Professor Qingdao University Qingdao, Shandong, China (People's Republic)
Abstract: Decreased trabecular meshwork (TM) cellularity is a critical pathogenic cause for primary open-angle glaucoma (POAG), yet therapies to regenerate the decellularized TM are very limited. Induced pluripotent stem cell-derived TM cells (iPSC-TM) can efficiently restore aqueous humor outflow and maintain intraocular pressure homeostasis. Here, we conducted a multi-modal RNA sequencing analysis to characterize the molecular mechanisms underlying TM regeneration. Our clustering analysis based on single-cell RNA sequencing identified a group of iPSC-derived alpha6 integrin-positive (iPSC-ITGA6+) cells with a distinct transcription pattern that was not observed among primary TM (pTM) cells. These iPSC-ITGA6+ cells not only stimulated cell proliferation of pTM much more efficiently than other iPSC-TM subtypes but are also capable of restoring aqueous humor outflow in glaucoma. Furthermore, iPSC-ITGA6+ cells repopulated the TM and reversed damage to the inner wall of Schlemm’s canal. The repair process in these cells primarily relied on the abundance of paraspeckles within iPSC-ITGA6+ cells, which triggered changes in cell cycle dynamics and cell fate of pTM, as elucidated by bulk RNA sequencing. Meanwhile, enhancing paraspeckle assembly by menRNA transfection triggered pTM proliferation and rejuvenation, becoming an alternative approach for TM regeneration. This study advances our understanding of the mechanism of cell therapy and facilitates the development of new treatments for POAG.
Funding Source: This study was supported by the National Key Research and Development Program (2022YEF0132500) and Taishan Scholar Youth Expert Program (tsqn202103055).
