SDF-1 improves wound healing ability of glucocorticoid-treated adipose tissue-derived mesenchymal stem cells

https://doi.org/10.1016/j.bbrc.2017.09.100Get rights and content

Highlights

  • Glucocorticoids diminish the expression of SDF-1 in AT-MSCs by reduction of PGE2.

  • The lowered expression of SDF-1 caused impaired wound-healing in AT-MSCs.

  • sAT-MSCs showed reduced expression of SDF-1 and wound-healing ability.

Abstract

Glucocorticoids cause the delayed wound healing by suppressing inflammation that is required for wound healing process. Adipose tissue-derived mesenchymal stem cells (AT-MSCs) play an important role for wound healing by their cytokine productions including stromal derived factor 1 (SDF-1). However, it has not been clear how glucocorticoids affect the wound healing ability of AT-MSCs.

In this study, we found that glucocorticoid downregulated SDF-1 expression in AT-MSCs. In addition, glucocorticoid-treated AT-MSCs induced less migration of inflammatory cells and impaired wound healing capacity compared with glucocorticoid-untreated AT-MSCs. Of note, prostaglandin E2 (PGE2) synthesis-related gene expression was downregulated by glucocorticoid and PGE2 treatment rescued not only SDF-1 expression in the presence of glucocorticoid but also their wound healing capacity in vivo. Furthermore, we found SDF-1-overexpressed AT-MSCs restored wound healing capacity even after treatment of glucocorticoid. Consistent with the results obtained from glucocorticoid-treated AT-MSCs, we found that AT-MSCs isolated from steroidal osteonecrosis donors (sAT-MSCs) who received chronic glucocorticoid therapy showed less SDF-1 expression and impaired wound healing capacity compared with traumatic osteonecrosis donor-derived AT-MSCs (nAT-MSCs). Moreover, the SDF-1 level was also reduced in plasma derived from steroidal osteonecrosis donors compared with traumatic osteonecrosis donors.

These results provide the evidence that concomitant application of AT-MSCs with glucocorticoid shows impaired biological modulatory effects that induce impaired wound healing.

Introduction

Glucocorticoids are known as one of effective anti-inflammatory medicine and often applied for various diseases such as autoimmune disorders or asthma [1]. However, because of those strong immunomodulation, glucocorticoids have severe side effects including the delayed wound healing [1]. Wound healing is dynamic and complex process involving a series of phase, inflammatory, proliferative, and remodeling [2]. In the inflammatory phase, platelets release cytokines including transforming growth factor (TGF-β) that induces the additional cytokines such as fibroblast growth factor. Then, neutrophils and macrophages arrive at the wound sites to release numerous cytokines including TGF-β1, interleukin 1α (IL-1α), tumor necrosis factor α (TNF-α), and platelet derived growth factor (PDGF) that stimulate the migration of other inflammatory cells and cell proliferation [3]. Glucocorticoids decrease the expression of these cytokines and impair proceeding further phases.

Mesenchymal stem cells (MSCs) are one of somatic stem cells and can be isolated from bone marrow, umbilical cord blood, adipose tissue, and various tissues. According to International Society for Cellular Therapy (ISCT), MSCs are characterized as their differentiation capacity into osteoblasts, chondrocytes, and adipocyte, and the expression pattern of surface antigens, such as CD73, CD90, and CD105 positive, CD14, CD34, CD45, and HLA-DR negative [4]. In addition to the differentiation capacity, MSCs have ability to produce various growth factor, cytokines, and chemokines that support tissue regeneration [5], [6].

Adipose tissue-derived mesenchymal stem cells (AT-MSCs) are considered as promising source of MSCs due to their simple isolation method from adipose tissue that is abundant in our body. Furthermore, compared with other source derived-MSCs, AT-MSCs have higher proliferation and differentiation activity, and cytokine production ability. Numerous studies have demonstrated that AT-MSCs improve wound healing by their differentiation ability into damaged tissue and facilitating migration and proliferation of various cells that support tissue repair as a paracrine regulator [7], [8].

Stromal cell derived factor 1 (SDF-1) is a strong chemoattractant that belongs to the CXC chemokine family and interacts with CXC chemokine receptor (CXCR) 4 and 7 [9]. SDF-1 is expressed by dendritic cells, fibroblasts, and endothelial cells in human skin, and production of SDF-1 from transplanted MSCs plays the central role for wound healing by promoting the migration of CXCR4 and 7 positive cells such as monocytes, endothelial progenitor cells, and epidermal stem cells [10]. In addition, previous studies have shown that glucocorticoids downregulate SDF-1 expression in prostate stromal cells and subacromial bursitis [11], [12]. From these insights, we hypothesized that glucocorticoids downregulate the expression of SDF-1 and impair the wound healing ability of AT-MSCs in vivo.

In this study, we examined the effect of glucocorticoids on wound healing ability of AT-MSCs using in vivo model, and investigated the mechanism how glucocorticoids affect to SDF-1 expression. We showed that glucocorticoid-treated AT-MSCs expressed reduced SDF-1, and exhibited the less wound healing capacity in vivo. This finding suggests that glucocorticoids induce the delayed wound healing by not only suppression of inflammation but also reduced SDF-1 production in AT-MSCs.

Section snippets

Isolation of adipose tissue derided mesenchymal stem cells

Human adipose tissues were collected from the Department of orthopedic surgery, University of Tsukuba Hospital (Tsukuba, Japan) with the approval of the ethics committee of the University of Tsukuba. AT-MSCs were isolated as previously described [13]. Isolated AT-MSCs were cultured in the maintenance medium [Iscove's modified Dulbecco medium (Invitrogen, Carlsbad, CA)/10% FBS/5 ng/mL bFGF (PeproTech, UK), and 0.1% (v/v) penicillin-streptomycin (100 U/mL penicillin, 0.1 mg/mL streptomycin;

Glucocorticoid suppressed SDF-1 expression dose dependently

Previous reports demonstrated that glucocorticoid induced the delayed wound healing because of the inhibition of inflammatory cells that was required for early process of wound healing [3]. By contrast, it is not clear the effect of glucocorticoid on adipose tissue-derived mesenchymal stem cells (AT-MSCs) that are located in subcutaneous tissue and also play an important role in wound healing process [14]. In this study, we investigated that the wound healing related factors expressed in

Discussion

In this study, we demonstrated that AT-MSCs treated by glucocorticoid showed reduced wound healing ability by downregulating of SDF-1 expression. The reduction of SDF-1 was caused by inhibition of PGE2 synthesis and combined treatment glucocorticoid and PGE2 rescued not only SDF-1 production but also wound healing potential of AT-MSCs. Furthermore, reduced SDF-1 expression and wound healing ability were also observed in sAT-MSCs consistent with AT-MSCs exposed to glucocorticoid in vitro.

Conflict of interests

The authors declare no conflicts of interest in association with the present study.

Acknowledgement

We thank the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT) for the Grants-in-Aid for Scientific Research.

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