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Preferential Regeneration of Hindlimb Corticospinal Axons into a Neural Progenitor Cell Graft After Cervical Spinal Cord Injury

  • Author(s): Kulinich, Daniel
  • Advisor(s): Tuszynski, Mark H
  • Leutgeb, Stefan
  • et al.
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Abstract

An estimated 300,000 people suffer from spinal cord injury (SCI) in the US, costing about $9.7 billion annually (French et al., 2007). Quadriplegic patients, comprising nearly 60% of SCI cases (National Spinal Cord Injury Statistics Center), list the loss of motor control, especially hand function, as the primary impediment to their daily lives. To overcome this loss, it is necessary for the corticospinal tract (CST) – the main tract controlling voluntary motor movement – to regenerate and reform functional synapses. One method to reverse such dysfunctions is to use neural progenitor cell (NPC) grafts which recapitulate lost neural tissue and promote axon regeneration, ultimately serving as a relay for neural signals.

Previously, our lab demonstrated functional recovery and robust CST regeneration into rat embryonic day 14 (E14) NPC grafts placed into cervical and thoracic SCI sites (Kadoya et al., 2016). CST regeneration into a cervical graft has the potential to restore voluntary motor function, especially hand function, for quadriplegic patients. However, whether forelimb, hindlimb or both CST populations regenerate into a cervically placed NPC graft, is unknown. Because both populations are axotomized, we hypothesized that both forelimb and hindlimb projecting CST axons would regenerate into a mid-cervically placed NPC graft. Here, we used a Cre-mediated intersectional viral approach to selectively label either forelimb or hindlimb projecting CST axons. All rats were then subjected to a C3 dorsal column lesion and received an E14 spinal cord-derived NPC graft. Surprisingly, we found preferential regeneration of hindlimb CST axons into the C3 NPC grafts, with sparse forelimb axon regeneration. This creates a functional mismatch: hypothetically, to achieve optimal functional recovery, CST axons controlling the forelimbs instead of the hindlimbs would regenerate into the lesion to form functional synapses. An examination of mechanisms underlying this selective regeneration is necessary, and will contribute to optimizing corticospinal regeneration after SCI.

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This item is under embargo until June 20, 2020.