The Benefits and Hazards of Intravitreal Mesenchymal Stem Cell (MSC) Based-Therapies in the Experimental Ischemic Optic Neuropathy.

Yao-Tseng Wen,Dah-Ching Ding,Rong-Kung Tsai,Yu-Chieh Ho,Pei-Kang Liu,Yueh-Chang Lee

doi:10.3390/ijms22042117

Abstract

Mesenchymal stem cell (MSC) therapy has been investigated intensively for many years. However, there is a potential risk related to MSC applications in various cell niches. Methods: The safety of intravitreal MSC application and the efficacy of MSC-derived conditioned medium (MDCM) were evaluated in the normal eye and the diseased eye, respectively. For safety evaluation, the fundus morphology, visual function, retinal function, and histological changes of the retina were examined. For efficacy evaluation, the MDCM was intravitreally administrated in a rodent model of anterior ischemic optic neuropathy (rAION). The visual function, retinal ganglion cell (RGC) density, and neuroinflammation were evaluated at day 28 post-optic nerve (ON) infarct. Results: The fundus imaging showed that MSC transplantation induced retinal distortion and venous congestion. The visual function, retinal function, and RGC density were significantly decreased in MSC-treated eyes. MSC transplantation induced astrogliosis, microgliosis, and macrophage infiltration in the retina due to an increase in the HLA-DR-positive MSC proportion in vitreous. Treatment with the MDCM preserved the visual function and RGC density in rAION via inhibition of macrophage infiltration and RGC apoptosis. Conclusions: The vitreous induced the HLA-DR expression in the MSCs to cause retinal inflammation and retina injury. However, the MDCM provided the neuroprotective effects in rAION.

Highlights

In middle-aged people, the most common type of acute optic neuropathy is nonarteritic anterior ischemic optic neuropathy (NAION), with an incidence of 3.72 per 100,000 in Taiwan and at least 6000 new cases a year [1]
Four weeks after intravitreal injection, we found that DiI-labeled human Wharton’s jelly mesenchymal stem cell (hWJMSC) aggregated at the central retina and caused severe venous congestion and retina distortion (Figure 1A)
The present study demonstrated that intravitreal delivery of hWJMSCs is not safe to develop an alternative therapy for retina and optic nerve diseases because allogeneic Mesenchymal stem cell (MSC) transplantation leads to visual function loss, retinal function loss, retinal ganglion cell (RGC) loss, retinal inflammation, retinal restructuration, and venous congestion

Summary

Introduction

In middle-aged people, the most common type of acute optic neuropathy is nonarteritic anterior ischemic optic neuropathy (NAION), with an incidence of 3.72 per 100,000 in Taiwan and at least 6000 new cases a year [1]. After the experimental induction of an ON infarct, blood–ON barrier disruption occurs within few hours, to be accompanied by the extrinsic macrophage infiltration and the resident microglia activation at the ischemic core of ON [3] The activated macrophages/microglia provide the phagocytic ability to remove myelin debris These activated macrophages/microglia release many different pro-inflammatory cytokines to induce severe inflammation, inhibit cell proliferation, and cause tissue damage [2,4]. These activated macrophages/microglia have been classified into M1-polarized type [5]. The inhibition of neuroinflammation may be vital for optic nerve protection in a rodent model of anterior ischemic optic neuropathy (rAION)

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Results

Discussion

Conclusion