Neurological diseases and trauma often cause demyelination, resulting in the disruption of axonal function and integrity. Endogenous remyelination promotes recovery, but the process is not well understood because no method exists to definitively distinguish regenerated from preexisting myelin. To date, remyelinated segments have been defined as anything abnormally short and thin, without empirical data to corroborate these morphological assumptions. To definitively identify regenerated myelin, we used a transgenic mouse with an inducible membrane-bound reporter and targeted Cre recombinase expression to a subset of glial progenitor cells after spinal cord injury, yielding remarkably clear visualization of spontaneously regenerated myelin in vivo. Early after injury, the mean length of sheaths regenerated by Schwann cells and oligodendrocytes (OLs) was significantly shorter than control, uninjured myelin, confirming past assumptions. However, OL-regenerated sheaths elongated progressively over 6 mo to approach control values. Moreover, OL-regenerated myelin thickness was not significantly different from control myelin at most time points after injury. Thus, many newly formed OL sheaths were neither thinner nor shorter than control myelin, vitiating accepted dogmas of what constitutes regenerated myelin. We conclude that remyelination, once thought to be static, is dynamic and elongates independently of axonal growth, in contrast to stretch-based mechanisms proposed in development. Further, without clear identification, past assessments have underestimated the extent and quality of regenerated myelin.regeneration | plasticity | internode N ervous system disorders including traumatic injury, stroke, and neurodegenerative diseases such as multiple sclerosis induce loss of myelin and myelinating cells, interrupting signal conduction and depriving axons of trophic support essential for survival (1-4). Postmitotic oligodendrocytes (OLs) do not readily participate in remyelination (5, 6). Instead, glial progenitors, distinguished by expression of the α-receptor for PDGF and the chondroitin sulfate proteoglycan neural/glial antigen 2 (NG2) proliferate following demyelination and differentiate into remyelinating cells within a few weeks (7-10). Regeneration of myelin membranes restores saltatory conduction and supports axonal integrity, leading to partial recovery of function (3,4,11,12). However, remyelination can fail during disease progression, and limited or abnormal myelin regeneration is thought to underlie chronic conduction deficits following trauma (11,13,14). Enhancing or substituting endogenous remyelination via pharmacological intervention or stem/progenitor cell transplantation has been a major, but unrealized, focus of clinical therapy development for decades (15)(16)(17).There is much we do not understand about spontaneous remyelination, including the rate of OL regeneration, whether remyelinating cells select specific phenotypes or morphotypes of axons to ensheathe, and whether the initial number, thicknes...

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Prostaglandin E 2 is one of several eicosanoid products of the cyclooxygenase isozymes and is a key regulator of innate immune responses; it also possesses paracrine effects on mature neurons. The prostaglandin E 2 receptor family consists of four subtypes of which EP1 and EP2 are known to be expressed by microglia. Lipopolysaccharide (LPS)-induced innate immune activation leads to the degeneration of intermediate progenitor cells (IPCs) that are destined for neuronal maturation in the hippocampal subgranular zone (SGZ); these cells can be identified by the expression of the transcription factor T-box brain gene 2 (Tbr2). Importantly, depletion of LPS-induced IPCs from the SGZ is suppressed by cyclooxygenase inhibitors. We therefore tested the hypothesis that either EP1 or EP2 is critical to LPS-induced depletion of Tbr2؉ IPCs from the SGZ. Expression of either EP1 or EP2 was necessary for Toll-like receptor 4-dependent innate immune-mediated depletion of these Tbr2؉ IPCs in mice. Moreover, EP1 activation was directly toxic to murine adult hippocampal progenitor cells; EP2 was not expressed by these cells. Finally, EP1 modulated the response of murine primary microglia cultures to LPS but in a manner distinct from EP2. These results indicate that prostaglandin E 2 signaling via either EP1 or EP2 is largely to completely necessary for Toll-like receptor 4-dependent depletion of IPCs from the SGZ and suggest further pharmacological strategies to protect this important neurogenic niche. (Am J Pathol