Pituitary organoids as models for congenital pituitary deficiencies.

Abstract

Pituitary deficiencies, or hypopituitarisms, are defined as insufficient production of one or more adenohypophyseal hormones (growth hormone, TSH, ACTH, LH-FSH and prolactin). Congenital hypopituitarism, a rare disease with severely disabling consequences, often takes the form of isolated hormone deficiencies, such as isolated growth hormone deficiency (GHD) or isolated ACTH deficiency (ACTHD), or combined pituitary hormone deficiencies (CPHD), when several pituitary hormones are affected. They are mainly the result of genetic mutations, developmental malformations or the harmful action of environmental factors during foetal development. The last two decades have seen the emergence of new in vitro models called organoids, which make it possible to partially recreate the development of an organ using pluripotent cells. Using human embryonic stem cells (hESCs) or induced human embryonic stem cells (hiPSCs), it has been possible to recreate various stages of hypothalamic-pituitary development, a complex mechanism requiring interaction between two embryonic structures of different origins, right up to the production of functional pituitary endocrine cells. Coupled with techniques for reprogramming patients' somatic cells, these organoids have made it possible to understand the cellular and molecular mechanisms leading to the pathogenicity of a mutation in the OTX2 gene, identified as being responsible for CPHD. Using the CRISPR-CAS9 gene-editing technique, they have also demonstrated that the endocrine phenotype of patients suffering from DAVID syndrome is indeed linked to a mutation in the NFKB2 gene, thereby identifying this gene as a central element in pituitary development. Finally, the ability of these organoids to present a secretory response to hypothalamic stimulation and the possibility of modulating these signals by mimicking feedback from the target organs suggest that they could be used therapeutically.