Corneal blindness affects millions of individuals world-wide and usually can only be treated by transplantation of donated tissue. In many regions of the world donor tissue is not available;in the US, the supply of corneas for transplant is threatened by increasing numbers of eyes with refractive surgeries. The long-term goal of this project is to address corneal blindness by developing therapies based on stem cells. This project has already identified and characterized adult human corneal stromal stem cells (CSSC), which can be expanded in culture while retaining the ability to adopt a keratocyte phenotype and to elaborate abundant stroma-like connective tissue. When CSSC were cultured on a scaffolding of aligned paralel nanofibers of poly(ester urethane)urea (PEUU), a biodegradable polymer, they secreted connective tissue with aligned collagen similar to that of normal corneal stroma. When CSSC were injected into stromas of lumican knockout mice, collagen in the stroma became more organized and corneal transparency was increased. Importantly, human CSSC exhibited an immune privilege in mice, remaining viable for months without immune rejection. The new proposal will test specific hypotheses emanating directly from these exciting findings.
Aim 1 documents the process of tissue regeneration by CSSC by testing the predictions that (a) CSSC first remove existing tissue by temporally regulated expression of a specific group of matrix metalloproteinases;(b) after this removal process, CSSC rebuild stromal tissue by deposition of new connective tissue;and (c) this regeneration process can remodel scar tissue similar to that causing most human corneal blindness.
Aim 2 combines CSSC with PEUU scaffolding to produce a novel bioengineered tissue and tests the predictions that (a) CSSC monolayers on PEUU nanofiber scaffolding can integrate and function as transparent stromal tissue in mouse corneal transplants;(b) CSSC can be incorporated into multilayered PEUU scaffolding with the thickness and strength of a corneal stroma;and (c) the multilayered constructs can functionally replace stroma after transplantation into rabbit corneas using deep anterior lamellar keratoplasty. The scientific impact of this study will be a demonstration of effectiveness of two novel stem-cell based therapeutic approaches for corneal scarring, indicating a readiness for translation of each to clinical trials.
Corneal blindness is a health problem world-wide. For many individuals with this condition there is no option for restoration of vision. This project will use adult human stem cells to develop therapy for corneal scarring, a major source of blindness. These stem cells can be produced in large numbers, are safe, and do cause tissue rejection. Successful development of these therapies may open new opportunity to restore vision to large numbers of people.
| Stern, Jeffrey H; Tian, Yangzi; Funderburgh, James et al. (2018) Regenerating Eye Tissues to Preserve and Restore Vision. Cell Stem Cell 22:834-849 |
| Syed-Picard, Fatima N; Du, Yiqin; Hertsenberg, Andrew J et al. (2018) Scaffold-free tissue engineering of functional corneal stromal tissue. J Tissue Eng Regen Med 12:59-69 |
| Shojaati, Golnar; Khandaker, Irona; Sylakowski, Kyle et al. (2018) Compressed Collagen Enhances Stem Cell Therapy for Corneal Scarring. Stem Cells Transl Med 7:487-494 |
| Gosselin, Emily A; Torregrosa, Tess; Ghezzi, Chiara E et al. (2018) Multi-layered silk film coculture system for human corneal epithelial and stromal stem cells. J Tissue Eng Regen Med 12:285-295 |
| Ghezzi, Chiara E; Marelli, Benedetto; Omenetto, Fiorenzo G et al. (2017) 3D Functional Corneal Stromal Tissue Equivalent Based on Corneal Stromal Stem Cells and Multi-Layered Silk Film Architecture. PLoS One 12:e0169504 |
| Hertsenberg, Andrew J; Shojaati, Golnar; Funderburgh, Martha L et al. (2017) Corneal stromal stem cells reduce corneal scarring by mediating neutrophil infiltration after wounding. PLoS One 12:e0171712 |
| Wang, Siran; Ghezzi, Chiara E; Gomes, Rachel et al. (2017) In vitro 3D corneal tissue model with epithelium, stroma, and innervation. Biomaterials 112:1-9 |
| Hertsenberg, Andrew J; Funderburgh, James L (2016) Generation of Corneal Keratocytes from Human Embryonic Stem Cells. Methods Mol Biol 1341:285-94 |
| Palchesko, Rachelle N; Funderburgh, James L; Feinberg, Adam W (2016) Engineered Basement Membranes for Regenerating the Corneal Endothelium. Adv Healthc Mater 5:2942-2950 |
| Funderburgh, James L; Funderburgh, Martha L; Du, Yiqin (2016) Stem Cells in the Limbal Stroma. Ocul Surf 14:113-20 |
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