Long-term cognitive effects of human stem cell transplantation in the irradiated brain

Abstract

Purpose: Radiotherapy remains a primary treatment modality for the majority of central nervous system tumors, but frequently leads to debilitating cognitive dysfunction. Given the absence of satisfactory solutions to this serious problem, we have used human stem cell therapies to ameliorate radiation-induced cognitive impairment. Here, past studies have been extended to determine whether engrafted cells provide even longer-term benefits to cognition.

Materials and methods: Athymic nude rats were cranially irradiated (10 Gy) and subjected to intrahippocampal transplantation surgery 2 days later. Human embryonic stem cells (hESC) or human neural stem cells (hNSC) were transplanted, and animals were subjected to cognitive testing on a novel place recognition task 8 months later.

Results: Grafting of hNSC was found to provide long lasting cognitive benefits over an 8-month post-irradiation interval. At this protracted time, hNSC grafting improved behavioral performance on a novel place recognition task compared to irradiated animals not receiving stem cells. Engrafted hESC previously shown to be beneficial following a similar task, 1 and 4 months after irradiation, were not found to provide cognitive benefits at 8 months.

Conclusions: Our findings suggest that hNSC transplantation promotes the long-term recovery of the irradiated brain, where intrahippocampal stem cell grafting helps to preserve cognitive function.

Keywords: Human stem cells; cognition; hippocampus; radiation; transplantation.

Figure 1

Study design. Athymic nude rats (2 months age) received a 10 Gy cranial dose of γ-rays and were transplanted with human stem cells 2-days post-IRR. Two groups of animals (1- and 8-month post-transplantation) were administered a novel place recognition (NPR) task.

Figure 2

Cognitive testing (familiarization phase) conducted 1 and 8 months after human stem cell transplantation and cranial IRR. Transplantation of hNSC ameliorates IRR-induced deficits in novel place recognition (NPR) performance at 1- and 8-months post-surgery. Time spent exploring both objects during the initial familiarization phase is shown. The 1- and 8-month IRR + hNSC group explored significantly more than the corresponding IRR group (IRR + hNSC, *, p’s < 0.01, Post hoc, Fisher’s LSD). The IRR + hESC group did not show improvement in object exploration at either post-grafting time. 1-month data adapted from (Acharya et al. 2009, 2011). Error bars indicate the standard error of the mean ± SEM (n = 12, 1-month data; n = 4, 8-month data). ^{+, #,} indicates significant difference versus 8 month post-surgery Control and IRR groups.

Figure 3

Cognitive testing (5-min novel place recognition) conducted 1 and 8 months after human stem cell transplantation and cranial IRR. Exploration ratios (time novel/time novel + time familiar) for the first minute of the 5 min NPR test session are plotted. Irradiated animals (IRR) at 1 month did not explore the novel spatial location more than expected by chance (indicated by dashed line) and showed a significant decline when compared to the non-irradiated Control group (p = 0.015). While the cohort of 8-month IRR animals did exhibit a trend toward improved performance they did not spend significantly more time exploring the novel place than expected by chance. The IRR + hNSC group at 1- and 8-month post-surgery showed comparable cognitive performance with controls. At the 1-month time the IRR + hESC group showed significant improvement (p = 0.013) in novel place exploration compared to the IRR group. Error bars indicate the standard error of the mean ± SEM (n = 12, 1-month data; n = 4, 8-month data). 1-month data adapted from (Acharya et al. 2009, 2011). * indicates significant difference between 8-month and 1-month IRR groups (i.e., p < 0.05 on Post hoc, Fisher LSD group comparisons). +, indicates significant difference compared to 0.5 (i.e., more than expected by chance, p’s < 0.05, one-sample t -test comparison).