Drug Development Targeting the Glycogen Synthase Kinase-3β (GSK-3β)-Mediated Signal Transduction Pathway: Targeting the Wnt Pathway and Transplantation Therapy as Strategies for Retinal Repair

Abstract

Abstract. Recent advances in stem cell biology have provided new insights that may lead to the development of regeneration therapy in the central nervous system to replenish lost neurons and to reconstitute neural circuits. The strategies for regeneration can be classified into two approaches: i) activation of endogenous neural stem cells and ii) transplantation of donor cells to replace lost cells. In the adult mammalian retina, Müller glia generate new retinal neurons in response to injury. The proliferation and differentiation of Müller glia-derived progenitors can be controlled by both intrinsic and extrinsic factors. Members of the Wnt / β-catenin signaling pathway, such as Wnt receptors and glycogen synthase kinase-3β, may be promising drug targets for neural regeneration. On the other hand, transplantation of photoreceptors or retinal pigment epithelia derived from human embryonic stem cells or induced pluripotent stem cells is also promising. Directed differentiation of pluripotent cells into retinal cells and purification to obtain retinal cells at a specific ontogenetic stage are required for donor cell preparation. Modulation of the host retinal environment to reduce the glial barrier is also critical for transplantation. To restore visual function, we need to understand the mechanisms underlying the integration of newly generated neurons or transplanted cells into the existing neural networks.

Activation of Wnt/β-catenin signaling in Muller glia protects photoreceptors in a mouse model of inherited retinal degeneration

“…The neuroprotection in our study raises an important translational question of whether long term activation of the Wnt pathway could be utilized as a therapy for retinal degeneration diseases. Activating the Wnt pathway has been proposed to as a therapy for neurodegenerations (Hackam, 2005; Osakada and Takahashi, 2009; Marchetti et al, 2013) and one would predict that continued neuroprotection is the outcome of sustained Wnt signaling. However, excessive Wnt activation in certain cell types has deleterious effects, including tumorigenesis and angiogenesis, the extent of which varies with the method of Wnt activation (Zhang et al, 2010; Cui et al, 2013).…”

Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis

“…22,23 IM-12 is a novel cell permeable indolyl maleimide which inhibits GSK-3β by competing for ATP binding. 24 The MDL28170 and IM-12 powder was dissolved in dimethyl sulfoxide (DMSO) and administered to the pigs orally. Pigs in the HCC received a placebo of DMSO without any drug dissolved.…”

Retinal stem cells and potential cell transplantation treatments

“…The selection of specific types of ESC-derived progenitors for transplantation into host mice relies on the identification of surface antigens coding rod photoreceptors on postnatal Days 3e6 and the purification of ES and iPS cell-derived rod photoreceptors corresponding to the postnatal stage of Days 3e6. 59 The host environment is also crucial for successful photoreceptor transplantation. 60 Retinal degeneration is well known, together with the corresponding microglial activation and glial scar formation that impedes the integration and survival of transplanted cells.…”