Does Electrical Stimulation Enhance the Capacity of Neural Stem Cell Transplants to Improve Recovery from Chronic Spinal Cord Injury

University Of Washington, Seattle WA

Investigators

Abstract

Project Summary/Abstract Stem cell (StC) treatments have enormous potential to restore function after chronic spinal cord injury (SCI) due to their regenerative potential. These cells provide trophic factors that support neurite outgrowth and replace lost cells through differentiation into neurons and glia. Despite many encouraging advances, StC therapies still face severe limitations, including the negative effects of the lesion environment on transplanted cells and insufficient integration of differentiated neurons and glia into existing neural circuits. Consequently, StC therapies have produced only modest behavioral improvement in animal studies and human trials for SCI. Several forms of electrical stimulation (ES) have led to improved function after SCI in animals and humans with partial SCIs. These include repetitive stimulus pulses delivered epidurally or intraspinally, and with either open- or closed-loop protocols. These approaches have led to improved motor and autonomic function by promoting neural plasticity in spinal and descending pathways. Electrical polarizations using either direct or oscillating field stimulation can reduce inflammatory responses, facilitate myelin regeneration, enhance neuronal excitability, and cause directed axonal growth. The effects of StC and ES therapies seem complementary. However, there are few studies that have combined StC transplants and any form of spinal ES as a treatment for SCI, and therefore it is not known if the two approaches can magnify or interfere with the rehabilitative benefits and potential of each. The objective of the proposed project is to begin an exploration of the interaction of these two promising treatments. The study will begin a new line of research whose long-term goal is to develop novel combinatorial therapies that will advance clinical practice and improve the quality of life of individuals living with SCI. We will study a rat model of contusive injury of the cervical spinal cord, and transplant rat embryonic neural stem cells derived from the spinal cord since these cells adopt normal motor and sensory fates and support regeneration in animals with SCI. We will apply three different forms of ES that in previous studies have improved the behavior of animals and/or humans with chronic SCI. Our primary goal will be to determine if ES supports the survival and differentiation of StCs, enhances the growth over long distances and synapse formation of axons of new neurons, and promotes the integration of the differentiated cells into spared neural circuits. We will also investigate whether the combined treatments produce improvement in the rats’ motor performance, although the scope of an R21 project will limit our ability to study this issue in depth. If the project is successful, future studies will focus on whether combined StC-ES therapies provide improvements in function beyond that achieved by each treatment alone.