Video and Abstract:
Impaired breathing is a devastating consequence of cervical spinal cord injury (SCI) that increases morbidity and the risk of mortality. Injuries at high-to-mid cervical levels (C1-4) result in the most severe deficits as the phrenic motor circuitry – controlling the diaphragm – is directly compromised, typically resulting in dependence on assisted ventilation. While there is mounting evidence for spontaneous respiratory improvement, the extent of recovery – or functional plasticity – remains limited. Thus, there is a need to develop therapeutic strategies for enhancing repair and recovery of respiratory pathways.
Our ongoing research aims to elucidate spinal and supraspinal changes that may influence respiration post-SCI, and assess whether treatments can harness ongoing neuroplasticity to improve function post-injury. These studies have identified that spinal interneurons represent a potential therapeutic target for enhancing plasticity and recovery of phrenic motor function. With a particular focus on the phrenic motor system, the goal of the present work is to assess whether transplantation of neural precursor and stem cells (NPCs/NSCs) can facilitate repair of the injured adult rat cervical spinal cord and promote lasting, functional recovery. We hypothesize that spinally derived NPCs, rich in interneuronal precursors, will provide a source of neurons that facilitate a novel neuronal relay capable of restoring input to phrenic motoneurons.
Adult, female Sprague-Dawley rats (~250g) received lateralized C3/4 contusions (200 kilodynes, Infinite Horizons Pneumatic Impactor). One week post-injury, NPCs derived from developing rat spinal cord (E13.5 Sprague Dawley or E13.5 Fisher rat, expressing green fluorescent protein) were injected directly into the injury cavity (~1 million cells). Transplanted animals are compared against injured, untreated animals. Four weeks or one year later, a transsynaptic, retrograde tracer (pseudorabies virus) was delivered to the ipsilateral hemidiaphragm or directly into the transplant. Tracing revealed synaptic integration between donor neurons and host phrenic circuitry at one month following transplantation. However, evidence for this connectivity is lost at one year following transplantation. Terminal electrophysiology analysis revealed variable phrenic and diaphragm recovery at both time points in those animals that received NPC transplants following cervical contusion injury. These ongoing studies are providing insight into the therapeutic potential for NPC therapy in the injured spinal cord.
Authors: *V. SPRUANCE1, L. ZHOLUDEVA2, K. NEGRON3, T. BEZDUDNAYA3, M. LANE3; 1Neurobio. and Anat., Drexel Univ. Col. of Med., Philadelphia, PA; 2Drexel Univ., Philadelphia, PA; 3Drexel Univ., Philadelphia, PA
Disclosures: V. Spruance: None. L. Zholudeva: None. K. Negron: None. T. Bezdudnaya: None. M. Lane: None.
Session 523 – Spinal Cord injury: Therapeutic Development