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

Abstract Decreased trabecular meshwork (TM) cellularity is a critical pathogenic cause of primary open-angle glaucoma, yet therapies to regenerate the decellularized TM are very limited. Induced pluripotent stem cell-derived TM-like cells (iPSC-TM) can efficiently restore aqueous humor outflow. Here, we conducted a multi-modal RNA sequencing analysis to characterize the molecular mechanisms underlying TM regeneration. Our clustering analysis identified a group of iPSC-derived alpha6 integrin-positive (iPSC-ITGA6 + ) cells with a distinct transcriptome that wasn’t observed in primary TM (pTM) cells. These iPSC-ITGA6 + cells not only stimulate pTM proliferation but also facilitate the repopulation of the TM and Schlemm’s canal in glaucoma, with a much higher efficiency than other iPSC-TM subtypes. Interaction with iPSC-ITGA6 + cells is characterized by the proliferation and rejuvenation of endogenous pTM cells, primarily through the transcription of long non-coding RNA nuclear paraspeckle assembly transcript1 and the abundance of paraspeckles within iPSC-ITGA6 + cells. Enhancing paraspeckle assembly by MEN β-associated RNA promotes the rejuvenation and proliferation of pTM, suggesting a novel and promising approach for TM regeneration.