Type 1 diabetes is an intractable disease that results from a decline in insulin production due to the autoimmune destruction of pancreatic β-cells that produce insulin. The standard treatment is lifelong insulin injections, but maintaining normal blood glucose levels is difficult and often leads to abnormally low or high blood glucose levels (i.e., hypoglycemia and hyperglycemia), which are often responsible for various comorbidities. Pancreas or islet transplantation is one of the most promising treatments for type I diabetes, but limited supplies of compatible donor cells remain a challenging problem.

There is an extensive effort to use pluripotent stem cells, such as embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, as a source of pancreatic β-cells in regenerative medicine due to their extraordinary proliferative and multilineage differentiation potential. Recently, methods to induce pancreatic β-cell differentiation using pluripotent stem cells have been developed, but a more efficient and reproducible differentiation process necessitates a deeper understanding of the differentiation mechanisms for pancreatic cell lineages.

The research team conducted this study to elucidate the differentiation mechanism of pancreatic endoderm by searching for new factors that regulate the expression of NKX6-1, a key marker gene of pancreatic endoderm. PDX1 is a gene long known to regulate NKX6-1 expression in pancreatic endoderm, and ONECUT1 was also recently reported, but no other factors are known.

They established a screening system using siRNA knockdown libraries to search for genes that regulate pancreatic endoderm differentiation using a cell model that differentiates human iPS cells into pancreatic endoderm and identified HHEX as a candidate gene. HHEX is known to be expressed in endodermal tissues during early development and to contribute to organogenesis, but its role in pancreatic endoderm development is not fully understood.

RNA sequencing revealed that HHEX knockdown in the pancreatic endoderm decreased the expression of genes vital to pancreatic development, including NKX6-1, PTF1A, ONECUT1, and ONECUT3, independent of PDX1 regulation.

In conclusion, this study revealed that HHEX operates independently of PDX1 to regulate pancreatic development and could be another master regulator of pancreatic endoderm differentiation.

The results of this study were published online in Scientific Reports on May 29, 2023.

• doi: 10.1038/s41598-023-35875-1