STEM CELL TRANSPLANTATION IN GLAUCOMA

 

Stem cells are immature, uncommitted cell types that possess the abilities to:

•   Self-renew indefinitely by symmetric cell division.
•  Undergo asymmetric cell division, generating another stem cell and a daughter cell capable of differentiating into multiple mature cell types.

Pluripotent stem cells (for e.g., embryonic stem [ES] and induced pluripotent stem [iPS] cells) are capable of generating all cell types in the developing and adult body.

Multipotent somatic stem cells are, however, committed to a certain developmental lineage.

During differentiation, stem cells undergo lineage commitment and lose their self-renewal capacity, turning into progenitor cells that are further restricted in potency. Progenitor cells are very similar to stem cells. They are biological cells and like stem cells, they too have the ability to differentiate into a specific type of cell. However, they are already more specific than stem cells and can only be pushed to differentiate into its "target" cell.

A variety of distinct stem and progenitor cells classes exist, each with particular characteristics that make them attractive for certain potential therapeutic purposes.

Until 1996, it was believed that the optic nerve axon was impossible to regenerate. Berry et al.  discovered that implanting a peripheral nerve graft into the vitreous body of the eye with optic nerve crush determined RGCs to regenerate axons at least 3–4 mm into the distal segment.

Stem cell transplantation therapy is of clinical interest because of its potential to treat degenerative conditions that are currently irreversible, such as glaucoma.  

Stem cells have come to the attention of researchers due to certain features that are advantageous for glaucoma therapy: 

1. The ability to differentiate or to be reprogrammed into many types of cells, with the possibility of selective cell replacement of RGCs or other specialized cells within the eye; 
2. The neuroprotective and immunomodulatory properties of certain types of stem cells, such as mesenchymal stem cells (MSCs); 
3. The presumable low immunogenicity, especially for pluripotent stem cells; 
4. The bioactivity of factors and molecules secreted by stem cells (the “secretome”), with roles in injury repair and immunomodulation, with proven therapeutic benefits rather than the integration of stem cells into the host tissue; this prerequisite can be achieved by using extracellular vesicles (EV) or miRNA; 
5. The possibility of using transplanted stem cells as intraocular delivery devices for the release of neurotrophic agents, growth factors, survival/anti-apoptotic factors with a prolonged and localized effect.

There are at least two mechanisms by which stem cell transplantation might be applied to glaucoma.

• The most significant therapeutic power of stem cells lies in their ability to generate new cells of many types and to effect tissue regeneration. Thus, it is conceivable that stem cells may offer therapeutic hope for glaucoma via selective cell replacement of RGCs and optic nerve regeneration to restore function.
• Secondly, certain types of stem cells possess neuro-protective properties capable of alleviating disease progression and promoting survival of endogenous tissue.

It is hypothesized that functional improvement in glaucomatous eyes might be attained by reorganizing existing retinal circuitry (e.g., the RGC receptive field size might be expanded to compensate for a reduction in the number of surviving RGCs) or by introducing new neural network components without overtly replacing RGCs. It is possible that stem cell transplantation could facilitate such a repair mechanism by promoting endogenous plasticity or by directly contributing to the local retinal circuitry.

Presumably, transplantation of certain types of stem cells activates multiple neuroprotective pathways simultaneously via secretion of various factors. In this sense, transplanted stem cells could conceivably be utilized as intraocular delivery devices for diffusible bioactive factors to achieve RGC neuroprotection in glaucoma. This approach would have the added advantage of a prolonged and localized effect, potentially mediated by multiple factors acting synergistically, and derived from a single treatment.

Transplantation of stem cells that secrete relatively high levels of NTFs (neurotrophic factors) is likely to be the most applicable short-term cell-based therapy for glaucoma. Perhaps owing to their lineage, neural stem cells secrete high levels of NTFs. It was reported that oligodendrocyte precursor cells can protect RGCs in experimental glaucoma. Mesenchymal stem/stromal cells (MSCs) are another stem cell type reported to secrete a battery of neurogenic signaling factors, including NTFs. Preclinical investigations have demonstrated that intravitreal transplantation of MSCs into rats with ocular hypertension, induced by either episcleral vein cauterization or laser photocoagulation of the trabecular meshwork, offers significant RGC protection.

MSCs demonstrate robust immunomodulatory effects and are currently under clinical trial for the treatment of multiple sclerosis. In addition, neural stem cells are reportedly capable of reducing CNS inflammation, thereby promoting functional recovery in a range of neurodegenerative diseases. If inflammation proves integral to glaucomatous RGC loss, then it is conceivable that the anti-inflammatory properties of transplanted stem cells could confer benefit in glaucoma.

There is evidence that some stem cells secrete factors that could modulate mediators of glaucomatous neurodegeneration such as oxidative stress, vascular insufficiency and excitotoxicity. For example, hematopoetic stem cells secrete factors that modulate blood vessel development and stability, and transplantation of these cells can ameliorate some forms of retinal neurodegeneration. In addition, MSCs secrete antioxidants, such as superoxide dismutase, and may thus curb oxidative stress-related neurodegeneration in certain instances.

Stem cell transplantation can also be done for RGC cell replacement. It is now accepted that ES and iPS cells, properly coaxed towards a photoreceptor fate, can be transplanted into the eye to generate mature rods integrated within the retina. the steps required for stem cell transplantation-based RGC replacement are more numerous and daunting compared with those for photoreceptors. Grafted cells must differentiate into a mature RGC phenotype responsive to afferent input and capable of generating appropriate electrophysiological output. To do so, they would need to migrate into the correct spatial localization within the retinal tissue, develop mature synapses with existing retinal circuitry, generate and extend a very long axon to targets in the brain, and create efferent synapses that recapitulate the retinotopic map and preserve higher order visual processing. To date, none of these steps have been adequately addressed and so it is easy to view the prospects of RGC replacement as science fiction.

Studies in animal models used intravitreal administration of neurotrophic growth factors (neurotrophins), which are acquired by retrograde axoplasmic transport: brain-derived neurotrophic factors (BDNF), nerve growth factors (NGF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4), neurokines (ciliary neurotrophic factor—CNTF). A delay of acute RGCs death has been shown, but the results were generally disappointing. One possible explanation is the rapid clearance of the NTF.

The risk associated with tumorigenesis after stem cell transplantation is not excluded and is widely discussed in the literature.

There are some cases of retinal detachments reported in patients with AMD after having received bilateral intravitreal injection of stem cells.