1. ¹The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel
2. ²Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Hospital, Jerusalem, Israel
3. ³Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA

Correspondence: Professor J Yanai, The Ross Laboratory for Studies in Neural Birth Defects, Department of Anatomy and Cell Biology, Hebrew University-Hadassah Medical School, Box 12272, Jerusalem 91120, Israel. E-mail: yanai@md.huji.ac.il

Received 10 January 2007; Revised 9 August 2007; Accepted 10 August 2007; Published online 18 September 2007.

Abstract

Grafting of neural progenitors has been shown to reverse a wide variety of neurobehavioral defects. While their role of replacing injured cells and restoring damaged circuitries has been shown, it is widely accepted that this cannot be the only mechanism, as therapy can occur even when an insufficient number of transplanted cells are found. We hypothesized that one major mechanism by which transplanted neural progenitors exert their therapeutic effect is by enhancing endogenous cells production. Consequently, in an allographic model of transplantation, prenatally heroin-exposed genetically heterogeneous (HS) mice were made defective in their hippocampal neurobehavioral function by exposing their mothers to heroin (10 mg kg^-1 heroin on gestation days 9–18). Hippocampal damage was confirmed by deficient performance in the Morris maze (P<0.009), and decreased production of endogenous cells in the dentate gyrus by 39% was observed. On postnatal day 35, they received an HS-derived neural progenitors transplant followed by repeated bromodeoxyuridine injections. The transplant returned endogenous cells production to normal levels (P<0.006) and reversed the behavioral defects (P<0.03), despite the fact that only 0.0334% of the transplanted neural progenitors survived and that they differentiated mainly to astrocytes. An immunological study demonstrated the presence of macrophages and T cells as a possible explanation for the paucity of the transplanted cells. This study suggests one mechanism for the therapeutic action of neural progenitors, the enhancement of the production of endogenous cells, pointing to future clinical applications in this direction by use of neural progenitors or by analogous cell-inducing techniques.