Integration of Transplanted Neural Precursors with the Injured Cervical Spinal Cord

Abstract

Cervical spinal cord injuries (SCI) result in devastating functional consequences, including respiratory dysfunction. This is largely attributed to the disruption of phrenic pathways, which control the diaphragm. Recent work has identified spinal interneurons as possible contributors to respiratory neuroplasticity. The present work investigated whether transplantation of developing spinal cord tissue, inherently rich in interneuronal progenitors, could provide a population of new neurons and growth-permissive substrate to facilitate plasticity and formation of novel relay circuits to restore input to the partially denervated phrenic motor circuit. One week after a lateralized, C3/4 contusion injury, adult Sprague-Dawley rats received allografts of dissociated, developing spinal cord tissue (from rats at gestational days 13-14). Neuroanatomical tracing and terminal electrophysiology was performed on the graft recipients 1 month later. Experiments using pseudorabies virus (a retrograde, transynaptic tracer) revealed connections from donor neurons onto host phrenic circuitry and from host, cervical interneurons onto donor neurons. Anatomical characterization of donor neurons revealed phenotypic heterogeneity, though donor-host connectivity appeared selective. Despite the consistent presence of cholinergic interneurons within donor tissue, transneuronal tracing revealed minimal connectivity with host phrenic circuitry. Phrenic nerve recordings revealed changes in burst amplitude after application of a glutamatergic, but not serotonergic antagonist to the transplant, suggesting a degree of functional connectivity between donor neurons and host phrenic circuitry that is regulated by glutamatergic input. Importantly, however, anatomical and functional results were variable across animals, and future studies will explore ways to refine donor cell populations and entrain consistent connectivity.

The Neuroplastic and Therapeutic Potential of Spinal Interneurons in the Injured Spinal Cord

“…The neuroplastic potential of SpINs after injury or disease makes these cells an attractive target for therapeutic interventions. Such interventions include activity-based therapies , such as exercise and rehabilitation [51, 71] (reviewed in [72]); neural interfacing , such as epidural stimulation [51] (reviewed in [73–75]); and cell therapies, such as transplantation of SpIN precursors [76–78]. The current challenge is to understand how to access, stimulate, and/or enhance these spinal networks, establishing sustainable excitability of damaged/denervated circuits.…”

“…Transplantation of neural precursor cells obtained from i) acutely dissected fetal spinal cord tissue (FSC), ii) FSC’s more selected in vitro expanded counterpart (lineage restricted neural progenitor cells (NPCs) devoid of extracellular and non-neural components), or iii) even neural stem cells, have been shown to survive, integrate with the injured adult spinal cord, and alter functional outcome (reviewed in [83, 85–88]). Despite the therapeutic benefit seen with transplantation, some caveats remain [78] (reviewed in [85]). Among these caveats is donor heterogeneity.…”

Application of stem cells and chitosan in the repair of spinal cord injury

“…Among these two stem cells, NSCs seem to be advantageous in regenerative medicine approach for curing SCI and have the potential of migrating, proliferating and differentiating into neurons and glial cells (Curtis et al, 2018;Carelli et al, 2014;Liu et al, 2019). Thus, NSCs have been chosen as the vintage stem cell source for curing SCI without serious adverse events (Zholudeva et al, 2019;Spruance et al, 2018;Bagher et al, 2018).On the other hand, MSCs have also attracted attention significantly as an another stem cell candidate to provide regenerated cells in the injury tissues than the NSCs, due to the ease of harvest, high proliferation and autologous transplantation properties (Gruber et al, 2012). Investigation on MSCs transplantation therapy has been focused on multimodal therapeutic effects in SCI, including the remyelination of axon fibers (Morita et al, 2016), axonal sprouting (Sasaki et al, 2009;Kuh et al, 2005) and neuroprotection (Morita et al, 2016;Sasaki et al, 2009).…”

Transplanting Cells for Spinal Cord Repair: Who, What, When, Where and Why?

“…However, treatment during this stage when plasticity is ongoing may enable better, if not most optimal, growth and integration between donor and host. References: 8,9,22,43,75,88,90 Chronic >4-12 weeks Goal: Cells that may facilitate delayed repair and contribute to additional plasticity. Modify the existing glial scar at the lesion site, and promote vascularization.…”