Introduction: Islets-like clusters derived from pluripotent stem cells can contain an off-target cell type with characteristics of gut enterochromaffin cells. Native insulin-secreting pancreatic beta cells and gut enterochromaffin cells both express the transcription factor Nkx6.1. Alternative stem cell-derived islets lacking expression of Nkx6.1 were developed to improve in vivo potency compared to populations containing Nkx6.1-expressing cells. This novel cell population has not been previously described.

Method: Populations of stem-cell derived islets containing abundant Nkx6.1-expressing cells and populations containing few Nkx6.1 expressing cells were transplanted to streptozotocin-induced diabetic rodents. Blood glycemia was monitored over time. Grafts were explanted and analyzed for pancreatic endocrine cell content.   

Results: Populations of stem-cell derived islets containing few Nkx6.1-expressing cells were more potent at controlling rodent blood glycemia than populations containing abundant Nkx6.1-expressing cells. Grafts from animals with low-nkx6.1 implants displayed higher quantities of cells with a mature pancreatic endocrine phenotype. These cells activated expression of Nkx6.1 after transplant.

Conclusion: A novel cell population lacking expression of the marker Nkx6.1 pre-implant exhibits higher potency in vivo compared to a population expressing Nkx6.1, presumably due to elimination of off-target enterochromaffin cells. Higher potency improves therapeutic potential by reduction of effective dose.