Adult Stem Cells Could Be Used To Model Cushing’s in the Lab: Study

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by Margarida Maia PhD |

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Adult stem cells derived from the belly skin of healthy people behaved in a similar way to fat cells when challenged to grow in an environment mimicking Cushing’s syndrome, a study found.

According to the study’s authors, these cells “could represent a reliable model to track the mechanisms” involved in the response to Cushing’s.

The study, “Mesenchymal stem cells exposed to persistently high glucocorticoid levels develop insulin-resistance and altered lipolysis: A promising in vitro model to study Cushing’s syndrome,” was published in Frontiers in Endocrinology by researchers in Italy.

Cushing’s syndrome occurs when there is too much cortisol, a glucocorticoid, in the body. Cortisol is involved in many body functions, but too much of it can cause a variety of symptoms.

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Mesenchymal stem cells are adult stem cells that can renew themselves by dividing. They can also grow into other types of cells, as varied as those making up fat, muscle, and bone tissues. As these tissues are often affected in people with Cushing’s, researchers wondered if mesenchymal stem cells could play a role in the disease.

They already knew that mesenchymal stem cells derived from the skin of patients with Cushing’s had changes in their ability to heal a wound, a known symptom of the syndrome. Now they wanted to know if these cells could shed some light on what happens in the body when there is an excess of cortisol.

They collected stem cells from the skin of seven healthy individuals (four men and three women with a mean age of 42.3 years) who had undergone abdominoplasty, a surgery to remove extra fat and skin from the abdomen.

As researchers grew stem cells in the lab, they treated them three times daily with hydrocortisone, a corticosteroid that mimics cortisol’s effects.

Two different treatment regimens were applied to separate sets of stem cells over three days. In the first group stem cells were treated with decreasing hydrocortisone doses each day to simulate what occurs naturally in the body on a 24-hour cycle, a process called the circadian cortisol rhythm. In the second group, stem cells were exposed to increasing doses of hydrocortisone each day to mimic the excess of cortisol as seen in Cushing’s syndrome.

Then, to mimic food’s effects, stem cells were given glucose (a sugar) and insulin, a hormone made by the pancreas that allows cells to take up and use glucose, also three times daily.

First, researchers found that decreasing hydrocortisone doses did not affect how much glucose cells were able to take up. But repeated doses of hydrocortisone reduced cells’ ability to take up glucose, starting at the end of the first day of treatment. This indicated a resistance to insulin, which occurs when cells are no longer able to take up glucose despite the presence of insulin.

To understand the mechanisms behind these changes, researchers also looked at certain genes and whether they were turned “on” or “off” in these stem cells.

They found that two genes involved in the breakdown of triglycerides, a type of fat found in blood, were turned off on day one in stem cells treated with increasing doses of hydrocortisone compared with those treated with decreasing doses. However, by the end of the experiment, when insulin resistance was observed, those genes were turned on again.

Genes providing instructions for making two proteins involved in the inflammatory response — IL-6 and TNF-alpha — also were turned on in stem cells exposed to an environment mimicking that seen in Cushing’s patients.

Based on these findings, researchers concluded that skin-derived mesenchymal stem cells might be a good model for studying Cushing’s syndrome in the lab.

“Like mature adipocytes [fat cells], they are responsive to insulin stimulation that promotes glucose uptake … and their chronic exposure to excessive levels of [glucocorticoids] induces the development of [insulin resistance],” the researchers wrote, adding that further functional studies are needed.