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The Potentials of Adrenal Cortical Stem Cells

by James Dunn, M.D., Ph.D.

The human body is made up of many different cell types that carry out specialized functions.  Blood, for example, contains red blood cells that carry oxygen and white blood cells that fight infections.  The origin of every cell within the body can be traced to the fertilized egg.  Within days of fertilization, a single cell develops into a cluster of special embryonic cells called the inner cell mass.  Under the right conditions, each of these cells can replicate and give rise to every cell type within the body.  These powerful cells are called embryonic stem cells.  Because of their origin from human embryos, embryonic stem cells have generated much controversy regarding their use for medical research.

Besides embryonic stem cells, there are also stem cells that persist in every organ of the body even after birth.  For example, cells in the skin are being replaced constantly by new cells generated from skin stem cells.  Such stem cells typically reside within a specific part of the organ and are present throughout life.  Unlike embryonic stem cells, these organ-specific stem cells give rise to only a limited number of cell types within the body.  These stem cells are usually small in numbers and are probably critical to the repair of the organ when injury occurs.  There is now evidence that the adrenal cortex also contains stem cells that can give rise to the different types of specialized adrenal cortical cells.

The adrenal cortex is classically divided into three zones: the glomerulosa, the fasciculata, and the reticularis.  The exact mechanism by which the three classic adrenal cortical zones arise is poorly understood.  Each zone contains specialized adrenal cortical cells that possess specific enzymes that are used to produce different steroid hormones, including mineralocorticoids, glucocorticoids, and adrenal androgens, in response to physiologic demand. 

17-hydroxyl

progesterone

progesterone

Figure 1. Diagram of the biochemical pathways of steroid production in the adrenal cortex. Only the glomerulosa and the fasciculata are illustrated here.

All adrenal steroid hormones are synthesized from cholesterol (Figure 1). 

Cholesterol is first converted to pregnenolone by cytochrome P450scc, which is present in every adrenal cortical zone.  Pregnenolone is converted to progesterone by 3b-hydroxysteroid dehydrogenase, which is also present in all adrenal cortical zones.  Progesterone is converted to deoxycorticosterone by cytochrome P450c21, which is present in both the glomerulosa and the fasciculata.  Aldosterone, a mineralocortiocoid released by angiotensin II stimulation, is synthesized from deoxycorticosterone by cytochrome P450aldo, which is present only in the glomerulosa.  On the other hand, cortisol, a glucocorticoid released by the adrenocortictropic hormone (ACTH) stimulation, is synthesized from deoxycortisol by the enzyme 11b-hydroxylase, which is found only in the fasciculata. 

When these biochemical pathways are disturbed, the production of the steroid hormones is altered, often leading to states of adrenal insufficiency.  In congenital adrenal hyperplasia, most patients have mutations of the 21-hydroxylase gene that encodes P450c21, a key enzyme in the production of both aldosterone and cortisol.  Current medical therapy for adrenal insufficiency employs the administration of steroid hormones to replace the missing hormones.  Such treatment is life-saving but is not ideal because the body’s need for steroid hormones varies with the physiologic states.  During periods of stress, the need for steroid is increased considerably, and the normal feedback regulation in the body would increase the production of steroids automatically.  The current medical therapy for adrenal insufficiency does not have such automatic adjustment.  Instead, extra steroids are empirically given during stress states such as a significant illness. 

Traditionally the adrenal cortex is viewed as a static organ where the cells do not grow in response to physiological changes.  More recently, it has been shown that this view is incorrect.   The functional zones within the adrenal cortex are dynamic layers of cells that do respond to changes in physiologic need by cell growth.  For example, when excess ACTH is present, the fasciculata increases in size to produce additional glucocorticoids.  Alternatively, when a salt-deficient diet is given, the glomerulosa increases in size to produce extra mineralocorticoids to retain salt within the body.  It is speculated that the additional cells that expand the functional zones are generated from stem cells that reside in an area between the glomerulosa and fasciculata.  Adrenal cortical cells in this area are actively growing on a continuous basis.  This can be demonstrated by using a special tracer, bromodeoxyuridine, to label the adrenal cortical cells that are making new DNA.  With special staining, such labeled cells appear as dark brown spots between the glomerulosa and the fasciculata soon after the label is given, and the labeled cells migrate toward the adrenal capsule and medulla over a period of several days (Figure 2).

Figure 2. A cross section through the adrenal cortex. Newly produced cells in the adrenal cortex are labeled as dark brown spots.  Most of these cells are located between the glomerulosa (G) and the fasciculata (F).  These cells also spread out towards the outer edge of the adrenal cortex and the reticularis (R).

There are numerous other studies in the literature that strongly suggest the existence of stem cells within the adrenal cortex.  These stem cells are capable of making new specialized adrenal cortical cells that produce different steroid hormones.  If such adrenal cortical stem cells could be used to regenerate functional cortical tissues in patients with adrenal insufficiency, then the physiological secretion of steroid hormones could be restored.

In our laboratory, we have developed methods to isolate and to grow adrenal cortical cells from mice.  Furthermore, we have transplanted these cells into other normal mice.  We found that these adrenal cortical cells continued to express many characteristics of the normal adrenal cortex after transplantation.  These observations suggest that it would be feasible to develop similar techniques for humans whereby adrenal cortical stem cells can be transplanted into patients with adrenal insufficiency.  As a first step toward that goal, we are working to identify the adrenal cortical stem cells that can regenerate the adrenal cortex.  If successful, the next phase of the experiments will utilize such stem cells for gene transfer so that a normal copy of the gene such as 21-hydroxylase can be inserted into these stem cells.  Ultimately, the objective is to procure adrenal cortical stem cells from patients with congenital adrenal hyperplasia so that these cells may be genetically modified in the laboratory.  The corrected adrenal cortical stem cells that carry a normal copy of the gene will be transplanted back into patients with congenital adrenal hyperplasia.  For those patients who do not have adrenal glands, it may still be possible to transplant adrenal cortical stem cells from another donor, but this will likely require immunosuppressive drugs to prevent rejection.  With the proper technique, the transplanted adrenal cortical stem cells will able to regenerate functional adrenal cortical tissues as a potential cure for adrenal insufficiency.

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