Editorial: Advances in β-cell development & regeneration

This is a provisional file, not the final article pathogenesis of diabetes mellitus is fundamentally linked to a decline in pancreatic β-31 cell mass (1). Replacing these insulin-producing cells remains a central goal of regenerative medicine, pursued through two primary avenues: guiding the differentiation human pluripotent 33 stem cells in vitro or harnessing the innate regenerative capacity of the pancreas in vivo (2, 3 meticulous re-analysis of single-cell datasets, they report that the transcriptional signature a 74 previously described adult progenitor population is not found in standard adult islet 75 preparations, but is instead identified in a subset of mesothelial cells of the embryonic pancreas in 76 both mice and humans. This work further identifies transcriptomic and epigenomic connections 77 between these embryonic cells and ductal/endocrine progenitors. Notably, a PROCR-like cell 78 subcluster was also found to be spontaneously co-specified during the differentiation of human iPSCs 79 into pancreatic progenitor cells. These compelling findings encourage a reinterpretation of Procr+ 80 progenitor cell origin, suggesting a potential developmental link to embryonic mesothelium and 81 highlighting the critical importance of cellular context in regenerative biology. 82 83The collective works in this Research Topic underscore key challenges for translational progress. A 85 priority is ensuring the long-term stability and function of new β-cells, which must fully integrate 86 into physiological glucose regulation without loss of identity or viability. This demands rigorous, 87 long-term validation in disease-relevant models. 88 Furthermore, the field must decisively bridge the gap between rodent models and human biology (7,89 8). Advancing human model systems-such as complex organoids and humanized mouse models-90 alongside the integration of human genomic data, will be essential to prioritize clinically relevant 91 targets (9-12). 92From a therapeutic standpoint, achieving safe and targeted delivery of regenerative cues, whether 93 pharmacological or genetic, is paramount. Strategies must minimize off-target effects, potentially 94 leveraging emerging delivery technologies. Furthermore, the success of these approaches, especially 95 in T1D, will hinge on modulating the pancreatic niche to create a supportive microenvironment for 96 new β-cells to mimic in vivo physiological settings. 97In conclusion, this collection highlights the multifaceted path toward β-cell regeneration. By 98 deepening our understanding of developmental principles, cellular plasticity, and niche interactions, 99 the prospect of a curative therapy for diabetes continues to gain momentum. 100 101The authors declare that they have no competing interests. 103