Abstract

Diabetes mellitus, particularly type 1 diabetes (T1D), results from a loss or dysfunction of insulin-producing 
pancreatic β-cells. Restoration of β-cell mass and function remains a major therapeutic goal. Two 
complementary strategies hold promise: endogenous β-cell regeneration, through stimulating proliferation, 
neogenesis, or transdifferentiation, and exogenous replacement using stem-cell-derived islet (SC-islet) 
transplantation. This review synthesizes recent advances in both areas, delineates key challenges including 
functional maturation, immune rejection, scaling, and safety, and explores bioengineering and 
immunomodulatory strategies designed to enhance outcomes. It examines in vitro differentiation protocols, in 
vivo regeneration stimuli, results from preclinical and early clinical trials, and technological innovations such 
as encapsulation, immune evasion, and gene editing that may help make SC-islet replacement a safe, durable 
therapy. Finally, future research directions are proposed to guide progress in this field. 
Keywords: β-cell regeneration; Stem cell-derived islets; Transplantation immunomodulation; Differentiation 
and maturation; Type 1 diabetes therapy