Abstract
The trabecular meshwork’s (TM) physiological role is to maintain normal intraocular pressure by regulating aqueous humor outflow. With age, and particularly in eyes with primary open angle glaucoma, the number of cells residing within the TM is markedly decreased and the function of the tissue is compromised. Here we evaluate if transplantation of induced pluripotent stem cell derived TM like cells (iPSC-TM) restores TM cellularity and function in human eyes obtained from older human donors. Human iPSC were differentiated into iPSC-TM and compared to primary TM cells by RNAseq. iPSC-TM were then injected into the anterior segments of human eyes maintained in perfusion culture. Seven and 14 days eyes after injection eyes that received iPSC-TM contained significantly more cells in the TM. Fewer than 1% of all cells appeared to be iPSC-TM, but significantly more cells in these eyes were immunopositive for Ki 67 and incorporated BrdU. Our study demonstrates that transplantation iPSC-TM stimulates proliferation of endogenous TM cells in perfusion cultured human eyes from aged donors. These data, in concert with our previous findings in animal models, suggest that functional regeneration of the TM may be possible in human eyes with primary open angle glaucoma.
Highlights
The aqueous humor in the eye is continuously replaced and is essential for many physiological functions, including provision of nutrients and removal of metabolic byproducts from the avascular tissues of the anterior segment
These induced pluripotent stem cells (iPSC) were differentiated into a cell type resembling TM cells through co-culture with human primary trabecular meshwork cells
In the days thereafter these primary trabecular meshwork cells (pTM)-like cells continue to increase in size until, after approximately 60 days of differentiation, they reach a size similar to that of pTM (Fig. 1). iPSC-TM can be maintained in culture for at least 120 days, but no additional morphological changes are noted past day 60
Summary
The aqueous humor in the eye is continuously replaced and is essential for many physiological functions, including provision of nutrients and removal of metabolic byproducts from the avascular tissues of the anterior segment. Based on the premise that replacing damaged or lost TM cells in glaucomatous eyes leads to prolonged functional restoration of the TM, we sought to develop a cell replacement approach that is translationally feasible Such cells should resemble TM cells in function, be obtained, and should be patient derived to enable autologous transplantation. Transplantation of iPSC-TM into the eyes of mouse models of glaucoma results in an increased number of TM cells, enhanced aqueous humor outflow facility, decreased IOP and preservation of retinal ganglion cells[11,12]. In these animals we detected a significant increase in TM cellularity in iPSC-TM recipient eyes, but only a small fraction of these additional cells could be identified as iPSC-TM. We further wanted to investigate whether these cells are capable of inducing a proliferation response in the TM of eyes obtained from donors of advanced age
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