Correction: Pericytes Derived from Adipose-Derived Stem Cells Protect against Retinal Vasculopathy

Abstract

Background: Retinal vasculopathies, including diabetic retinopathy (DR), threaten the vision of over 100 million people. Retinal pericytes are critical for microvascular control, supporting retinal endothelial cells via direct contact and paracrine mechanisms. With pericyte death or loss, endothelial dysfunction ensues, resulting in hypoxic insult, pathologic angiogenesis, and ultimately blindness. Adipose-derived stem cells (ASCs) differentiate into pericytes, suggesting they may be useful as a protective and regenerative cellular therapy for retinal vascular disease. In this study, we examine the ability of ASCs to differentiate into pericytes that can stabilize retinal vessels in multiple pre-clinical models of retinal vasculopathy.Methodology/Principal Findings: We found that ASCs express pericyte-specific markers in vitro. When injected intravitreally into the murine eye subjected to oxygen-induced retinopathy (OIR), ASCs were capable of migrating to and integrating with the retinal vasculature. Integrated ASCs maintained marker expression and pericyte-like morphology in vivo for at least 2 months. ASCs injected after OIR vessel destabilization and ablation enhanced vessel regrowth (16% reduction in avascular area). ASCs injected intravitreally before OIR vessel destabilization prevented retinal capillary dropout (53% reduction). Treatment of ASCs with transforming growth factor beta (TGF-b1) enhanced hASC pericyte function, in a manner similar to native retinal pericytes, with increased marker expression of smooth muscle actin, cellular contractility, endothelial stabilization, and microvascular protection in OIR. Finally, injected ASCs prevented capillary loss in the diabetic retinopathic Akimba mouse (79% reduction 2 months after injection).Conclusions/Significance: ASC-derived pericytes can integrate with retinal vasculature, adopting both pericyte morphology and marker expression, and provide functional vascular protection in multiple murine models of retinal vasculopathy. The pericyte phenotype demonstrated by ASCs is enhanced with TGF-b1 treatment, as seen with native retinal pericytes. ASCs may represent an innovative cellular therapy for protection against and repair of DR and other retinal vascular diseases.

The Importance of Pericytes in Healing: Wounds and other Pathologies

“…Human cells derived from adipose stem cells and expressing αSMA, PDGFRβ and NG2 can protect against diabetic retinopathy in a mouse model, causing revascularisation of the retina after injection which was not achieved by injection of human BM-MSCs [91]. This effect of pericyte injection was enhanced when the cells were pre-treated with TGF-β1.…”

Intra-Vitreal Administration of Microvesicles Derived from Human Adipose-Derived Multipotent Stromal Cells Improves Retinal Functionality in Dogs with Retinal Degeneration

“…Currently, adipose-derived stromal cells (ASCs) are considered to be the most suitable source of MSCs, mainly due to their highly proliferative activity and immunomodulatory properties, but also due to the safe method of their isolation [17]. Recently, it has been reported that ASCs exhibit a neuroprotective effect by secreting trophic/neuroregulatory factors [17,18]. The pro-regenerative potential of ASCs is explained by their ability to produce and secrete nano- and micro-sized extracellular vehicles (EVs), which include both exosome and microvesicles (MVs) populations [19,20].…”

Pericytes in Microvessels: From “Mural” Function to Brain and Retina Regeneration

“…In these conditions ASC-derived pericytes adopt pericyte morphology, showing pericyte-specific markers, and their phenotype is enhanced with TGF-β1 treatment demonstrating that ASCs could be used to protect against DR and to treat retinal vascular disease. [133]. Due to the unavailability of human retinal pericytes for transplantation, these cells, that are able to stabilize existing retinal microvasculature, could therefore represent an alternative therapy to the destructive laser treatment of hypoxic retina.…”