Adrenocortical cell transplantation reverses a murine model of adrenal failure

Abstract

Purpose Although adrenal insufficiency can be managed with steroid replacement, transplantation of adrenocortical cells may represent a more definitive therapy. Methods An adrenal failure model was created by adding stress to mice that underwent staged bilateral adrenalectomy. Murine adrenocortical cells were seeded onto collagen sponges. The grafts were implanted under the renal capsule during the first adrenalectomy. Some mice had an additional graft placed next to the kidney. A contralateral adrenalectomy and a laparotomy were performed one week after the first adrenalectomy. Two weeks later, blood was collected for costicosterone measurement, and implants were retrieved for adrenal-specific mRNA analysis and histology. Mice that underwent the same procedures but received a graft without cells served as controls. Results Control group mortality was 100%. Mice that had only one cell-seeded implant had 42% survival, whereas mice that had two cell-seeded implants had 100% survival. Retrieved implants demonstrated viable cells and expression of adrenocortical genes. The plasma corticosterone concentration of survived animals was similar to that in normal mice. Conclusion Cells transplantation restored the adrenocortical function in these mice. Further optimization of this technique could bring a curative therapy to patients with adrenal insufficiency.

The adrenal gland microenvironment in health, disease and during regeneration

“…Considering these drawbacks related to adrenal hormone supplementation, several alternative therapeutic approaches have been proposed and tested. 129 These include auto-and allotransplantations of the adrenal glands, 130 adenoviral-associated virus (AAV)-mediated gene targeting, 131,132 and either allo-or xenotransplan-tation of adrenocortical cells, [133][134][135][136][137][138][139] or various stem cells reprogrammed into steroidogenic-like cells. [140][141][142] Apart from allotransplantation of a whole human adrenal with its intact microenvironment, all the other experiments were performed in animals, preferentially using rodent models.…”

“…[140][141][142] Apart from allotransplantation of a whole human adrenal with its intact microenvironment, all the other experiments were performed in animals, preferentially using rodent models. 129 Usually in these experiments adrenocortical cells were either transplanted directly under the kidney capsule or into the adrenal glands as single cell suspensions, or were incorporated inside various 3D scaffoldings or devices, such as polycarbonate cylinders, 143 collagen sponges, 139 alginate slabs or oxygenated immunoisolating devices. 144 In many of these approaches, the transplanted adrenocortical cells managed to survive in vivo and to restore adrenal function in animals that underwent bilateral adrenalectomy.…”

“…144 In many of these approaches, the transplanted adrenocortical cells managed to survive in vivo and to restore adrenal function in animals that underwent bilateral adrenalectomy. 135,139,143 By contrast to adrenocortical cell transplantations, the majority of the studies using reprogrammed stem cells were performed only in vitro, hence the protective abilities of these adrenocortical-like cells are not known. Another important aspect is whether the amount of steroids produced by these transplanted cells can sufficiently protect the animals during stress conditions.…”

“…Modulation of the experimental protocol with removal of the second adrenal gland 1 week after cell transplantation demonstrated a 42% survival rate within the first 14-days after exposure. 139 Better understanding of the adrenal gland microenvironment should greatly improve the functional efficiency of adrenal transplants. As in many of these approaches only a single clonal population of adrenocortical cells from the glucocorticoid-producing zone was used, few reports demonstrated successful restoration of aldosterone production, as e.g.…”

New Directions for the Treatment of Adrenal Insufficiency

“…Further work to assess the function of implanted cells seeded on a collagen matrix, using a mouse model with adrenal insufficiency, determined that treatment involving staged bilateral adrenalectomy of the animals and implantation of collagen sponges each time was the most beneficial. This protocol lead to a 100% survival rate (up from 42% in mice with only one implant and 0% in animal receiving the graft without cells) and reversal of adrenal insufficiency, supported by restoration of corticosterone levels and the expression of adrenal markers by the transplanted cells ( 46 ).…”