Survival, differentiation, and reversal of heroin neurobehavioral teratogenicity in mice by transplanted neural stem cells derived from embryonic stem cells

Meital Kazma, Michal Izrael, Michel Revel, Judith Chebath, Joseph Yanai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

Cell therapies in animal models of neurobehavioral defects are normally derived from neural stem cells (NSC) of the developing cortex. However, the clinical feasibility of NSC therapies would be greatly improved by deriving transplanted cells and from a tissue culture source that is self-renewing, containing cells that potentially differentiate into the desired neuronal phenotypes. These cultures can be engineered to contain the appropriate factors to support their therapeutic action and likely evoke lesser immune reactions. In the current study, we employed our model of mice neurobehaviorally impaired via prenatal exposure to heroin, to test the therapeutic efficacy of NSC derived from murine embryonic stem cells culture (ESC). The culture contained elongated bipolar cells, 90% of which are positive for nestin, the intermediate filament protein found in neural precursors. After removal of growth factors, the NSC differentiated into neurons (34.0% 6 3.8% NF-160 positive), including cholinergic cells (ChAT positive), oligodendrocytes (29.9% 6 4.2% O4), and astrocytes (36.1% 6 4.7% GFAP positive). Rreverse transcriptase polymerase chain reaction (RTPCR) analysis confirmed the immunocytochemical findings. Mice made deficient in Morris maze behavior by prenatal heroin exposure (10 mg/kg heroin S.C. on gestational days 9-18) were transplanted into the hippocampus region on postnatal day 35 with the ES culture-derived NSC (ES-NSC) labeled with dialkylcarbocyanine (Dil) cell tracker. Dil1 and NF1601 cells were detected in the hippocampal region (50% 6 8% survival). The transplantation completely restored maze performance to normal; e.g., on day 3, transplantation improved the behavior from the deficient level of 11.9-sec latency to the control of 5.6-sec latency (44.5% improvement).

Original languageEnglish
Pages (from-to)315-323
Number of pages9
JournalJournal of Neuroscience Research
Volume88
Issue number2
DOIs
StatePublished - 1 Feb 2010

Keywords

  • ES culture
  • Heroin
  • Mice
  • Morris maze
  • Neural stem cell therapy
  • Neural stem cells
  • Prenatal exposure
  • Transplantation

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