Melissa Trotman-Lucas, PhD

Nguyen H, Lee JY, Sanberg PR, Napoli E, Borlongan CV. Eye Opener in Stroke: Mitochondrial Dysfunction and Stem Cell Repair in Retinal Ischemia. Stroke. 2019;50:2197–2206.

Retinal damage is a significant stroke-associated outcome, with 92% of patients suffering visual impairments during the initial recovery phase. Partial, and in some cases complete, recovery can occur; however, 20% of patients will suffer persistent or permanent visual impairment. The anatomic link between the ophthalmic artery and the middle cerebral artery is a potential factor in the reduction of retinal blood flow during middle cerebral artery occlusion (MCAO). The reduced blood flow leads to ischemic retinal damage and subsequent visual impairment. Visual disability is much less evident than other motor or speech deficits following stroke, yet can significantly affect a patient’s rehabilitation, including functional recovery and quality of life. Reduction in rapid eye movements, visual acuity and visual field defects can occur, affecting daily activities and capabilities such as reading, mobility, postural stability, spatial recognition and more. These directly affect a patient’s independence, increasing fear and disorientation, reducing confidence and leading to social withdrawal. Current therapy for stroke-associated visual impairment is neurovisual rehabilitation, involving guiding a patient to learn coping strategies to improve quality of life. Retinal ischemia also shares parallels in pathology to other ocular vascular diseases, such as diabetic retinopathy, glaucoma, retinal vein occlusion and central retinal artery occlusion. There is a need to better understand the similarities and relationship between cerebral ischemia and retinal ischemia, particularly ischemic stroke that incorporates retinal ischemic damage. The lack of current understanding may contribute to the absence of effective treatments for this prevalent post-stroke outcome.

Nguyen et al. investigated the role of mitochondrial dysfunction in stroke-related retinal ischemia, examining the effect stem cells may play in mitochondrial repair and post-stroke outcome. Mitochondria play a key role in cell survival and death, acting as a power source for the cell, producing energy and maintaining metabolic activity. Mitochondria lead activities become interrupted during ischemia, reducing energy supply and initiating cell death events. Investigation into mitochondrial dysfunction during retinal ischemia may reveal mechanic and translational insights towards the development of effective stroke treatments. Using the in vivo MCAO model, the group showed that blood flow reduced in both the ipsilateral hemisphere and ipsilateral eye by 80%, resulting in ganglion cell loss and decreased optic nerve width. These outcomes significantly improved by day 14 following post MCAO intravenous mesenchymal stem cell (MSC) treatment. The group similarly demonstrated consistent retinal pigmented epithelium (RPE) cell loss using an in vitro oxygen-glucose deprivation model, with concurring alterations in the RPE cell’s mitochondria in terms of mitochondrial respiration, network morphology and dynamics. Both cell loss and mitochondria alterations were ameliorated by treatment with MSCs distinguished by increased cell proliferation, restored mitochondrial respiration and normalised mitochondrial network morphology. The group suggests that the MSCs transferred functional mitochondria to the impaired retinal cells, reporting an increase in JC-1 red/green intensity ratio values and colocalization between the mitochondria of the MSCs and cultured RPE cells. The JC-1 dye exhibits potential-dependent accumulation in mitochondria resulting in an emissions shift and increased red/green ratio. The ratio reduces under depolarisation, such that occurs during ischemia. Therefore, the increased ratio shown by the group suggests a return to normal membrane function. This, alongside the co-localisation of mitochondria staining, suggests trans-cell migration of healthy mitochondria from the stem cells to the damaged retinal cells.

The research presented by Nguyen and colleagues provides evidence that stem cell transplantation can result in reparative benefits following cerebral and retina ischemia, to some extent by the improvement of mitochondrial dysfunction by mitochondrial transfer. Both delivery routes and the timing of stem cell treatment with or without tPA treatment need to be optimised, as this may prove to be a worthwhile treatment for retinal ischemia. Clinical stroke diagnosis needs to be closely combined with retinal ischemia assessments with more consideration towards correlative post-stroke treatments. Reports from stroke survivors and their carers suggest there is a need for education improvements to promote knowledge and increase awareness of post-stroke visual impairment. The work presented here lays a basis for future research into characterising the in vivo mechanisms of stem cell treatment in stroke-associated visual impairment. The characterization of functional and cognitive outcomes within in vivo ischemia models when treated with stem cells will help enhance understanding of how this treatment could result in an improved quality of life for stroke sufferers.