Abstract
Main Objectives Stem cell transplantation is to date one of the most promising therapies for chronic ischemic stroke. The human conditionally immortalised neural stem cell line, CTX0E03, has demonstrable efficacy in a rodent model of stroke and is currently in clinical trials. Nonetheless, the mechanisms by which it promotes brain repair are not fully characterised. This study investigated the cellular events occurring after CTX0E03 transplantation in the brains of rats that underwent ischemic stroke.Methods We focused on the endogenous proliferative activity of the host brain in response to cell transplantation and determined the identity of the proliferating cells using markers for young neurons (doublecortin, Dcx) and microglia (CD11b). So as to determine the chronology of events occurring post-transplantation, we analysed the engrafted brains one week and four weeks post-transplantation.Results We observed a significantly greater endogenous proliferation in the striatum of ischemic brains receiving a CTX0E03 graft compared to vehicle-treated ischemic brains. A significant proportion of these proliferative cells were found to be Dcx+ striatal neuroblasts. Further, we describe an enhanced immune response after CTX0E03 engraftment, as shown by a significant increase of proliferating CD11b+ microglial cells.Conclusions Our study demonstrates that few Dcx+ neuroblasts are proliferative in normal conditions, and that this population of proliferative neuroblasts is increased in response to stroke. We further show that CTX0E03 transplantation after stroke leads to the maintenance of this proliferative activity. Interestingly, the preservation of neuronal proliferative activity upon CTX0E03 transplantation is preceded and accompanied by a high rate of proliferating microglia. Our study suggests that microglia might mediate in part the effect of CTX0E03 transplantation on neuronal proliferation in ischemic stroke conditions.
Highlights
Stroke is the third major cause of death and the single major source of disability in developed countries
Our study demonstrates that few Dcx+ neuroblasts are proliferative in normal conditions, and that this population of proliferative neuroblasts is increased in response to stroke
We further show that CTX0E03 transplantation after stroke leads to the maintenance of this proliferative activity
Summary
Stroke is the third major cause of death and the single major source of disability in developed countries. The CTX0E03 cell line recently entered a non-randomised, single-dose phase I clinical trial (PISCES), aiming at assessing their safety after transplantation in the brain of male patients who remained disabled after 6 months to 5 years following an ischemic stroke and aged over 60 years old. Details on this trial (NCT01151124), which is currently recruiting patients, can be found on the clinical trials database (clinicaltrial.gov). Given the clinical prospects carried by CTX0E03, the need to understand better this mode of action is critical
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