Investigation of mesenchymal stem cells and the development of experimental strategies for rescuing glaucomatous eyes using a stem cell-based therapy

摘要

Glaucoma, the second leading cause of blindness in the world, is a hereditary ocular disease and about 60 million people suffer from it. However, currently there are no remedies to cure glaucoma. As a potential solution to rescue degenerating retinas, stem cells have been investigated extensively and the effects of morphological neuroprotection or functional recovery have been reported. In the present studies, I aimed to investigate two main topics of research. From the first topic, we demonstrated MSCs from Brown Norway rats are a self-renewing, multi-potent population. More importantly, we provide the first evidence that bone marrow MSCs are capable of promoting neurite outgrowth from adult hippocampal progenitor cells (AHPCs).For the second topic of research, mouse MSCs were engineered to over-express brain-derived neurotrophic factor (BDNF) and/or glial cell-derived neurotrophic factor (GDNF) together with green fluorescent protein (GFP), as a strategy for stem cell-based therapy. Our results show MSCs, infected with lentiviral vectors encoding BDNF or GDNF, noticeably increased the release of bioactive neurotrophic factors in vitro.For our in vivo study of stem cell-therapy, two different mouse models of experimental glaucoma were studied. MSCs, following intraocular transplantation, survived up to 4 months post-transplant (PT) in the host retina of adult DBA/2J mice. Interestingly, our results indicated MSCs expressing GDNF played a potential role in alleviating glial activation on host retinas. Importantly, our data show GDNF/BDNF-MSCs contributed to preservation of the inner retina of the recipient eye, compared to the control fellow eye.An additional transgenic mouse model of glaucoma, Myocilin (MYOC)-mutant mice, was investigated. Our preliminary study showed transplanted MSCs survived up to 11.5 months-PT in the adult host retina. No significant changes in the number of retinal ganglion cells between experimental and control eyes were found at 11.5 months-PT.These studies are the first to characterize bone marrow-derived MSCs from Brown Norway rats and to study potential neuroprotective effects of transplanted MSCs on the host retinas of DBA/2J and MYOC-mice. This study provides an experimental strategy towards clinical applications in terms of using MSCs as a potential autograft and long-term neuroprotection via neurotrophic factor delivery for retinodegenerative diseases.