Characterising differential maturation of stem cell‐derived islets in mice: Graft function and transcriptomic analysis
Rosie Sullivan, Lydia F. Daniels Gatward, Tzu‐Wen Hong, Zekun Lyu, William T. Blackstone Whines, Claire Duff, Ryea Arora, Adya Lonsane, Min Zhao, Victoria Salem, Aileen J. F. King, Peter M. Jones, Shanta J. PersaudAbstract
Aims
Stem cell‐derived islets (SC‐islets) offer the potential to revolutionise type 1 diabetes treatment. However, functional maturation in vivo is variable, suggesting that specific, but as‐yet undefined, environmental cues are critical. We aimed to identify pathways associated with SC‐islet in vivo maturation in mice, assess early functional markers of this, and determine whether a hyperglycaemic graft environment impairs this.
Methods
Mice transplanted with 800 SC‐islets but exhibiting differing glycaemic outcomes (cured, semi‐cured, uncured) were selected and glucose tolerance and human C‐peptide concentrations over time were measured. Single‐cell transcriptomic analysis of the graft from the cured mouse was compared with in vitro‐maintained SC‐islets. The impact of hyperglycaemia on in vivo maturation was assessed by comparing mouse recipients of SC‐islet grafts which were either hyperglycaemic or normoglycaemic for 1 month post‐transplantation.
Results
Superior SC‐islet in vivo maturation was broadly associated with progressive improvements in C‐peptide and glucose tolerance. In vivo maturation was associated with a distinct transcriptomic pattern (including increased MAFA and INS expression) compared with SC‐islets maintained in vitro. Finally, a hyperglycaemic post‐transplant environment did not affect long‐term SC‐islet maturation, with no impairment in plasma human C‐peptide seen at 6 months, and no changes in gene expression of β‐cell maturity markers after SC‐islets were transplanted into diabetic mice.
Conclusion
Longitudinal plasma C‐peptide and glucose tolerance can be used to characterise in vivo SC‐islet maturation, which is associated with transcriptomic changes not observed in vitro. Additionally, elevated blood glucose does not impair long‐term functional maturation. These findings support the importance of in vivo cues for SC‐islet maturation to inform future preclinical studies.