ESPE Yearbook of Paediatric Endocrinology

Front Endocrinol (Lausanne). 2022 Feb 18;13:837450. doi: 10.3389/fendo.2022.837450. PMID: 35250887.

Brief Summary: This paper discusses the use of Pluripotent Stem Cell (PSC)-derived pancreatic islets (SC-islets) for studying the basic biology, molecular mechanisms and therapeutic potentials of patients with congenital hyperinsulinism (CHI). The availability of CHI patient islets opens new avenues for research and development of new treatments.

PSCs represent the epiblast cells of the early embryo, capable of differentiation to any cell type in the human body. Tissue differentiated from PSCs holds enormous promise in regenerative medicine to replace or repair a damaged or degenerated organ. PSCs can also serve as a powerful research tool by allowing limitless generation of difficult-to-procure tissue and would thus serve as an attractive solution for preclinical study of CHI.

PSCs can be derived from two main sources 1) from preimplantation embryos (embryonic stem cells, ESCs) and 2) from somatic cells that have been reprogrammed back to pluripotent state by overexpression of key genes (induced pluripotent stem cells, iPSCs). iPSCs reprogrammed from a patient sample carry the disease-causing mutations of that individual and should thus phenocopy the disease, such as CHI, when differentiated. A similarly differentiated healthy iPSC line would serve as a non-isogenic control for this type of approach.

Stem cell derived islets represent a powerful tool for modeling diseases of the pancreatic beta cell, due to the potential to produce them in limitless quantities with high consistency and with high disease phenotype fidelity. In the case of CHI, the SC islets can be harnessed to discover novel anti-hypoglycemic medications, to study molecular mechanisms of newly discovered CHI genes and to study the basic biology of a hyperactive beta cell.

Thus, the modeling of CHI with SC-islets will serve as a critical next step required for the development of specific and efficient anti-hypoglycemic drugs. The availability of CHI patient islets presents an additional challenge due to the rarity of the disease. The limited tissue availability challenges any study that requires large amounts of tissue, such as screening for novel pharmacotherapeutics.