Cushing Syndrome: The Role of MSCs in Wound Healing, Immunosuppression, Comorbidities, and Antioxidant Imbalance.

Miriam Caffarini,Tatiana Armeni,Laura Cianfruglia,Giorgio Arnaldi,Anna Campanati,Monia Orciani,Giovanni Di Benedetto,Pamela Pellegrino,Marianna Martino,Annamaria Offidani

doi:10.3389/fcell.2019.00227

Miriam Caffarini, Tatiana Armeni + Show 8 more

Open Access

https://doi.org/10.3389/fcell.2019.00227

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Abstract

Cushing syndrome (CS), caused by glucocorticoid (GCs) excess, is strictly connected to onset of different metabolic diseases and impaired wound healing. The source of excessively high levels of GCs allows the identification of endogenous and exogenous (iatrogenic) CS. Iatrogenic patients usually receive also anti-metabolites serving as the foundation to modern steroid-sparing immunosuppressive therapy. Tissues mainly targeted by CS are bone and fat, both derived from progenitor cells named mesenchymal stem cells (MSCs). In addition, the pathogenic role of MSCs in other diseases sharing common properties with CS, such as an altered inflammatory profile and increased oxidative stress, has been identified. In this light, MSCs isolated from skin of control healthy subjects (C-MSCs), patients affected by endogenous CS (ENDO-MSCs), patients affected by iatrogenic CS (IATRO-MSCs) and patients affected by exogenous CS receiving steroid-sparing drugs (SS-MSCs), respectively, have been isolated and analyzed. ENDO- and IATRO-MSCs showed a reduced differentiative potential toward osteogenic and adipogenic lineages compared to C-MSCs, whereas SS-MSCs re-acquired the ability to differentiate, with a trend similar to control cells. In addition, MSCs from CS groups, compared to control MSCs, displayed a reduction in the secretion of cytokines (immune-suppression), a decreased expression of genes related to wound healing and a dysregulation of the enzymes/genes related to antioxidant capacity. In conclusion, our results suggest that the hallmarks of CS, such as wound healing impairment and immunosuppression, are already detectable in undifferentiated cells, which could be considered a potential therapeutic early target for control of CS.

Highlights

Cushing syndrome (CS) is a clinical condition resulting from chronic exposure to excessively high levels of glucocorticoids (GCs)
For mesenchymal stem cells (MSCs) isolation, 12 patients were included into the study and divided in four groups: 3 controls (C-MSCs, healthy subjects), 3 endogenous (ENDO-MSCs, patients affected by pituitary CS), 3 iatrogenic (IATRO-MSCs, patients affected by exogenous CS), 3 steroid-sparing (SS-MSCs, patients affected by exogenous CS receiving steroid-sparing drugs)
The level of secreted cytokines was lower in MSCs derived from CS patients [both affected by endogenous and exogenous CS] and SS-MSCs than in C-MSCs (Figure 3B)

Summary

Introduction

Cushing syndrome (CS) is a clinical condition resulting from chronic exposure to excessively high levels of glucocorticoids (GCs) (endogenous or exogenous/iatrogenic). The most common form of CS is secondary to chronic treatment with GCs, commonly used for their anti-inflammatory action in many chronic immune-mediated and inflammatory clinical conditions. Endogenous hypercortisolism is a rare disease (incidence 1.2−2.4 cases per million/year) dividing classically into two variants: ACTH-dependent (70%) and ACTH-independent (30%). The ACTH-dependent forms are characterized by the hypersecretion of ACTH by pituitary or, more rarely, extra-pituitary tumors. Glucocorticoids excess, whatever the etiology, determines multiple and complex consequences including obesity, hypertension, diabetes, thromboembolism, osteoporosis and fractures, myopathy, infections, skin alterations, and poor wound healing (Arnaldi et al, 2003). Care and control of all comorbidities should be one of the primary goals during the diagnosis and long-term follow-up of these patients

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