Unlocking the paradoxical endogenous stem cell response after spinal cord injury

Abstract

Nearly a century ago, the concept of the secondary injury in spinal cord trauma was first proposed to explain the complex cascade of molecular and cellular events leading to widespread neuronal and glial cell death after trauma. In recent years, it has been established that the ependymal region of the adult mammalian spinal cord contains a population of multipotent neural stem/progenitor cells (NSPCs) that are activated after spinal cord injury (SCI) and likely play a key role in endogenous repair and regeneration. How these cells respond to the various components of the secondary injury remains poorly understood. Emerging evidence suggests that many of the biochemical components of the secondary injury cascade which have classically been viewed as deleterious to host neuronal and glial cells may paradoxically trigger NSPC activation, proliferation, and differentiation thus challenging our current understanding of secondary injury mechanisms in SCI. Herein, we highlight new findings describing the response of endogenous NSPCs to spinal cord trauma, redefining the secondary mechanisms of SCI through the lens of the endogenous population of stem/progenitor cells. Moreover, we outline how these insights can fuel novel stem cell-based therapeutic strategies to repair the injured spinal cord. K E Y W O R D S ependymal cells, neural stem/progenitor cells, pathophysiology, spinal cord injury, secondary injury

Infantile Cocktail of Erythropoietin and Melatonin Restores Gait in Adult Rats with Preterm Brain Injury

“…Altamentova and colleagues [57] demonstrated that methylprednisolone administered on P21, equivalent to a 2-year-old toddler and 14 days after hypoxia-ischemia on P7, provided durable improvement in both histology and gait through young adulthood (P56). While methylprednisolone reduces neuroinflammation, broad immunosuppression during development may have secondary unintended consequences [58][59][60], such as limiting the neurorestorative potential of the endogenous stem cell response that may be essential for replenishing lost neural cell progenitors [61]. Neuro-immunomodulation with endogenous neurorestorative hormones, such as EPO and MLT, may mitigate against unintended effects.…”

Stem Cell Neurodevelopmental Solutions for Restorative Treatments of the Human Trunk and Spine

“…The in vivo direct lineage conversion and activation of endogenous NSCs is an alternative to the replacement of injured cells in the CNS. One approach applies recombinant cytokines to promote host tissue regeneration by stimulating endogenous stem cells pharmacologically (Lowry and Temple, 2007;Hachem et al, 2020). Alternatively the in vivo direct lineage conversion of somatic cells to neurons by forced expression of transcription factors could overcome endogenous NSC limitations.…”

Thyroid Hormone and Neural Stem Cells: Repair Potential Following Brain and Spinal Cord Injury

“…However, here, ependymal cells (ECs) surrounding the central canal in the spinal cord express the same NSC markers as those in the SVZ, such as Sox2, Sox9 and CD133. Multipotent ECs are largely quiescent, proliferate at low rates, and generate few astrocytes and oligodendrocytes in healthy conditions (Hachem et al, 2020), indicating that spinal cord tissue is by default pro-gliogenic. EAE activates ECs, that besides predominantly generating astrocytes, also form OPCs that subsequently differentiate into myelinating oligodendrocytes (Meletis et al, 2008).…”