iPSC-derived ITGA6-positive cells restore aqueous humor outflow in glaucoma eyes

Decreased trabecular meshwork (TM) cellularity, which is a critical pathological cause of primary open-angle glaucoma (POAG), lacks effective regenerative therapies. Here, we used multi-modal RNA sequencing to investigate regeneration mechanisms of induced pluripotent stem cell-derived TM cells (iPSC-TM). We identified a distinct iPSC-derived alpha6 integrin-positive (iPSC-ITGA6+) cell population with unique transcriptional signatures absent in primary TM cells. Particularly, iPSC-ITGA6+ cells demonstrated superior capacity to induce TM proliferation, restore aqueous humor outflow, and repopulate damaged ocular drainage tissues. Furthermore, we uncovered paraspeckle assembly as the key molecular mechanism enabling rejuvenation of endogenous cells, establishing a novel menRNA-based strategy for TM regeneration.

小梁网（trabecular meshwork, TM）细胞密度降低是原发性开角型青光眼（primary open-angle glaucoma, POAG）的关键病理成因，目前尚无有效的再生治疗手段。本研究采用多模态RNA测序（multi-modal RNA sequencing）技术，探究诱导多能干细胞来源的小梁网细胞（induced pluripotent stem cell-derived TM cells, iPSC-TM）的再生机制。我们鉴定出一类独特的iPSC来源的α6整合素阳性（alpha6 integrin-positive, ITGA6+）细胞群，该细胞群具备原代小梁网细胞所不具备的独特转录组特征。具体而言，iPSC-ITGA6+细胞展现出优异的性能：可诱导小梁网细胞增殖、恢复房水流出（aqueous humor outflow），并能重新填充受损的眼引流组织。此外，我们揭示了旁斑（paraspeckle）组装作为介导内源性细胞年轻化的关键分子机制，由此建立了一种基于menRNA的全新小梁网再生策略。