Faculty of Health and Medical Sciences, University of Adelaide, Adelaide 5005, Australia.
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia.
Endocrinology. 2024 Jul 1;165(8). doi: 10.1210/endocr/bqae086.
Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, 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 intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing 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 endpoint. 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-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe 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.
认识到当前治疗艾迪生病的局限性，需要新的治疗方法，这些方法可以复制受 ACTH 控制的动态生理皮质类固醇分泌。这些实验的目的是评估在大型动物模型中进行肾上腺皮质细胞移植（ACT）的可行性，方法是适应已成功用于皮内胰岛细胞移植的方法，使用完全可生物降解的临时基质。通过双侧肾上腺切除术、细胞分离、培养和皮内注射到使用可生物降解临时基质（BTM）泡沫预先准备的皮肤部位来进行自体猪 ACT。在肾上腺皮质细胞移植时提供氢化可的松支持，并根据耐受情况逐渐减少。监测血液肾上腺皮质激素浓度，并在终点检查移植部位。结果测量包括细胞组织化学、全身激素产生和氢化可的松独立性。移植的肾上腺皮质细胞在皮内部位具有存活和增殖的能力，并能够自我组织成具有正常肾上腺组织学结构特征的离散组织类器官。由于在死后的肾上腺床中发现了副肾上腺和再生皮质组织，系统激素水平的解释变得复杂。皮质类固醇无法完全停止。大型动物模型中的 ACT 以前从未尝试过，但这是向临床转化迈出的重要一步。这些结果表明，基于 BTM 部位的肾上腺类器官的发展，ACT 具有潜力。然而，由于输送剂量和随后的增殖导致细胞数量不足，无法实现临床相关的全身激素产生，这表明功能不足。
