Letter to the Editor Rebuttal to Qi et al. (2025): “Alpha 9 integrin in spinal cord repair: a critical appraisal of mechanisms, circuitry, and translational potential”

Tissue repair in the embryonic rat spinal cord following exposure to N-ethyl-N-nitrosourea

In response to the groundbreaking study by Stepankova et al. (Acta Neuropathol Commun 13:89, 2025) demonstrating that activated α9 integrin enables sensory axon regeneration after spinal cord injury, this letter provides a critical perspective on the mechanistic underpinnings and translational implications of their findings. While acknowledging the significance of identifying α9 integrin as a potent pro-regenerative driver, we highlight several areas requiring deeper investigation. Specifically, we interrogate the precise ligand-receptor interactions within the inhibitory injury environment and potential crosstalk with inhibitory signaling pathways. Furthermore, we raise critical concerns regarding the long-term stability and functional specificity of the regenerated sensory circuits, emphasizing the risk of maladaptive synaptogenesis leading to neuropathic pain. Finally, we contextualize these findings within the challenges of clinical translation, arguing that the efficacy of this approach must be validated in more severe, contusive injury models that better recapitulate the human pathology. This critical analysis aims to frame the essential next steps required to transform this compelling biological discovery into a viable therapeutic strategy.

Administration of hypoxic pretreated adipose-derived mesenchymal stem cell exosomes promotes spinal cord repair after injury via delivery of circ-Astn1 and activation of autophagy.

Is placental growth factor involved in spinal cord repair?

The limited ability for axonal repair after spinal cord injury underlies long-term functional impairment. Dual leucine-zipper kinase [DLK; MAP kinase kinase kinase 12; MAP3K12] is an evolutionarily conserved MAP3K implicated in neuronal injury signaling from Caenorhabditis elegans to mammals. However, whether DLK or its close homolog leucine zipper kinase (LZK; MAP3K13) regulates axonal repair in the mammalian spinal cord remains unknown. Here, we assess the role of endogenous DLK and LZK in the regeneration and compensatory sprouting of corticospinal tract (CST) axons in mice of both sexes with genetic analyses in a regeneration competent background provided by PTEN deletion. We found that inducible neuronal deletion of both DLK and LZK, but not either kinase alone, abolishes PTEN deletion-induced regeneration and sprouting of CST axons, and reduces naturally-occurring axon sprouting after injury. Thus, DLK/LZK-mediated injury signaling operates not only in injured neurons to regulate regeneration, but also unexpectedly in uninjured neurons to regulate sprouting. Deleting DLK and LZK does not interfere with PTEN/mTOR signaling, indicating that injury signaling and regenerative competence are independently controlled. Together with our previous study implicating LZK in astrocytic reactivity and scar formation, these data illustrate the multicellular function of this pair of MAP3Ks in both neurons and glia in the injury response of the mammalian spinal cord.SIGNIFICANCE STATEMENT Functional recovery after spinal cord injury is limited because of a lack of axonal repair in the mammalian CNS. Dual leucine-zipper kinase (DLK) and leucine zipper kinase (LZK) are two closely related protein kinases that have emerged as regulators of neuronal responses to injury. However, their role in axonal repair in the mammalian spinal cord has not been described. Here, we show that DLK and LZK together play critical roles in axonal repair in the mammalian spinal cord, validating them as potential targets to promote repair and recovery after spinal cord injury. In addition to regulating axonal regeneration from injured neurons, both kinases also regulate compensatory axonal growth from uninjured neurons, indicating a more pervasive role in CNS repair than originally anticipated.

Strategies for spinal cord repair after injury: A review of the literature and information

To study the effect of fetal rat spinal cord tissue transplants with different gestational days on the repair of transected spinal cord in adult rats, fetal rat spinal cord tissue obtained on gestational day 12, 13 and 14 was implanted to the cavity in the transected spinal cord in adult rats. The routine histologic examinations were performed postoperatively. The results revealed a total graft survival rate of 82.5 % . The transplants could have a better growth and differentiation, and integrate with the recipient spinal cord tissues at the injured sites. The transplant in gestation day 13 may be the best donor tissue because it had the greatest potential for promoting the repair of the transected host spinal cord. Key words: Spinal-cord injuries; Embryo; Spinal-cord; Transplantation

Zebrafish Spinal Cord Repair Is Accompanied by Transient Tissue Stiffening

Research over the past decade has demonstrated that, under some circumstances, structural reorganization of the CNS, including the spinal cord, can occur after injury, raising hopes that spinal cord repair associated with functional recovery, although a daunting goal, may not be an unreachable one. This brief review dis cusses recent approaches to this problem: use of neurotrophins and the rerouting of axons within the transected spinal cord from white matter to gray matter through nerve grafts, and the transplantation of exogenous myelin-forming glial cells to spinal cord tracts in which myelin has been lost. Results available to date indicate that, in models mimicking some aspects of human spinal cord injury, these approaches may yield anatomical repair that is associated with partial restoration of physiological and behavioral func tion. Many important questions remain unanswered. Nevertheless, although the clinical goal of repairing spinal cords in humans is a very challenging one, results in animal models suggest that spinal cord repair is a realistic objective and provide a glimpse of what is likely to be a period of rapid progress. NEURO SCIENTIST 3:263-269, 1997

Gait analysis of adult paraplegic rats after spinal cord repair.

Drug-eluting microfibrous patches for the local delivery of rolipram in spinal cord repair

Over the past 2 decades, the biological understanding of the mechanisms underlying structural and functional repair of the injured central nervous system has strongly increased. This has resulted in the development of multiple experimental treatment strategies with the collective aim of enhancing and surpassing the limited spontaneous recovery occurring in animal models and ultimately humans suffering from spinal cord or brain injuries. Several of these experimental treatments have revealed beneficial effects in animal models of spinal cord injury. With the exception of neurorehabilitative therapies, however, therapeutic interventions that enhance recovery are currently absent within the clinical realm of spinal cord injury. The present review surveys the prospects and challenges in experimental and clinical spinal cord repair. Major shortcomings in experimental research center on the difficulty of closely modeling human traumatic spinal cord injury in animals, the small number of investigations done on cervical spinal injury and tetraplegia, and the differences in lesion models, species, and functional outcome parameters used between laboratories. The main challenges in the clinical field of spinal cord repair are associated with the standardization and sensitivity of functional outcome measures, the definition of the inclusion/exclusion criteria for patient recruitment in trials, and the accuracy and reliability of an early diagnosis to predict subsequent neurological outcome. Research and clinical networks were recently created with the goal of optimizing animal studies and human trials. Promising clinical trials are currently in progress. The time has come to translate the biologic-mechanistic knowledge from basic science into efficacious treatments able to improve the conditions of humans suffering from spinal cord injury.

Myostatin is a negative regulator of adult neurogenesis after spinal cord injury in zebrafish.

Spinal cord injury (SCI) triggers a series of endogenous processes, including neuroinflammation and reactive astrogliosis, which may contribute to the failure of neural regeneration and functional recovery. In the present study, the effect of ethyl pyruvate on spinal cord repair was explored. Functional assessment and histological analyses of astrogliosis, neuroinflammation, neuronal survival and axonal regeneration were performed to investigate the effects of ethyl pyruvate (0.086, 0.215, 0.431 or 0.646 mmol·kg(-1) ·day(-1) ) on spinal cord repair in a rat model of SCI. The effect of ethyl pyruvate (5, 10 or 15 mM) on astrocytic activation was also evaluated in an in vitro'scratch-wound' model. Functional assessment showed evident improvement of behavioural functions in the ethyl pyruvate-treated rats. Reactive astrogliosis was significantly inhibited in vivo, after injection of ethyl pyruvate (0.431 mmol·kg(-1) day(-1) ), and in vitro'scratch-wound' model in the presence of 10 or 15 mM ethyl pyruvate. The difference between effective concentration in vitro and in vivo suggests that the inhibitory effect of ethyl pyruvate on astrogliosis in damaged spinal cord is indirect. In addition, ethyl pyruvate (0.431 mmol·kg(-1) day(-1) ) attenuated SCI-induced neuroinflammation; it decreased the Iba-1-, ED-1- and CD11b-positive cells at the lesion site. Importantly, histological analyses showed a significantly greater number of surviving neurons and regenerative axons in the ethyl pyruvate-treated rats. Ethyl pyruvate was shown to inhibit astrogliosis and neuroinflammation, promote neuron survival and neural regeneration, and improve the functional recovery of spinal cord, indicating a potential neuroprotective effect of ethyl pyruvate against SCI.

The present study aimed to analyse how anatomical regeneration contributes to functional recovery after experimental spinal cord repair. Thoracic spinal cord of neonatal rats was completely transected to make a gap and repaired by grafting a section of embryonic spinal cord. Six weeks after surgery, outcome of locomotor performance was assessed using an open field locomotor scale (BBB scale). Axonal regeneration across the repaired site was quantitatively assessed in the raphe, vestibular, and red nuclei and the sensorimotor cortex by a retrograde tracing method. The rats that had no labelled neurons in any of the supraspinal nuclei showed no hind-forelimb coordination. The rats that had labelled neurons in the brainstem nuclei but not in the sensorimotor cortex showed hind-forelimb coordination of varying grades depending on the amount of regeneration. The rats that had labelled neurons in all of the examined nuclei showed almost normal locomotion. In addition to a relationship between distribution of the labelled neurons and functional recovery, a positive correlation was observed between number of the labelled neurons in each of the supraspinal nuclei and locomotor performance of the rat. Thus the grade of restored function appeared to be regulated by distribution and number of fibres regenerated across the repaired site and into the target region. These results suggest that accurate reconstruction of neural connections is essential for significant functional recovery after spinal cord repair.