Journal Club: Comparative and integrative single cell analysis reveals new insights into the transcriptional immaturity of stem cell-derived β cells

by Lucas Unger

The differentiation of human pluripotent stem cells into insulin-producing beta cells holds great potential for both transplantation-based treatment of insulin-dependent diabetes and diabetes research.

In this study, a comprehensive analysis of publicly available single-cell RNA sequencing data was performed to compare stem cell-derived beta cells (SC-β) across different protocols. They were compared to fetal and adult beta cells to assess their maturation state and identify key differences.

The analysis revealed that SC-β cells, regardless of the differentiation protocol used, exhibited similar transcriptional profiles. This suggests that they reach comparable developmental stages despite variations in the protocols. The SC-β cells represent an intermediate state between fetal and adult beta cells. They lack fetal beta cell markers but show high expression of transcription factors associated with progenitor states, reflecting incomplete maturation. While they express essential beta cell genes, their transcriptional patterns remain distinct from those of fully mature beta cells.

A key finding was the consistent under expression of specific genes—INS, IAPP, FAM159B, CHGB, G6PC2, ADCYAP1, MAFA, and HADH—in SC-β cells compared to mature beta cells. Despite differences in protocols and starting materials, all SC-β cells displayed a similar pattern of immaturity. This suggests that current differentiation approaches may share a fundamental limitation.

The study also identified crucial transcriptional regulators that could be pivotal in driving full beta cell maturation. These insights offer valuable directions for refining differentiation protocols, bringing the field one step closer to generating fully functional beta cells.