Cellular Mechanisms Regulating Conventional Outflow of Aqueous Humor

Despite its small size, the trabecular meshwork (TM, including the inner wall of Schlemm's canal) is functionally complex, containing multiple cell "types" segregated by location and playing a central role in intraocular pressure (IOP) homeostasis. TM cells are functionally coupled through multiple mechanisms, including paracrine signaling; through transmission of biomechanical stimuli (stretch and shear stress); and, hydrodynamically, through the funneling effect. This tight cellular coordination appears to be central to TM function and its many roles. For example, TM cells maintain an intricate extracellular matrix which is turned over rapidly and appears to play an important role in determining IOP. They are avidly phagocytic, particularly in the inner TM, so as to protect the narrow flow channels of the outer TM and inner wall of Schlemm's canal. They are mechanoresponsive to multiple stimuli, which appears to play a key role in IOP homeostasis. They are dynamically contractile, and their acto-myosin tone influences their contractile properties and stiffness. Significantly, these contractile properties are pivotal for overall TM function; indeed, the recently introduced cytoskeletal relaxing agents directly target their contractility for therapeutic benefit. Further, the TM contains a resident population of stem cells that likely play a role in maintaining tissue function over a lifetime. Because TM cells are lost at a higher rate in glaucoma, there exists the possibility of restoring TM function through stem cell-based therapies. In this chapter, we provide a holistic view of TM cellular phenotype and function, identifying opportunities for therapeutic intervention and unsolved questions about this enigmatic tissue.