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Stem Cell Therapy for Mood and Memory

Original article from STEM CELLS Translational Medicine

“Neural Stem Cell Grafting Counteracts Hippocampal Injury-Mediated Impairments in Mood, Memory, and Neurogenesis”

Injury to the hippocampus, an organ vital for cognitive and mood function (Deng et al and Samuels and Hen), is understood to lead to increased neurogenesis from neural stem cells (NSCs) in early stages (Gray and Sundstrom and Hattiangady et al 2008) thought of as a compensatory mechanism for injury-mediated dysfunction. This early stage upregulation in NSC is short lived; reduced NSC proliferation in the neurogenic subgranular zone (SGZ) of the dentate gyrus (DG) and aberrant hippocampal neurogenesis are linked to mood and memory dysfunction observed after hippocampal injuries (Jorge et al and Potvin et al). This therefore suggests that therapeutic strategies such as NSC transplantation therapy to enhance neurogenesis beyond the early stage may allow the alleviation of post-injury afflictions. NSCs have the ability to survive, migrate, and engraft into brain regions exhibiting neuron loss (Blurton-Jones et al), are able to introduce new neurotrophic-secreting astrocytes (Waldau et al) and also can stimulate endogenous NSCs in the neurogenic SGZ (Hattiangady et al, 2007). Now, in a study published in the September edition of Stem Cells Translational MedicineHattiangady and Shetty have studied the effect on NSC grafting into the hippocampus shortly after injury on counteracting impairments in mood and memory function and neurogenesis.

NSCs were dissected from anterior subventricular zone (SVZ) of the mouse forebrain, reduced to single cells, and then grown as neurospheres. The SVZ was chosen as a source of NSCs due to SVZ-NSCs ability to grow for extended periods in vitro without loss of self-renewal (Gritti et al and Ahlenius et al) and the relative ease of isolation from autopsied and live human brains (Leonard et al and Ayuso-Sacido et al). Cells from the neurospheres expressed the expected neurotropic factors (BDNF, GDNF, VEGF, and FGF2) and could differentiate into GABA+ interneurons, GFAP+ cells, S100b+ mature astrocytes, O4+ oligodendrocytes and Tuj-1+ neurons of which most expressed GABA, an important factor in NSC proliferation, differentiation and integration of newly generated neurons. In order to generate the unilateral partial hippocampal injury, kainic acid was administered leading to extensive loss of neurons in the cornu ammonis 3 (CA3) pyramidal cell layer spanning the CA3b and CA3c regions and a partial loss of neurons in the dentate hilus.   Five days after injury, grafts of SVZ-NSCs with BDNF (SVZ-NSC grafted) or BDNF alone as control (control-grafted) were placed into the injured hippocampus along its septotemporal axis and were later analysed in comparison to non-injured control mice (control). 1.5 months after surgery the mice were assessed for depressive like behaviour using the widely used forced swim test which demonstrated that while the control-grafted mice displayed depressive-like behaviour as compared to control, indicated by an increased time spent in immobility/floating, the SVZ-NSC grafted mice showed behaviour similar to the control. Recognition memory was tested using a novel object recognition test (NORT), with increasing time exploring a novel object linked to the use of learning and recognition memory processes. This demonstrated that while control and SVZ-NSC grafted mice spent 65% of their time exploring the new object, control-grafted mice only explored the novel item for 35% of their time. Following this, a water maze test was used as a measurement of spatial learning and memory retrieval function, and again control-grafted mice exhibited a considerable defect in this test as compare to the SVZ-NSC grafted mice and the control.

Next, analysis of the graft itself was undertaken. This found the presence of grafted cores at the injured CA3 region and the migration of graft-derived cells into the DG and CA1 regions of the injured hippocampus, with the occasional graft-derived cell being found in the adjoining entorhinal cortex and the corpus callosum.  Stereological quantification of the surviving graft-derived cells suggested that grafts gave rise to an average of around 350,000 cells in each hippocampus; an equivalent yield of 116% of the injected cells (initially ~270,000). Analysis of cell type found that SVZ-NSC grafted cells gave rise to NeuN+ neurons (29%), GABA+ neurons (25%) CBN+ interneurons (10%), PV+ interneurons (5%), S100b+ astrocytes (46%), CNPase+ oligodendrocytes (16%) and NG2+ oligodendrocyte progenitors (16%). Graft derived cells also expressed neurotropic factors in a significant percentage of cells; GDNF (52%), BDNF (40%), FGF2 (42%) and VEGF (68%). Importantly, no CD4+ lymphocytes were observed suggesting that there was no immune response, and additionally no signs of tumourigenesis were observed.

Long-term (2.5 months) assessment found that neurogenesis was reduced by ~37% in the control-grafted mice, while the SVZ-NSC grafted mice had a similar rate to the control mice. Specifically, neurogenesis in the dorsal region (linked to memory) fell by 40% while neurogenesis in the ventral segment (linked to mood function) fell by a similar amount, although the decrease in the central segment was not statistically significant. Additional neurogenesis was also observed in the hippocampus contralateral to the injury in the SVZ-NSC grafted mice only. Abnormal patterns of neurogenesis are also associated with hippocampal injury and indeed this was observed in the control-grafted mice; ~23% of new neurons migrated into the dentate hilus while only ~13% of new neurons migrated abnormally in the SVZ-NSC grafted mice, as compared to only ~2% in the control mice. NSC (GFAP+) proliferative activity in the SGZ was also reduced in the control-grafted mice (to ~7% Ki67+ cells) as compared to ~17% in control mice and SVZ-NSC grafted mice (~14%). Finally a significant reduction in Reelin+ interneurons in the SGZ-granule cell layer and the dentate hilus was also observed, again indicative of abnormal neurogenesis.

Collectively, this study finds that the grafting of SVZ-NSCs into the site of a hippocampal injury allowed for the preservation of mood and memory function. Perhaps the limiting step taking this research forward into humans will be the availability of these SVZ-NSCs. Cells taken from human brains, be they live or dead, will be of limiting number, while expansion in vitro carries its own potential risk from loss of function due to adaption to culture. Additionally, the authors note that the selection of a particular type of NSCs is challenging for clinical application (Ge et al) while specific differentiation from embryonic stem cells or induced pluripotent stem cells still remains a challenge with the risk of tumourigenesis also a fear (Marr et al).



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STEM CELLS correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.