Adipose stem cells and their paracrine factors are therapeutic for early retinal complications of diabetes in the Ins2Akita mouse

Background: Early-stage diabetic retinopathy (DR) is characterized by neurovascular defects. In this study, we hypothesized that human adipose-derived stem cells (ASCs) positive for the pericyte marker CD140b, or their secreted paracrine factors, therapeutically rescue early-stage DR features in an Ins2(Akita) mouse model. Methods: Ins2(Akita) mice at 24weeks of age received intravitreal injections of CD140b-positive ASCs (1000 cells/1 mu L) or 20x conditioned media from cytokine-primed ASCs (ASC-CM, 1 mu L). Age-matched wildtype mice that received saline served as controls. Visual function experiments and histological analyses were performed 3weeks post intravitreal injection. Biochemical and molecular analyses assessed the ASC-CM composition and its biological effects. Results: Three weeks post-injection, Ins2(Akita) mice that received ASCs had ameliorated decreased b-wave amplitudes and vascular leakage but failed to improve visual acuity, whereas Ins2(Akita) mice that received ASC-CM demonstrated amelioration of all aforementioned visual deficits. The ASC-CM group demonstrated partial amelioration of retinal GFAP immunoreactivity and DR-related gene expression but the ASC group did not. While Ins2(Akita) mice that received ASCs exhibited occasional (1 in 8) hemorrhagic retinas, mice that received ASC-CM had no adverse complications. In vitro, ASC-CM protected against TNF alpha-induced retinal endothelial permeability as measured by transendothelial electrical resistance. Biochemical and molecular analyses demonstrated several anti-inflammatory proteins including TSG-6 being highly expressed in cytokine-primed ASC-CM. Conclusions: ASCs or their secreted factors mitigate retinal complications of diabetes in the Ins2(Akita) model. Further investigation is warranted to determine whether ASCs or their secreted factors are safe and effective therapeutic modalities long-term as current locally delivered therapies fail to effectively mitigate the progression of early-stage DR. Nonetheless, our study sheds new light on the therapeutic mechanisms of adult stem cells, with implications for assessing relative risks/benefits of experimental regenerative therapies for vision loss.