Dysregulation of Hyaluronan Homeostasis During White Matter Injury

Abstract

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.

Keywords: Extracellular matrix; Hyaluronan; Neuroinflammation; White matter injury.

Figure 1.. CD44 protein levels rapidly increase following neonatal hypoxic-ischemic injury.

To define how reactive gliosis, myelination and ECM remodeling are temporally related in evolving WMI, expression of GFAP (as a marker of reactive gliosis and injury), Myelin Basic Protein (MBP, as a marker of myelination) and the HA receptor CD44 was analyzed by western blot at five successive time points (n=18 animals/time point) after H-I between P4 and P21. H-I was induced as previously described (82) and generated unilateral WMI with the contralateral hemisphere serving as control. The data is presented as the mean fold-change for the 18 animals relative to the controls. (A, B) Chronic WMI led to a rapid increase in CD44 protein levels (panel A) in the lesions (black bars) compared to controls (unfilled bars). Note that increase in CD44 levels precede that of GFAP (panel B) suggesting that it could be used as a more sensitive indicator of WMI. C) The protein levels of the myelination marker, MBP, were lower in lesions relative to controls through P10. Additional studies employed area fraction analysis, which revealed significantly lower levels of MBP at P14 and P21 (70) in the WM lesions. Western blots did not detect such changes, which may have been related to the reduced sensitivity of this approach in anatomically complex white matter lesions.

Figure 2.. Generation of bioactive HA fragment via hyaluronidase activity induces a tolerant-like state that attenuates AKT activity and promotes myelination failure.

Intact ECM allows for signaling via pro-myelination receptors to restrain FoxO3 in the cytoplasm and promote myelination via the Brg1-SWI/SNF complex, which interacts with myelin gene promoters. A bioactive HA fragment inactivates AKT downstream of TLR4 and drives FoxO3 nuclear localization. Recruitment of SWI/SNF and Olig 2 to myelination gene promoters is disrupted, which blocks transcription of myelination genes to negatively impact repair and regeneration of CNS lesions.