Functional integration of human neural precursor cells in mouse cortex.

Fu-Wen Zhou,Hildabelis Martinez-Diaz,Brent A Reynolds,Jeff M Fortin,Steven N Roper,Lung-Ji Chang,Huan-Xin Chen,Thomas E Lane

doi:10.1371/journal.pone.0120281

Abstract

This study investigates the electrophysiological properties and functional integration of different phenotypes of transplanted human neural precursor cells (hNPCs) in immunodeficient NSG mice. Postnatal day 2 mice received unilateral injections of 100,000 GFP+ hNPCs into the right parietal cortex. Eight weeks after transplantation, 1.21% of transplanted hNPCs survived. In these hNPCs, parvalbumin (PV)-, calretinin (CR)-, somatostatin (SS)-positive inhibitory interneurons and excitatory pyramidal neurons were confirmed electrophysiologically and histologically. All GFP+ hNPCs were immunoreactive with anti-human specific nuclear protein. The proportions of PV-, CR-, and SS-positive cells among GFP+ cells were 35.5%, 15.7%, and 17.1%, respectively; around 15% of GFP+ cells were identified as pyramidal neurons. Those electrophysiologically and histological identified GFP+ hNPCs were shown to fire action potentials with the appropriate firing patterns for different classes of neurons and to display spontaneous excitatory and inhibitory postsynaptic currents (sEPSCs and sIPSCs). The amplitude, frequency and kinetic properties of sEPSCs and sIPSCs in different types of hNPCs were comparable to host cells of the same type. In conclusion, GFP+ hNPCs produce neurons that are competent to integrate functionally into host neocortical neuronal networks. This provides promising data on the potential for hNPCs to serve as therapeutic agents in neurological diseases with abnormal neuronal circuitry such as epilepsy.

Highlights

Proper brain function requires a strict balance between neuronal excitation and inhibition [1,2]
For firing patterns of GFP+ cells in response to depolarizing current, putative PV-ir cells displayed high frequency repetitive discharges without adaptation, putative CR-ir cells fired an initial spike burst followed by irregularly spaced Action potential (AP), and putative SS-ir cells exhibited lower frequency firing with adaptation (Fig. 1)
Recorded GFP+ pyramidal cells were characterized by their pyramidal soma, a single long, thick apical dendrite (Fig. 5), and slower firing rates with obvious frequency adaptation (Fig. 1) that were distinguished from recorded GFP+ interneurons

Summary

Introduction

Proper brain function requires a strict balance between neuronal excitation and inhibition [1,2]. Previous studies have revealed that transplanted animal and human embryonic stem cell-derived GABAergic neuron precursors can attenuate behavioral deficits in rodent models of human disorders [2, 5, 7, 17, 23, 30,31,32]. The major goal of human stem cell transplantation for neurodegenerative disorders is to elucidate its role in disease treatment To achieve this goal it is essential to investigate both the specific phenotypes of transplanted stem cells and the ability of these cells to influence the behavior of the host neural circuitry in animal studies

Results

Discussion

Conclusion