Abstract
The aim of the present report was to investigate whether, in the mammalian spinal cord, cell death induced by transient excitotoxic stress could trigger activation and proliferation of endogenous neuroprogenitor cells as a potential source of a lesion repair process and the underlying time course. Because it is difficult to address these issues in vivo, we used a validated model of spinal injury based on rat organotypic slice cultures that retain the fundamental tissue cytoarchitecture and replicate the main characteristics of experimental damage to the whole spinal cord. Excitotoxicity evoked by 1 h kainate application produced delayed neuronal death (40%) peaking after 1 day without further losses or destruction of white matter cells for up to 2 weeks. After 10 days, cultures released a significantly larger concentration of endogenous glutamate, suggesting functional network plasticity. Indeed, after 1 week the total number of cells had returned to untreated control level, indicating substantial cell proliferation. Activation of progenitor cells started early as they spread outside the central area, and persisted for 2 weeks. Although expression of the neuronal progenitor phenotype was observed at day 3, peaked at 1 week and tapered off at 2 weeks, very few cells matured to neurons. Astroglia precursors started proliferating later and matured at 2 weeks. These data show insult-related proliferation of endogenous spinal neuroprogenitors over a relatively brief time course, and delineate a narrow temporal window for future experimental attempts to drive neuronal maturation and for identifying the factors regulating this process.
Highlights
The adult spinal cord is derived from the caudal neural tube, which is initially composed of heterogeneous neuroepithelial cells surrounding a central lumen with distinct proliferative and differentiation potential.[10]
The aims of the present study were to assess: (1) how long cell death continued beyond the first 24 h; (2) whether any intrinsic progenitor cells could proliferate in response to excitotoxicity; (3) what their fate could be; and (4) whether they might restore the network ability to release the main excitatory transmitter glutamate essential for locomotor network function.[18]
Previous experiments have indicated that kainate induces delayed excitotoxic cell death but is a potent tool to evoke the release of endogenous glutamate that is a useful, simple index of spinal network activity in culture.[19]
Summary
The adult spinal cord is derived from the caudal neural tube, which is initially composed of heterogeneous neuroepithelial cells surrounding a central lumen with distinct proliferative and differentiation potential.[10]. Received 03.9.13; revised 26.9.13; accepted 27.9.13; Edited by A Verkhratsky access to the lesion evolution at serial time points after an acute SCI always produced, for ethical reasons, under general anesthesia that might partially constrain damage severity To partially circumvent these problems, organotypic spinal cultures, that retain the basic spinal cytoarchitecture, have been used as an in vitro model of acute SCI induced by transient excitotoxicity with consequent moderate loss of neurons, minimal glial damage and strong impairment in endogenous glutamate release 24 h later.[16,17] The short duration of excitotoxic stress is suggested to mimic the timeframe of clinical injuries usually treated with minimal delay in intensive care to restore metabolic dysfunction. The aims of the present study were to assess: (1) how long cell death continued beyond the first 24 h; (2) whether any intrinsic progenitor cells could proliferate in response to excitotoxicity; (3) what their fate could be; and (4) whether they might restore the network ability to release the main excitatory transmitter glutamate essential for locomotor network function.[18]
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