Biology and MB&B

Graduate Student Career Retreat 2008

Name:  Nathaniel Hartman       

   Lab:  Laura Grabel [Biology]

 Abstract

YC5 embryonic stem cell-derived neural progenitor migration

is guided by the chemokine SDF-1α following seizures in SCID mice

Nathaniel W. Hartman, Joe E. Carpentino², Kristi A. LaMonica¹,

Gloster Aaron¹, Janice R. Naegele¹, Laura B. Grabel^1
1Biology Department, Wesleyan University,  ²University of Florida

Embryonic stem cell derived neural progenitors (ESNPs) can be readily derived in vitro and are a potential source of cells for treatment of neurodegenerative diseases. Adult SCID mice treated with the chemoconvulsant kainic acid (KA) exhibit hippocampal sclerosis and upregulate adult neurogenesis following seizures. Using this model of temporal lobe epilepsy, we transplanted ESNPs that express enhanced yellow fluorescent protein (EYFP) into the CA3 region of KA-treated mice. Following transplantation, ESNPs migrated and incorporated into the dentate gyrus (DG), a niche for endogenous adult neural stem cells, where they differentiated into DG-specific cell types, including granule neurons. Whole cell patch clamp recordings suggest that transplanted cells exhibit region-specific physiological properties in the host hippocampus. Transplanted cells recorded in the dentate granule cell layer exhibited spike train accomodation and action potential characteristics similar to endogenous dentate granule neurons. Our preliminary electrophysiological data suggest that transplanted ESNPs functionally incorporate into the host hippocampal circuitry. Our previous data suggest that seizure-induced changes in the host environment promote migration of transplanted ESNPs. Based upon a demonstrated role in dentate granule cell migration during development, we propose that the chemokine SDF-1a directs ESNP migration to the dentate gyrus. We show that the SDF-1a receptor CXCR4 is expressed by ESNPs, and that SDF-1a acts as a chemoattractant without altering the proliferation or differentiation of ESNPs in vitro. A pharmacological inhibitor of CXCR4, AMD3100, blocks SDF-1a-mediated migration in vitro. In addition, SDF-1a is upregulated in the hippocampus following seizures. When AMD3100 was administered in vivo by osmotic minipump, transplanted ESNPs failed to migrate and incorporate into the dentate gyrus, suggesting that SDF-1a contributes to ESNP migration following transplant to the hippocampus.