Role of Aldynoglia Cells in Neuroinflammatory and Neuroimmune Responses after Spinal Cord Injury

Abstract

Aldynoglia are growth-promoting cells with a morphology similar to radial glia and share properties and markers with astrocytes and Schwann cells. They are distributed in several locations throughout the adult central nervous system, where the cells of the aldynoglia interact and respond to the signals of the immune cells. After spinal cord injury (SCI), the functions of resident aldynoglia, identified as ependymocytes, tanycytes, and ependymal stem cells (EpSCs) of the spinal cord are crucial for the regeneration of spinal neural tissue. These glial cells facilitate axonal regrowth and remyelination of injured axons. Here, we review the influence of M1 or M2 macrophage/microglia subpopulations on the fate of EpSCs during neuroinflammation and immune responses in the acute, subacute, and chronic phases after SCI.

Keywords: aldynoglia; axonal growth; bdnf; ensheathing cells; epscs; gfap; macrophage; microglia; p75 ngfr; sci; vimentin.

Figure 1

Locations of the aldynoglia cell subpopulation in the human CNS. The magnetic resonance imaging show neural niches for aldynoglia in the brain (a–d) and spinal cord (e–i): olfactory bulbs, hypophysis, third ventricle, pineal gland, cerebellum in (a), and both retinas (b). A coronal section of MRI showing the lateral ventricles (c) with enlarged third ventricle filled with cerebrospinal fluid (d), high presence of aldynoglia cells in the floor, and the lateral walls are marked. Spinal cord as a broad zone for aldynoglia, sagittal MRI section of the cervical zone of SC floating in CSF is shown (e). The axial section at C7 level (f) is enlarged showing the medullar channel with CSF surrounding white matter and grey matter, which contains aldynoglia cells (g). Arrows pointed to the location of resident aldynoglia in the ependyma of a normal individual (g) or activated aldynoglia in widened ependyma with hydromyelia in the spinal cord of patient (i). 3th V, third ventricle; C7, seventh vertebral cervical level; CSF, cerebrospinal fluid; GM, grey matter; Hp, hypophysis; MRI, magneting resonance imaging; OB, olfactory bulbs; PG, pineal gland; SC, spinal cord; WM, white matter.

Figure 2

The processes that provokes secondary mechanisms of cell death in the spinal cord after injury.

Figure 3

Cellular and molecular components in the three phases of inflammation after a spinal cord injury. After SCI, the first cells to arrive are the neutrophils and later the macrophages; these clean the area of injury and secrete different molecules (Proteases, myeloperoxidase), chemokines (CXCL-10), and reactive oxygen species (ROS). ROS activates microglia and astrocytes, secrete interleukins and more reactive oxygen species, promoting a pro-inflammatory environment. In the sub-acute phase, macrophages and microglia are found in the M1 phenotype and secrete interleukins (IL-6, IL-12, IL-1β) and chemokines (CCL2, CXCL2) that maintain the pro-inflammatory microenvironment. Also to the area of injury are the Th1 cells, which also help this inflammatory environment by secreting interleukins (IL-12, TNF-α, IFN-γ, and secrete antigens recognized by B cells, increasing the system production of autoantibodies. In the chronic phase, astrocytes secrete anti-inflammatory interleukins (IL-10, TGF-β), which produce a balance by changing microglia and macrophages to an anti-inflammatory effect M2, promoting neuroprotection to the surviving cells by the secretion of growth factors (BDNF, NGF, EGF, CNTF, IGF-1) and anti-inflammatory interleukins (IL-13, IL-4, IL-10, TGF-β). This anti-inflammatory microenvironment causes naïve T lymphocytes to become activated in the Th2 helper fate increasing this neuroprotective microenvironment, and therefore B cells decrease autoantibody production.

Figure 4

The response of aldynoglia cells in sub-acute and chronic inflammatory phases after SCI. After mechanical damage to the spinal cord, the resident astrocytes near the damaged zone proliferate, enlarge their fibrous processes, produce chondroitin sulfate proteoglycans and form a glial scar containing a cystic cavity in the spinal cord. The ependymal stem cells, EpSCs (a spinal aldynoglia), migrate from the central canal to the injury site; depending on the microenvironment, the EpSCs will proliferate or differentiate. In the sub-acute phase, the TNF-α secreted by macrophages/microglia M1 activates SOX 2, promoting the proliferation of EpSCs. In the chronic phase with the anti-inflammatory microenvironment, the BDNF secreted by macrophages/microglia M2 is attached to the TrkB receptor found in the EpSCs cell surface inducing SITR2 in EpSCs; and promoting its differentiation into astrocytes or oligodendrocytes, which will migrate at fibroglial scar area or remyelinate axons, respectively.