In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation

Abstract

Recognising the limitations of current therapies for Addison’s disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of adrenocorticotropic hormone, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intra-cutaneous pancreatic islet cell transplantation, using a fully biodegradable temporising matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture and intracutaneous injection into a skin site pre-prepared using a biodegradable temporising matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored and the transplant site was examined at end-point. Outcome measures included cellular histochemistry, systemic hormone production and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site, and an ability to self-organise into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by identification of accessory adrenals and regenerative cortical tissue within the adrenal bed post-mortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step towards clinical translation. These results demonstrate potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.