Glycogen synthase kinase-3β inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A

Abstract

Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated β-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3β inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1β expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1β, and IL6 expression without affecting microglia density. GSK-3β inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3β inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3β inhibitors might improve the neurological outcome of preterm infants with IVH.

Complement C3a induces axonal hypomyelination in the periventricular white matter through activation of WNT/β‐catenin signal pathway in septic neonatal rats experimentally induced by lipopolysaccharide

“…WNT/β-catenin/Tcf4 signaling pathway has been implicated in OPCs maturation and differentiation (21,67,70). In general, β-catenin does not accumulate in the cytoplasm under normal physiological condition because an existing complex consisting of AXIN2, APC, PP2A, GSK3, CK1α, could phosphorylate β-catenin (44).…”

Human Cord Blood-Derived Unrestricted Somatic Stem Cell Infusion Improves Neurobehavioral Outcome in a Rabbit Model of Intraventricular Hemorrhage

“… Microglia cell density was assessed using Iba‐1 specific antibody (catalog # AB5076, Abcam, Cambridge, U.K., http://www.abcam.com) as we and others previously described. A blind cell count was performed by two investigators to determine the cell density using ImageJ software with grid. We counted four sections in each pup and 5–6 pups from each group.…”

Aberrant Oligodendrogenesis in Down Syndrome: Shift in Gliogenesis?

“…Moreover, increased AICD levels can promote Gsk3β activity, thereby reducing the translocation of β-catenin to the nucleus, which may contribute to the suppression of the Wnt/β-catenin pathway [118]. Interestingly, a study in the field of intraventricular hemorrhage (IVH), a common neurological complication of prematurity causing cognitive deficits and ID [119], which is accompanied by inhibited proliferation/maturation of OPCs and hypomyelination [120], demonstrated that Gsk3β activity interfered with OPC differentiation and myelination [121]. Furthermore, a cross-talk of Gsk3β and Notch signaling was shown, as inhibition of Gsk3β downregulated Notch signaling.…”