A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination

Weiping Su, Steven Matsumoto, Fatima Banine, Taasin Srivastava, Justin Dean, Scott Foster, Peter Pham, Brian Hammond, Alec Peters, Kesturu S. Girish, Kanchugarakoppal S. Rangappa, Basappa, Joachim Jose, Jon Hennebold, Melinda J. Murphy, Jill Bennett-Toomey, Stephen Back, Lawrence (Larry) Sherman

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalGLIA
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Oligodendroglia
Hyaluronoglucosaminidase
Flavonoids
Stem Cells
Central Nervous System
Hyaluronic Acid
Digestion
Lysophosphatidylcholines
Corpus Callosum
Glycosaminoglycans
Matrix Metalloproteinases
Wounds and Injuries

Keywords

  • flavonoid
  • hyaluronan
  • hyaluronidase
  • myelin
  • oligodendrocyte

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination. / Su, Weiping; Matsumoto, Steven; Banine, Fatima; Srivastava, Taasin; Dean, Justin; Foster, Scott; Pham, Peter; Hammond, Brian; Peters, Alec; Girish, Kesturu S.; Rangappa, Kanchugarakoppal S.; Basappa; Jose, Joachim; Hennebold, Jon; Murphy, Melinda J.; Bennett-Toomey, Jill; Back, Stephen; Sherman, Lawrence (Larry).

In: GLIA, 01.01.2019.

Research output: Contribution to journalArticle

Su, W, Matsumoto, S, Banine, F, Srivastava, T, Dean, J, Foster, S, Pham, P, Hammond, B, Peters, A, Girish, KS, Rangappa, KS, Basappa, Jose, J, Hennebold, J, Murphy, MJ, Bennett-Toomey, J, Back, S & Sherman, LL 2019, 'A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination', GLIA. https://doi.org/10.1002/glia.23715
Su, Weiping ; Matsumoto, Steven ; Banine, Fatima ; Srivastava, Taasin ; Dean, Justin ; Foster, Scott ; Pham, Peter ; Hammond, Brian ; Peters, Alec ; Girish, Kesturu S. ; Rangappa, Kanchugarakoppal S. ; Basappa ; Jose, Joachim ; Hennebold, Jon ; Murphy, Melinda J. ; Bennett-Toomey, Jill ; Back, Stephen ; Sherman, Lawrence (Larry). / A modified flavonoid accelerates oligodendrocyte maturation and functional remyelination. In: GLIA. 2019.
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AU - Su, Weiping

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AU - Banine, Fatima

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AU - Dean, Justin

AU - Foster, Scott

AU - Pham, Peter

AU - Hammond, Brian

AU - Peters, Alec

AU - Girish, Kesturu S.

AU - Rangappa, Kanchugarakoppal S.

AU - Basappa,

AU - Jose, Joachim

AU - Hennebold, Jon

AU - Murphy, Melinda J.

AU - Bennett-Toomey, Jill

AU - Back, Stephen

AU - Sherman, Lawrence (Larry)

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N2 - 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.

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