Chondroitinase ABC Treatment Enhances Synaptogenesis between Transplant and Host Neurons in Model of Retinal Degeneration

Abstract

Although recent studies revealed chondroitinase ABC (ChABC), an enzyme that degrades chondroitin sulfate proteoglycans, promotes CNS regeneration in vivo, the usefulness of its application for transplantation is not clear. We investigated if treatment with ChABC can promote synapse formation between graft and host neurons following retinal transplantation. Dissociated retinal cells were prepared from neonatal Nrl-GFP transgenic mice in which rod photoreceptors and their progenitor cells are labeled with GFP. Each cell suspension with or without ChABC (Nrl/ChABC group and Nrl group, respectively) was injected subretinally into the eyes of mice following chemically induced photoreceptor degeneration. The survival and functional integration of the transplanted photoreceptors were examined by histologically and electrophysiologically. Up to 4 weeks after transplantation, almost all the grafted GFP+ photoreceptor cells were widely distributed at the outer margin of the host retina where the photoreceptor layer was located originally. In the Nrl/ChABC group, 33.6% of the GFP+ photoreceptors elaborated neurites horizontally or vertically, and 4.6% elaborated neurites toward the retina. These neurites extended over the glial seal at the graft-host interface, and established synaptic contacts with neurons in the host retina as determined by confocal microscopy and three-dimensional analysis. Although 30.7% cells (p = 0.68) elaborated neurites in the Nrl group, only 1.2% cells (p < 0.05) projected neurites towards the host tissue and synaptic contacts were rare. Our results illustrate the potential utility of ChABC for enhancing synaptogenesis between transplanted neurons and host retina.

Migration, Integration and Maturation of Photoreceptor Precursors Following Transplantation in the Mouse Retina

“…Color images available online at www.liebertpub.com/scd other stages do not. Similarly, knowing the timing of maximal donor cell migration is of particular importance when designing strategies that transiently manipulate the recipient retina and/or donor cell behavior in order to promote donor cell migration and integration [31,32,41,42]. Here, we find that donor cell migration occurs within the first week posttransplantation, predominantly as single entities and involving a stereotyped sequence of morphologies, typical of locomoting cells elsewhere in the central nervous system (CNS).…”

In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction

“…Robust integration of transplanted retinal cells into the retinas of host mice deficient in both vimentin and glial fibrillary acidic protein has been reported (Kinouchi et al, 2003). Moreover, matrix metalloproteases and chondroitinases that degrade the extracellular matrix in the diseased retina aid in the integration of transplanted photoreceptors (Suzuki et al, 2007;Suzuki et al, 2006). Disruption of the outer limiting membrane also increases photoreceptor integration following transplantation (West et al, 2008).…”

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

“…However, robust integration of transplanted retinal cells into the retina of host mice deficient in both vimentin and glial fibrillary acidic protein has been reported (27). Moreover, chondroitinases and matrix metalloproteases-2 that degrade the extracellular matrix in the diseased retina aid in the integration of transplanted photoreceptors (28,29). Disruption of the outer limiting membrane also increases photoreceptor integration following transplantation (30).…”