Retinal lineage specific therapeutic effect of human Orbital and Abdominal adipose-derived mesenchymal stem cells

Abstract

Purpose : This study compared the therapeutic potential for retinal regeneration of human mesenchymal stem cells derived from abdominal subcutaneous fat (ABSCs) or from orbital fat (OASCs) due to their accessibility and mutual embryonic origin with retinal tissue, respectively.

Methods : Human ABASCs and OASCs were harvested from sub cutaneous and orbital fat by collagenase digestion. Conditioned medium was collected to treat RPE cells under oxidative stress, and was studied for content by cytokine array. Differentiation towards RPE was assessed by qRT-PCR and immunostainig after a co culture system. OASCs, ABASCs, or PBS were transplanted in the sub retinal space of sodium iodate mice, retinas were analyzed By Immunohistochemistry after 3 weeks.

Results : OASCs conditioned medium prevented RPE cell death compared to cells treated with standard medium (40%±3.85 decrease,p< 0.01). OASCs and ABASCs showed secretion of anti-apoptotic and neuroprotective cytokines, however, ABASCs showed stronger secretion of immunmodulatory chemokines(threshold>1.4 folds). OASCs exhibited a potential to differentiate towards RPE lineage evident by upregulation of nuclear OTX2 and PAX6(929.7±76.2, 57.6±5.6 folds respectively). ABASCs exhibited a broader differentiation potential into retinal precursors with cytoplasmic localization of OTX2. ABASCs have specifically restored photoreceptor of sodium iodate (SI) mice, exhibited by higher ONL thickness and rhodopsin intensity when compared to PBS (ONL: ABASCs-51.8±11.7,PBS-31.1±5.76 µm. rhodopsin: ABASCs-27.4±4.09,PBS-21.5±2.57, p< 0.05). This effect was correlated with higher retinal infiltration of Iba1+ cells compared to PBS (ABASCs 50.9±14.5, PBS 28.2±8.17 cells/area, p < 0.05). SI induced RPE injury was salvaged by OASCs demonstrated by higher RPE65 intensity (OASCs-50.2±20.5, PBS-23.4±5.51, p < 0.05).

Conclusions : In summary, OASCs exhibited in vitro protective effect on RPE cell death, and differentiation potential to RPE, which translated to salvage of RPE layer in vivo. ABASCs showed immunomodulatory chemotactic secretion in vitro, as well as differentiation ability to retinal precursors, translated to restoration of photoreceptors in vivo. These data suggest a lineage specific therapeutic potential of OASCs and ABASCs in the treatment of retinal degeneration and distinguishes the potential of using each population for future cell therapy application.

This is a 2021 ARVO Annual Meeting abstract.