Loss of β-cell mass and insulin-producing ability is a major challenge in type 1 diabetic patients, and β-cells have notoriously low proliferating rates in adult humans. Therapeutic approaches that could lead to even partial restoration of the insulin-producing ability of the pancreas would address a major therapeutic need.  The concept that the exocrine compartment of the pancreas harbors progenitor cells with the ability to give rise to new β-cells through differentiation has been debated for years. Our work has focused on the description and characterization of a novel population of multipotent BMP-7-responsive progenitor-like cells within the human exocrine pancreas with the potential to generate functional endocrine cells. These cells are characterized by the expression of PDX1 and ALK3, a canonical BMP receptor. We also confirmed that these cells are present in the mouse pancreas, which affords us the possibility of studying endogenous regeneration in a setting not involving transplantation. Importantly, preliminary analysis of samples from the nPOD tissue network supports the concept that these cells are present in patients who have had T1D for many years, thus opening the possibility of developing regenerative therapies for T1D. In this talk, we will present our general strategies to: (a) Expand the high-resolution characterization of the human pancreatic progenitor cell niche by single-cell analytical techniques (Qadir et al, PNAS, 2020); and (b) Explore real-time β-cell regeneration in human pancreatic slices (Qadir et al., Nature Communications, 2020). We will also briefly discuss our parallel studies on the CRISPR/cas9-mediated insertion of “kill switches” into human pluripotent stem cells to enhance their safety and efficacy in the context of ongoing and future clinical trials. Taken together, the topics discussed in today’s seminar will present a clear roadmap towards the implementation of state-of-the-art regenerative medicine approaches in the clinical arena.