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Thomas Allan Mendel, Stephen Cronk, Jaymes Beech, Alexander M Guendel, Shayn Peirce, Paul Andrew Yates; Adipose derived stem cell therapeutic potential for treatment of diabetic retinopathy is modulated by both oxygen tension and diabetic status of donor cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):1384.
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© ARVO (1962-2015); The Authors (2016-present)
Adipose derived stem cells (ASCs) stabilize the retinal microvasculature in the Akimba model of diabetic retinopathy (DR) through both direct contact and paracrine effects. Factors influencing the therapeutic efficacy are unknown, but critical to elucidate towards translational application. In this study, we examine the impact of oxygen tension and diabetic status of ASC donor on the secretome ASC-derived-pericytes in vitro and how they alter therapeutic efficacy in vivo.
ASCs were isolated from both diabetic Akimba (dASC) and normo-glycemic wildtype mice (nASC) at 9 weeks of age. DiI-labeled passage 4 dASC and nASCs-pericytes were then injected intravitreally in 6 week old Akimba mice, with eyes harvested 4 weeks later for analysis of ASC incorporation and impact on the microvasculature. Supernatant from in vitro cultured dASCs and nASCs-pericytes was collected and evaluated by multiplex ELISA with respect to angiogenic secretome. In parallel, normoxic passage 5 human ASCs were subjected to hypoxic conditions (1% oxygen) or left in normoxic conditions, with supernatant collected 24 hours later and analyzed by multiplex ELISA.
Pericytes derived from diabetic ASCs, in contrast to normo-glycemic ASCs, were unable to prevent damage to the retinal microvasculature that occurs in the Akimba DR mouse (Fig 1A). A number of pro-angiogenic factors were found to be diminished in the supernatant of dASCs as compared to nASCs, including IGFBP3 (Fig 1B). In vitro assays of proliferation and apoptosis were also altered in dASCs as compared to nASCs. Similarly, hypoxia diminished IBFBP3 expression in cultured hASCs (Fig 2).
Exogenous diabetic ASC-pericytes show diminished ability to protect retinal microvasculature in a murine model of DR. Diabetes impairs ASC-pericyte viability and alters the pro-angiogenic secretome. Hypoxia similarly impacts ASC-pericyte paracrine activity, reducing IGFBP3, a factor known to ameliorate oxygen-induced retinopathy. These findings may explain the inability of native retinal pericytes to rescue the microvasculature in a diabetic environment, and suggest autologous stem cell approaches to treating DR may be problematic. It may be possible to enrich environmental conditions as well as establish viability assays that can both predict and enhance ASC therapeutic efficacy.
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