Ependymal Stem Cell Niche Disruption Hypothesis

Ependymal cells line the inner cerebrospinal fluid pathways of the brain and spinal cord. They are critical for cerebrospinal fluid homeostasis, cellular signaling and wound repair in the brain and spinal cord (1). Cells of the ependymal region are vestiges of neuroepithelial cells (a subtype of stem cells) that give rise to neurons and glia during mammalian development (2) and are known to orchestrate the regenerative response in tailed amphibians (3). Ependymal region cells have been shown to proliferate and migrate following central nervous system injury (2; 4-6). Indeed, the kinetics of ependymal region cell proliferation and differentiation has been correlated with the recovery of lower limb motor function in rats following contusion injuries (6).

Of note, neural stem cells have been isolated from the adult central nervous system (7-10), including regions near the subventricular zone and the central canal. Neurogenesis has been reported from the adult subventricular zone (11). Additionally, gliogenesis has been reported from the brain and spinal cord, as well, including the generation of new ependymal cells (4), reactive astrocytes (6; 7; 12), oligodendrocyte precursors (13) and microglia (14). Glia are the supportive cells of the central nervous system and are critical for maintaining the structural and functional integrity of the brain and spinal cord after injury. Therefore, disruption of the ependyma could have profound effects on brain and spinal cord function which may have implications for neurodegenerative disorders, such as Alzheimer’s disease. Sources of this disruption could include local ischemia, changes in cerebrospinal fluid dynamics and the composition of the cerebrospinal fluid.

Normally, cerebrospinal fluid circulates in the subarachnoid space, traverses the brain and spinal cord several times a day and exhibits a craniocaudal flow pattern influenced by the cardiac cycle. The cerebrospinal fluid is produced by ependymal cells and is absorbed in the dural venous sinuses and along lymphatic channels near the nerve roots. Some cerebrospinal fluid, driven by the heart’s systolic pulsations, is thought to enter the substance of the brain and spinal cord via the Virchow-Robin perivascular spaces and flow toward the ventricles and central canal, essentially bathing the brain and spinal cord’s extracellular space. This process is thought to clear the brain and spinal cord of harmful substances generated during metabolism, thereby “flushing” away the byproducts. Therefore, disturbances in this process through ependymal dysfunction could have profound effects on the brain and spinal cord which may have implications for neurodegenerative disease, such as Alzheimer’s disease.

Ependymal cells are ciliated cells that line the ventricular cavity and are critical for maintaining cerebrospinal fluid homeostasis, cerebrospinal fluid hydrodynamics and the local subependymal stem cell niche. Cilia are specialized projections of ependymal cells that promote the flow of cerebrospinal fluid along brain and spinal cord (15). Ependymal ciliary loss is known to predispose to hydrocephalus (15) and is a feature of the disease (16). Therefore, loss of cilia could have profound effects on cerebrospinal fluid propulsion, leading to alterations in cerebrospinal fluid homeostasis and cerebrospinal fluid dynamics. Changes in the clearance of certain brain metabolites have been hypothesized in the pathogenesis of Alzheimer’s disease (17). Ependymal ciliary loss may be a mechanism in this process. This loss of ependymal cell cilia may result in a local stasis and accumulation of cerebrospinal fluid adjacent to the ependyma, leading to an accumulation of toxic levels of electrolytes and metabolites and proteins in the ependymal and periependymal areas and subsequently the substance of the brain itself. This impaired clearance of proteins in the brain tissue could be thought of by analogy as a form of "protein-neuria.” Normal adults do demonstrate ciliary loss in the ventricles, which could be thought of as an early form of senescence, but other factors are certainly at work in the development of complex neurodegenerative diseases such as Alzheimer’s dementia.

The ependyma are known to receive a vascular supply from very small subependymal arteries (18), making them very susceptible to microvascular disease, such as that which occurs with diabetes and cardiovascular disease. Diabetes and cardiovascular disease are known to increase the risk of Alzheimer’s disease. Moreover, changes in periventricular blood flow have been documented as an early finding in various caused of dementia (19). Therefore, beyond mere ciliary loss, disruption of the ependymal epithelium lining itself through local ischemia, buildup of toxic metabolites and pressure gradients could lead to profound changes in brain function. Normally, the ependyma consists of a pseudostratified monolayer of cells that plays an important role in cerebrospinal fluid homeostasis by regulating fluid and electrolyte balance between the cerebrospinal fluid and the substance of the brain and spinal cord (4). Disruption and denudation of the ependymal layer could therefore result in the loss of a protective epithelium. This incompetence of the ventricular linings would lead to an exposure of the adjacent grey and white matter to pressure gradients and an eventual dissection of non-circulating cerebrospinal fluid from within the ventricles and canal. Ependyma disruption has been documented following exogenous toxin administration (20) so should result equally with accumulation of internal toxins. Furthermore, fluid from non-circulating cerebrospinal fluid collections, such as subdural hematomas, is known to differ from normal cerebrospinal fluid, usually having a higher protein content, which may give rise to oncotic pressures (21). Prolonged exposure of peri-ependymal tissues to this microenvironment may lead to structural degeneration as well as functional deficits, such as conduction failures. Eventually, local disruptions of the blood brain barrier may contribute to the edema, but also may represent a source of additional inflammatory molecules and plasma proteins that may adversely influence the microenvironment of nearby cells, including cells with stem/progenitor characteristics, thereby influencing their viability and patterns of differentiation. Indeed, the presence of serum in ependymal cell cultures leads to differentiation into lineages associated with scarring (22). Beyond Alzheimer’s disease, this latter process may have profound implications for other neurodegenerative diseases such as Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

Finally, it stands to reason that disruption of the ependymal stromal epithelium, along with periependymal stem/progenitor cells, may represent a heretofore unrecognized pathogenic mechanism in neurodegenerative disorders such as Alzheimer’s disease. Loss of subependymal stem cells would hinder neurogenesis and gliogenesis (i.e., self-repair) in the ependymal region (including the replacement of damaged ependymal cells). Moreover, because these cells are known to migrate in disease and injury, loss of subependymal stem cells would eventually lead to loss of self-repair in the entire brain and spinal cord. Indeed, the progressive disruption of this ependymal region, through ischemic, mechanical and cytotoxic means, could represent a disease mechanism that tips the balance between injury and repair in the brain toward further cytoarchitectural destruction of lesions over time, with profound effects on cognitive abilities. As an example, there is a rostral migratory stream of neuronal precursors from the subventricular zone towards the olfactory bulb (23). Disruptions in neurogenesis would therefore result in a loss of the sense of smell. Of note, anosmia is a known early symptom of several neurodegenerative disorders, including Alzheimer’s disease.

Therefore, bypassing ependymal dysfunction through cerebrospinal dialysis procedures may be a temporizing measure until a true repair of the ependymal region is possible.

Taken from “On the role of ependymal disruption in neurodegeneration” copyright 2004-2010 Milan Radojicic MD. All rights reserved. Used with permission by author.

See www.neurosyntec.com for additional information. References

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