In an effort to advance the treatment strategies for the ocular surface diseases, I am focused on a regenerative medicine and single cell RNA sequencing based approaches to better comprehend the cellular biomarkers and molecular mechanisms involved in corneal tissue development and diseases.
1. Reprogramming of corneal epithelial cells into iPSC to differentiate into various ocular cell types: As advancement in methods to differentiate iPSC into ocular lineages progresses, new non-integrative transfection strategies shows more promise for safe clinical application. The cellular source of iPSC is a key determinant in differentiation efficiency due to its epigenetic memory. We hypothesize that iPSC reprogrammed from ocular epithelial cells will be more efficient in differentiating into ocular lineages and exhibit higher functionality than non-ocular sources such as fibroblasts or blood. We intend to harness the inherent epigenetic memory of the ocular epithelial cells for superior and quicker protocol to regenerate cornea.
2. Non-integrative transient reprogramming to rejuvenate aging corneal epithelial cells: Cornea is constantly regenerated from a small population of limbal epithelial stem cells via transiently amplifying cell (TAC) states. Partial reprogramming is an innovative new strategy to reverse the chronological clock of cells. Employing this specific strategy, we wish to explore the transdifferentiated or partially reprogrammed state in ocular epithelial cell types by giving pulsed reprogramming factors.
3. Eye Cell Atlas: We wish to establish an Eye Cell Atlas. Our aim is to establish phenotypically and transcriptionally characterized different subsets of primary human ocular cells. The knowledge gained from separating and identifying different cells types of the eye will provide greater understanding into the physiology and overall function of the various eye tissues. In addition, characterizing these tissues based on age will provide more information on changes that occur in the eye with aging.
4. Improving corneal transplant immune tolerance with co-transplant of hematopoietic stem cells (HSC): Hematopoietic stem cell (HSC) replacement transplantation can ameliorate diseased hematologic system, thus inhibiting immune disorders including autoimmune diseases and immunodeficient disorders. One of the promising studies from Weissman Lab show that transplantation of MHC-mismatched HSCs can be performed with selective antibody conditioning bypassing the need for chemo and radiotherapy. The resultant chimeric immune systems were demonstrated to be immunologically tolerant to heart tissue from the HSC donor, providing a safe platform for HSC transplantation as a means to solid organ transplantation. We are further investigating the potential of this therapy in improving immune tolerance and graft versus host diseases associated with corneal transplantation.
5.Targeting cellular repair of corneal aging, inflammation, and oxidative stress by intercellular mitochondrial transfer strategy: Mitochondrial dysfunction is one of the critical hallmarks of both aging and inflammation. The perturbances in cellular redox homeostasis leads to high free radical burden thereby causing oxidative stress in the cells. The major pathway of free radical leakage is the electron transport chain inside the damaged mitochondria. Thus, mitochondrial replacement strategies like intercellular transfer of healthy mitochondria is paving way to the emerging new avenue of subcellular organelle therapy. We hypothesize that the ocular cells maintain their health regenerative capability by intrinsic intercellular mitochondrial exchange. We aim to identify the potential mitochondrial donor cells in the eye and employ them exogenously for corneal tissue injury repair.
