Human neural stem cell transplantation into the corpus callosum of Alzheimer's mice

Abstract

The hippocampus has been the target of stem cell transplantations in preclinical studies focused on Alzheimer's disease, with results showing improvements in histological and behavioral outcomes. The corpus callosum is another structure that is affected early in Alzheimer's disease. Therefore, we hypothesize that this structure is a novel target for human neural stem cell transplantation in transgenic Alzheimer's disease mouse models. This study demonstrates the feasibility of targeting the corpus callosum and identifies an effective immunosuppression regimen for transplanted neural stem cell survival. These results support further preclinical development of the corpus callosum as a therapeutic target in Alzheimer's disease.

Human neural stem cell transplantation improves cognition in a murine model of Alzheimer’s disease

“…Given that stem cell therapies target multiple disease mechanisms, we examined the long-term efficacy of NSI-HK532-IGF-1, a human NSC line that we previously characterized in vitro 23 , in the APP/PS1 AD mouse model. In line with previous transplantation studies of this particular cell line 24 , this study supports the safety and feasibility of intracranial transplantation of human NSCs, with no adverse findings throughout the 17-week post-transplant period. Moreover, NSC transplantation targeted to the fimbria fornix significantly improved hippocampal-dependent cognitive function and was associated with reduced plaque load and increased microglial activation, but with no observable tissue integration or impact on synaptic density or cholinergic function.…”

“…Alternative explanations generally include NSC differentiation into glia or neuronal phenotypes and subsequent functional integration. In the present study, functional improvements and tissue changes occurred in vivo , although well-established PCR or IHC methods 14 , 23 , 24 , 47 , 48 did not identify human stem cells post-mortem. Transplanted cell survival and engraftment is determined by multiple parameters including animal model, cell type, dose, route of administration and treatment duration.…”

“…Since the majority of studies to date have assessed efficacy at much earlier time points, our experimental design investigated the longer-term impact of a well-characterized human NSC line and required an immunosuppression regimen. Using the same immunosuppression protocol and cell dose, we previously reported NSC survival 8 weeks post-transplant in APP/PS1 mice 24 , and in our preclinical ALS studies we have shown human spinal stem cell survival in similarly immunosuppressed rats 47 , 49 . In studies by others, human donor cell survival and integration is reported in various mouse models, although at much shorter time points ranging from 1 to 6 weeks post-transplant 14 , 17 , 30 , 32 .…”

“…Intracranial transplantation of NSCs was performed using the same approach described in our previous studies 23 , 24 . Briefly, at 12 weeks of age, mice were anesthetized with isoflurane and placed in a standard Kopf stereotactic frame (David Kopf Instruments).…”

“…With Neuralstem, Inc., we developed a unique line of human cortex-derived neural stem cells (NSCs; NSI-HK532-IGF-1), safely engineered to produce multiple neurotrophic factors 23 . We previously reported that this specific NSC line is neuroprotective in vitro and survives and migrates after in vivo grafting 23 , 24 . Furthermore, we have obtained investigational new drug status for the sister spinal cord-derived cell line of this NSC candidate (NSI-566RSC), currently in an FDA-approved clinical trial in ALS patients 13 , 25 .…”