Transforming growth factor beta-2 drives trabecular meshwork progenitor cell differentiation through SMAD2/3 signaling.

Primary open-angle glaucoma (POAG) is a major cause of irreversible blindness, yet its underly mechanisms remain unclear. Elevated intraocular pressure (IOP), the only modifiable risk factor for POAG, arises from increased resistance to aqueous humor outflow within the conventional outflow pathway, which comprises the trabecular meshwork (TM) and the inner wall of Schlemm's canal. Dysfunction and cellular loss within this pathway, particularly in the TM, are consistent features of the disease; however, the mechanisms responsible for impaired tissue maintenance and regenerative failure remain unclear. TM progenitor cells (TMPCs) have the capacity to replace lost TM cells, suggesting that impaired progenitor function may contribute to disease progression. Transforming growth factor beta 2 (TGFβ2), which is consistently elevated in the aqueous humor of POAG patients, plays a key role in regulating stem cell differentiation. We proposed that excess TGFβ2 disrupts TMPC function, leading to progenitor depletion and TM dysfunction. Here, we show that TGFβ2 drives TMPCs toward a differentiated, fibrotic phenotype, increasing TM and profibrotic gene expression while reducing progenitor markers. These effects are mediated through TGFβ2-SMAD2/3 signaling, as inhibition of this pathway preserves TMPC characteristics and suppresses fibrotic gene induction. Our findings identify TGFβ2-SMAD2/3 signaling as a regulator of TMPC fate in vitro and suggest a potential mechanism by which elevated TGFβ2 may influence TMPC behavior under pathological conditions.