Regeneration and Cancer-The Two Sides of a "Stem Cell" Coin: The 2025 Mildred Weisenfeld Award Lecture.

Abstract

Stem cells endowed with properties of self-renewal and differentiation have opened new avenues for restoration and regeneration of damaged tissues. The same adult stem cells, when they undergo irreversible mutations, transform into cancer cells and generate a tumor. In this lecture, I present our work on these two aspects of stem cells: one focuses on regeneration of the ocular surface, whereas the other targets cancer stem cells (CSCs) in retinoblastoma (Rb). In regeneration, I present our experience of transplantation of the cultured limbal epithelial cells to restore the ocular surface in severe limbal stem cell deficiency, with 60% to 70% success. The technique proved that transplanted cells survive, network, integrate, contribute to function, and cause no harm to the patient. We also developed a technique wherein both limbal and conjunctival cells could be cultured on a single membrane utilized ring barrier. This approach was effective in reconstructing the conjunctiva and fornices in patients with severe ocular disease. Furthermore, our work led identification of a subpopulation of limbal-derived stromal cells with features of mesenchymal stem cells. We also saw success with culturing human lacrimal gland tissues marked by the presence of epithelial stem cells and mesenchymal stem cells with secretory potential. These cultures we believe could pave the way of lacrimal gland regeneration through cell therapy. We then flip to the "dark side" of stem cells: the isolation and characterization of CSCs in Rb. We worked on both primary tumors as well as Rb y79 cell lines, with a special focus on reversing their chemoresistant properties. Our work demonstrated the possible role of small extracellular vesicles in Rb as a diagnostic and prognostic marker. The reduction of chemoresistance using nano-formulated drugs and targeted delivery of drug-loaded small extracellular vesicles derived from the tumor cells shows promise.