parental F3 cell line in vitro, induces behavioral improvement, and produces a threefold increase in cell survival at 2 weeks and 8 weeks posttransplantation. Brain transplantation of human NSCs overexpressing BDNF provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results indicate that the F3.BDNF human NSCs should be of great value as a cellular source for experimental studies involving cellular therapy for human neurological disorders, including ICH.

Rescuing the neonatal brain from hypoxic injury with autologous cord blood

“…Other strategies include delivery of stem cells overexpressing neurotrophic factors and lineage predisposition of stem cells before transplantation. 104,[107][108][109][110] Route of stem cell administration Migration of various types of stem cells to the site of injury has been documented in HIE animal studies following either systematic or local injection. 70,84,111,112 Considering the volume of CB and the young age of the neonates with HIE, i.v.…”

Part I: Minicircle vector technology limits DNA size restrictions on ex vivo gene delivery using nanoparticle vectors: Overcoming a translational barrier in neural stem cell therapy

“…Several preclinical models of CNS pathology have demonstrated the utility of genetically engineered NSCs for improving functional neurological outcomes [12][13][14][15][16]. Recent data prove that transplantation of NSCs engineered to release insulin-like growth factor (IGF-1) reduced plaque pathology and enhanced learning, cognitive and memory processes in a mouse model…”

Self-renewal induced efficiently, safely, and effective therapeutically with one regulatable gene in a human somatic progenitor cell

“…Our ICSP cells proved to be regulatable so as to offset their limited capacity for self-renewal. They matched the predilection of other neural progenitor cell preparations to become neuronal (10) and to be effective in clinical disease models (10)(11)(12)(13)(14)(15)(16). Although, in these experiments, the neural progenitors were obtained from the brain, they could likely be obtained from such more accessible sources as olfactory neuroepithelium or skin.…”

“…Please see SI Materials and Methods for details of clone genesis and subsequent cytogenetic, RT-PCR, Western blot, immunohistochemical, electrophysiological, and transplantation procedures. Most reagents and methods were previously described (16).…”