Corrigendum: Purinergic signaling systems across comparative models of spinal cord injury

Correction: Neural Regeneration Research, November, 2022; doi: https://doi.org/10.4103/1673-5374.338993. Due to the editorial office’s error, a number of corrections were not made to the article prior to its publication; the publisher wishes to apologize to all concerned. The corrected version of the article appears in full below. Review Purinergic signaling systems across comparative models of spinal cord injury Eva E. Stefanova, Angela L. Scott* https://doi.org/10.4103/1673-5374.338993 Date of submission: August 20, 2021 Date of decision: September 29, 2021 Date of acceptance: October 25, 2021 Date of web publication: March 23, 2022 Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada *Correspondence to: Angela L. Scott, PhD, [email protected] Abstract Within the last several decades, the scientific community has made substantial progress in elucidating the complex pathophysiology underlying spinal cord injury. However, despite the many advances using conventional mammalian models, both cellular and axonal regeneration following spinal cord injury have remained out of reach. In this sense, turning to non-mammalian, regenerative species presents a unique opportunity to identify pro-regenerative cues and characterize a spinal cord microenvironment permissive to re-growth. Among the signaling pathways hypothesized to be dysregulated during spinal cord injury is the purinergic signaling system. In addition to its well-known role as energy currency in cells, ATP and its metabolites are small molecule neurotransmitters that mediate many diverse cellular processes within the central nervous system. While our understanding of the roles of the purinergic system following spinal cord injury is limited, this signaling pathway has been implicated in all injury-induced secondary processes, including cellular death, inflammation, reactive gliosis, and neural regeneration. Given that the purinergic system is also evolutionarily conserved between mammalian and non-mammalian species, comparisons of these roles may provide important insights into conditions responsible for recovery success. Here, we compare the secondary processes between key model species and the influence of purinergic signaling in each context. As our understanding of this signaling system and pro-regenerative conditions continues to evolve, so does the potential for the development of novel therapeutic interventions for spinal cord injury. Key Words: cell death; differentiation; glia; inflammation; neurogenesis; proliferation; purinergic signaling; reactive gliosis; regeneration; spinal cord injury; teleost Introduction Following spinal cord injury (SCI), functional recovery is extremely limited in adult mammals. This lack of recovery is reflective of the collective failure of lesioned axons to re-grow and damaged neurons to regenerate in the spinal cord following the primary trauma. The result is a debilitating reduction in sensorimotor function and quality of life in approximately 770,000 people of all ages, genders, ethnicities, and socioeconomic backgrounds each year (Kumar et al., 2018). In contrast to the devastating consequence of spinal cord injury in mammals, several non-mammalian species within the vertebrate subphylum have a much higher regenerative capacity within the central nervous system (CNS) and can undergo functional recovery in adulthood. Although the underlying source of the regenerative differences between regenerating and non-regenerating species is not fully understood, landmark work studying these comparisons has begun to shed light on the defining features and characteristics of successful regeneration and functional recovery. While all vertebrates have a certain degree of regenerative capacity in the CNS during development, by adulthood, this plasticity is highly restricted in birds and mammals. Limitations to regeneration are largely attributed to a secondary cellular insult involving acute and chronic processes of neuroinflammation, cellular death, reactive gliosis, and axonal degeneration within the spinal cord following injury. The species who maintain some regenerative ability beyond development appear to be members of the more primitive classes of vertebrates including Agnatha (jawless fish), Reptilia, Amphibia, and Osteichthyes (teleost fish), suggesting that regeneration is an ancestral trait that is diminished over evolution. Indeed, zebrafish (Danio rerio) (Reimer et al., 2008; Hui et al., 2010; Goldshmit et al., 2012), sea lamprey (Petromyzon marinus) (Herman et al., 2018), axolotl (Ambystoma mexicanum) (Sabin et al., 2019), knifefish (Apteronotus leptorhynchus) (Vitalo et al., 2016), goldfish (Carassius auratus) (Takeda et al., 2015, 2017), and newts (Notophthalmus viridescens) (Zukor et al., 2011) are all non-mammalian vertebrate species with a preserved high degree of CNS regeneration capacity. One particularly distinct difference between these select species and mammals is the ability to undergo injury-induced neurogenesis following SCI (Reimer et al., 2008; Takeda et al., 2008; Sirbulescu et al., 2009; Hui et al., 2010; Goldshmit et al., 2012; Joven and Simon, 2018). In adult zebrafish for instance, newly generated motoneurons are integrated into the existing circuitry to restore locomotion below the level of the lesion within 6 weeks post SCI (Reimer et al., 2008). A further understanding of the neuroprotective and regenerative mechanisms in these species will help to uncover the molecular cues associated with limiting secondary injury and promoting regeneration and recovery. One evolutionarily conserved family of signaling factors involved in various aspects of secondary responses to injury in both regenerative and non-regenerative species is the purinergic signaling system. Purinergic signaling has been associated with regulating cellular proliferation, migration, differentiation, and survival during development and in adulthood (Burnstock and Ulrich, 2011; Gomez-Villafuertes, 2016; Oliveira et al., 2016; Ribeiro et al., 2016). Purines and pyrimidines, such as adenosine triphosphate (ATP) and uridine triphosphate (UTP) respectively, along with their metabolites, function as extracellular signaling molecules that mediate cellular communication via purinergic receptors (Burnstock, 2018). These receptors have extensive protein families, including metabotropic adenosine A1, A2A, A2B, A3, ionotropic nucleotide P2X1–7, and metabotropic nucleotide P2Y1, 2, 4, 6, 11, 12, 13, 14 receptors (Burnstock, 2018). Following mammalian SCI, Wang et al. (2004) found that extracellular ATP is elevated within the lesion site for several hours, thus suggesting a role for injury-induced purinergic signaling. Since then, it has been proposed that ATP may function as an early distress signal within the tissue that is involved in the chemoattraction of various cell types and induction of cell reactivity and proliferation (Haynes et al., 2006; Suadicani et al., 2006; Dou et al., 2012; Shinozaki et al., 2017; Quintas et al., 2018; Kobayakawa et al., 2019). While accumulating evidence supports a role for purinergic signaling in the CNS injury response of mammals, how this complex system may be adapted in regeneratively competent, non-mammalian species is less clear. Here, we review on the role of purinergic signaling during each phase of the secondary injury [(1) cellular death, (2) neuroinflammation, (3) reactive gliosis, and (4) axonal degeneration] and examine the variations of this signaling system in regenerative and non-regenerative species. Search Strategy and Selection Criteria Bibliographic citation databases searched include PubMed and Google Scholar. Search terms include: P1 receptors, P2X receptors, P2Y receptors, teleost spinal cord injury, mammalian spinal cord injury, P1/P2X/P2Y and inflammation, P1/P2X/P2Y and cell death, P1/P2X/P2Y and gliosis, P1/P2X/P2Y and neurogenesis, P1/P2X/P2Y axonal regeneration. All searches were completed between 2020–2021. Cell Death Following an initial mechanical trauma to the spinal cord, secondary injury is associated with a wave of cell death that exacerbates damage and expands the lesion size (Figure 1). In rodent models of SCI, the predominant mechanism of neuronal cell death is necrosis. This begins almost immediately, peaks at 1–2 days, and continues for months (Hassannejad et al., 2018; Kwiecien et al., 2020). Glial cells similarly reach peak levels of necrotic cell death between 1–2 days following SCI (Kwiecien et al., 2020). Meanwhile, apoptosis of neurons peaks first and at days (Hassannejad et al., 2018). In it peaks within and continues for weeks et al., and in it peaks at et al., 2019). mechanisms of secondary cell death include and et al., 2016; et al., the secondary cellular injury response following mammalian spinal cord primary mechanical trauma is by cell death, inflammation, reactive gliosis, and axonal These successful regeneration and sensorimotor recovery. with with and regeneratively species as to cell death following a CNS injury (Figure et al., a response that to further apoptosis is and 2008). The of secondary cell death in regenerative species that some degree of cell death following injury may be and for successful CNS regeneration. Indeed, of apoptosis following in adult zebrafish and et al., of cell death within the first post injury found to regeneration following in the et al., However, the of cell death between regenerative and non-regenerative species. In apoptosis peaks between post SCI and days et al., 2009; Hui et al., The of weeks post SCI in et al., and weeks in et al., that regenerative failure in mammals may not be by the of secondary cell death, by its necrotic and the secondary cellular injury response following non-mammalian spinal cord primary mechanical trauma cell death, inflammation, reactive gliosis, neurogenesis, and axonal regeneration. These within weeks and recovery and of function in non-mammalian with

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