Abstract
We have previously characterized human neuronal progenitor cells (hNP) that can adopt a retinal ganglion cell (RGC)-like morphology within the RGC and nerve fiber layers of the retina. In an effort to determine whether hNPs could be used a candidate cells for targeted delivery of neurotrophic factors (NTFs), we evaluated whether hNPs transfected with an vector that expresses IGF-1 in the form of a fusion protein with tdTomato (TD), would increase RGC survival in vitro and confer neuroprotective effects in a mouse model of glaucoma. RGCs co-cultured with hNPIGF-TD cells displayed enhanced survival, and increased neurite extension and branching as compared to hNPTD or untransfected hNP cells. Application of various IGF-1 signaling blockers or IGF-1 receptor antagonists abrogated these effects. In vivo, using a model of glaucoma we showed that IOP elevation led to reductions in retinal RGC count. In this model, evaluation of retinal flatmounts and optic nerve cross sections indicated that only hNPIGF-TD cells effectively reduced RGC death and showed a trend to improve optic nerve axonal loss. RT-PCR analysis of retina lysates over time showed that the neurotrophic effects of IGF-1 were also attributed to down-regulation of inflammatory and to some extent, angiogenic pathways. This study shows that neuronal progenitor cells that hone into the RGC and nerve fiber layers may be used as vehicles for local production and delivery of a desired NTF. Transplantation of hNPIGF-TD cells improves RGC survival in vitro and protects against RGC loss in a rodent model of glaucoma. Our findings have provided experimental evidence and form the basis for applying cell-based strategies for local delivery of NTFs into the retina. Application of cell-based delivery may be extended to other disease conditions beyond glaucoma.
Highlights
Stem or progenitor cells can be used to restore function in two distinct ways: direct integration into target tissue and/or as carriers of biologically active factors
We show that human neuronal progenitor cells (hNP) that secrete biologically active IGF-1 in the form of a fusion protein with TD (IGF-TD) selectively enhance survival and neurite outgrowth when co-cultured with P0 mouse retinal ganglion cell (RGC), and that this effect can be abrogated with selective inhibitors
Using an established and reproducible model of glaucoma, we show that sustained delivery of IGF-TD by hNPIGF-TD cells effectively protect against loss of RGCs
Summary
Stem or progenitor cells can be used to restore function in two distinct ways: direct integration into target tissue and/or as carriers of biologically active factors. Cells are able to secret NTFs in culture media [5] or in the target location leading to the intended effects in a paracrine manner with mild direct cellular integration [5,6,7]. Studies regarding this paradigm confirm that RGC and axon survival can be increased both in vitro and in vivo by transplanting human dental pulp stem cells [6] or bone marrow-derived mesenchymal stem cells [5,6,7] by intravitreal injection. Grafted cells remain viable for a relatively short period within the target area [7,8]
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