A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination

Abstract

Myelination delay and remyelination failure following insults to the central nervous system (CNS) impede axonal conduction and lead to motor, sensory and cognitive impairments. Both myelination and remyelination are often inhibited or delayed due to the failure of oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes (OLs). Digestion products of the glycosaminoglycan hyaluronan (HA) have been implicated in blocking OPC maturation, but how these digestion products are generated is unclear. We tested the possibility that hyaluronidase activity is directly linked to the inhibition of OPC maturation by developing a novel modified flavonoid that functions as a hyaluronidase inhibitor. This compound, called S3, blocks some but not all hyaluronidases and only inhibits matrix metalloproteinase activity at high concentrations. We find that S3 reverses HA‐mediated inhibition of OPC maturation in vitro, an effect that can be overcome by excess recombinant hyaluronidase. Furthermore, we find that hyaluronidase inhibition by S3 accelerates OPC maturation in an in vitro model of perinatal white matter injury. Finally, blocking hyaluronidase activity with S3 promotes functional remyelination in mice with lysolecithin‐induced demyelinating corpus callosum lesions. All together, these findings support the notion that hyaluronidase activity originating from OPCs in CNS lesions is sufficient to prevent OPC maturation, which delays myelination or blocks remyelination. These data also indicate that modified flavonoids can act as selective inhibitors of hyaluronidase activity and can promote OPC maturation, making them excellent candidates to accelerate myelination or promote remyelination following perinatal and adult CNS insults.

Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

“…Stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutical advance in the recent decade. Several studies have shown that BMSCs might exert certain functions on the oligodendrocyte precursor cells (OPCs), the progenitor cells of mature oligodendrocytes (OLs), and promote their enrichment to the sites of injury, differentiation and remyelination of the damaged nerve fibers [12][13][14]. For example, in vitro co-culture of OPCs with BMSCs has been found to preferentially drive the differentiation of OPCs into oligodendrocytes (oligodendroglial fate) rather than the astrocytes (astroglial fate) [15,16].…”

Bone Marrow Mesenchymal Stem Cells Promote Remyelination in Spinal Cord by Driving Oligodendrocyte Progenitor Cell Differentiation Via Tnfα/Relb-Hes1 Pathway: A Rat Model Study of 2,5-Hexanedione-Induced Neurotoxicity

“…Stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising therapeutical advance in the recent decade. Several studies have shown that that BMSCs might exert certain functions on the oligodendrocyte precursor cells (OPCs), the progenitor cells of mature oligodendrocytes (OLs), and promote their enrichment to the sites of injury, differentiation and remyelinating the damaged nerve bers [9][10][11]. For example, in vitro co-culture of OPCs with BMSCs has been found to preferentially drive the differentiation of OPCs into oligodendrocytes (oligodendroglial fate) rather than the astrocytes (astroglial fate) [12,13].…”

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

“…Very recently, Su and colleagues developed a modified flavonoid (called S3) that potently and selectively inhibits the enzymatic activity of PH20 but not Hyal1 or Hyal2. S3 treatment was able to improve OPC maturation in vitro in presence of HMW HA and to promote functional remyelination in the LPC-induced demyelination model [106], suggesting that selective hyaluronidase inhibitors can be exploited to foster endogenous remyelination following CNS injuries. Several flavonoids (i.e., apigenin and hesperidin) have been shown to exert neuroprotective and immunomodulatory activity in the EAE model [107,108], suggesting that flavonoids can be potentially used as therapeutic compounds to counteract dysfunctional processes causing demyelination.…”