Dysregulation of Hyaluronan Homeostasis During White Matter Injury

Although the extra cellular matrix (ECM) comprises a major proportion of the CNS parenchyma, new roles for the ECM in regeneration and repair responses to CNS injury have only recently been appreciated. The ECM undergoes extensive remodeling following injury to the developing or mature CNS in disorders that -include perinatal hypoxic-ischemic cerebral injury, multiple sclerosis and age-related vascular dementia. Here we focus on recently described mechanisms involving hyaluronan (HA), which negatively impact myelin repair after cerebral white matter injury. Injury induced depolymerization of hyaluronan (HA)-a component of the neural ECM-can inhibit myelin repair through the actions of specific sizes of HA fragments. These bioactive fragments selectively block the maturation of late oligodendrocyte progenitors via an immune tolerance-like pathway that suppresses pro-myelination signaling. We highlight emerging new pathophysiological roles of the neural ECM, particularly of those played by HA fragments (HAf) after injury and discuss strategies to promoter repair and regeneration of chronic myelination failure.