Human neural progenitor cell engraftment increases neurogenesis and microglial recruitment in the brain of rats with stroke

PLoS One. 2012;7(11):e50444. doi: 10.1371/journal.pone.0050444. Epub 2012 Nov 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Brain Ischemia / metabolism
  • Brain Ischemia / pathology
  • Brain Ischemia / therapy*
  • CD11b Antigen / biosynthesis
  • Cell Line, Transformed
  • Cell Movement
  • Cell Proliferation
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Humans
  • Male
  • Microglia / cytology
  • Microglia / metabolism*
  • Microtubule-Associated Proteins / biosynthesis
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neural Stem Cells / transplantation*
  • Neurogenesis / physiology*
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuropeptides / biosynthesis
  • Rats
  • Stroke / metabolism
  • Stroke / pathology
  • Stroke / therapy*
  • Transplantation, Heterologous

Substances

  • Biomarkers
  • CD11b Antigen
  • Microtubule-Associated Proteins
  • Neuropeptides
  • doublecortin protein

Grant support

This work was supported by Wolfson Charitable Trust, the US NIH, and RCUK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.