Study findings may improve production of stem cell-derived insulin-producing cells
A study has identified reasons why insulin-producing beta cells derived from human pluripotent stem cells are not as effective and efficient at producing insulin in response to blood sugar as their natural counterparts.
In recent years, stem cell-derived beta cells have emerged as a potential therapy for the treatment of insulin-dependent diabetes. The clinical translation of stem cell-derived beta cells for insulin production has remained a major issue, particularly at the differentiation stage. As part of efforts to uncover the reasons why these cells are not as efficient as natural cells, a team of researchers from Washington University School of Medicine (MO, USA) has outlined key distinctions between natural beta cells and stem cell-derived beta cells. It is hoped that the findings from the study will improve the efficacy and efficiency of the cells as well as accelerate manufacturing advancements to improve the treatment of insulin-dependent diabetes.
The team utilized a technique known as single-cell multiomic sequencing to identify chromatin and transcriptional differences between the stem cell-derived islets and the natural islets. Multiomic analysis revealed that stem cell-derived beta cells are less mature than normal beta cells, rendering them less effective at producing insulin. The researchers also found that the cells had a genetic profile more like liver and intestinal cells than beta cells.
Further analysis of the stem cell-derived beta cells revealed irregularities in chromatin, a molecule that is involved in regulating gene expression in cells. Discussing their findings, the team suggested the efficacy of the beta cells could be improved by keeping the chromatin in an active state to enable the activation of genes involved in insulin production and secretion, whilst suppressing the expression of genes that cause the cells to behave more like other cell types.
Senior investigator of the study, Jeffery Millman, commented, “having learned about chromatin differences between natural beta cells and stem-cell derived beta cells, we believe it will be possible to regulate chromatin to improve the quality of stem-cell derived beta cells, as well as the quantity of the cells that we can produce.”
Testing their theory, the team transplanted stem cell-derived beta cells into mice. After 6 months, they found that the chromatin regions associated with other cell lineages were inaccessible and observed an improvement in the lineage-specific gene expression of the cells. Extended in vivo culturing did not lead to improvements in the lineage-specific gene expression of the cells, suggesting that chromatin plays an important role in the process.
“The more efficient the beta cells are, the closer we will be to ramping up the manufacturing necessary to produce treatments,” commented Millman.