Abstract
Mesenchymal stem/stromal cells (MSC) are well known for immunomodulation; however, the mechanisms involved in their benefits in the ischemic retina are unknown. This study tested the hypothesis that MSC induces upregulation of transcription factor forkhead box protein P3 (Foxp3) in T cells to elicit immune modulation, and thus, protect against retinal damage. Induced MSCs (iMSCs) were generated by differentiating the induced pluripotent stem cells (iPSC) derived from urinary epithelial cells through a noninsertional reprogramming approach. In in-vitro cultures, iMSC transferred mitochondria to immune cells via F-actin nanotubes significantly increased oxygen consumption rate (OCR) for basal respiration and ATP production, suppressed effector T cells, and promoted differentiation of CD4+CD25+ T regulatory cells (Tregs) in coculture with mouse splenocytes. In in-vivo studies, iMSCs transplanted in ischemia-reperfusion (I/R) injured eye significantly increased Foxp3+ Tregs in the retina compared to that of saline-injected I/R eyes. Furthermore, iMSC injected I/R eyes significantly decreased retinal inflammation as evidenced by reduced gene expression of IL1β, VCAM1, LAMA5, and CCL2 and improved b-wave amplitudes compared to that of saline-injected I/R eyes. Our study demonstrates that iMSCs can transfer mitochondria to immune cells to suppress the effector T cell population. Additionally, our current data indicate that iMSC can enhance differentiation of T cells into Foxp3 Tregs in vitro and therapeutically improve the retina’s immune function by upregulation of Tregs to decrease inflammation and reduce I/R injury-induced retinal degeneration in vivo.
Highlights
IntroductionIschemic retinopathies, including diabetic retinopathy (DR), retinopathy of prematurity (ROP), and retinal vascular occlusion (RVO), are increasing in prevalence, represent a significant economic burden, and are major causes of vision loss and blindness worldwide [1,2,3]
We show that intravitreal delivery of Induced mesenchymal stem cells (MSCs) (iMSCs) in a retinal ischemia-reperfusion (I/R) injury model display therapeutic potential and suggests the mechanism of action may involve recruitment of Foxp3Tregs
Our in-vitro culture data show that iMSCs transferred mitochondria to immune T cells via F-actin nanotubes, suppressed effector T cells, and promoted differentiation CD4+CD25+forkhead box protein P3 (Foxp3)+ T regulatory cells (Tregs) in coculture with mouse splenocytes on par with ASC
Summary
Ischemic retinopathies, including diabetic retinopathy (DR), retinopathy of prematurity (ROP), and retinal vascular occlusion (RVO), are increasing in prevalence, represent a significant economic burden, and are major causes of vision loss and blindness worldwide [1,2,3]. A wide variety of traditional treatment therapies, including photocoagulation and anti-VEGF therapies during the neovascularization phase, showed benefits, with no treatments currently approved that address underlying proinflammatory pathways that are known to trigger neurovascular degeneration [2]. Mainly multipotent mesenchymal stem cells (MSCs), recently gained significant attention as a potential therapy for the treatment of ischemic retinopathies [3,4]. Our previous studies utilizing MSCs derived from the stromal vascular fraction of adult human adipose tissue (adipose-derived stem cells, ASC) [5,6], and independently corroborated with bone marrow (BM-MSC) [7]
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