Evaluation of secretomes derived from human dermal and adipose tissue mesenchymal stem/stromal cells for skin wound healing: not as effective as cells

Abstract

Background Although the paracrine effects of mesenchymal stem/stromal cells (MSCs) have been recognized as crucial mediators of their regenerative effects on tissue repair, the potential of MSC secretomes as effective substitutes for cellular therapies remains underexplored. Methods In this study, we compared MSCs from the human dermis (DSCs) and adipose tissue (ASCs) with their secretomes regarding their efficacy for skin wound healing using a translationally relevant murine model. Results Proteomic analysis revealed that while there was a substantial overlap in protein composition between DSC and ASC secretomes, specific proteins associated with wound healing and angiogenesis were differentially expressed. Despite a similar angiogenic potential in vivo, DSC and ASC secretomes were found to be less effective than cells in accelerating wound closure and promoting tissue remodeling. Conclusions Overall, secretome-treated groups showed intermediary results between cells- and control-treated (empty scaffold) groups. These findings highlight that although secretomes possess therapeutic potential, their efficacy might be limited compared to cellular therapies. This study contributes to the growing understanding of MSC secretomes, emphasizes the need for further protocol optimization, and offers insights into their potential applications in regenerative medicine.

1. Introduction

Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells present in virtually all adult tissues that participate in homeostasis and repair by the secretion of paracrine factors and differentiation in tissue-specific cells [1–4]. MSCs can be isolated with high yield and maintain their proliferative capacity and genetic stability for several passages in vitro [5–7]. They are classified as low or non-immunogenic as they express low levels of MHC I and lack MHC II and other co-stimulatory molecules. They do not cause T-cell activation and consequent rejection when allogeneically or xenogeneically transplanted [8–10], and due to their limited plasticity, they do not form tumors in vivo [9–12]. MSCs have been tested for multiple therapeutic applications in regenerative medicine, including neurodegenerative disorders, renal failure, diabetes, and skin wound healing [4, 13–16]. Their ability to promote cell growth, angiogenesis, and immunomodulation has been widely described and supported by basic, pre-clinical, and clinical studies [16–19].

We have previously isolated and characterized MSCs derived from the human dermis and adipose tissue (DSCs and ASCs, respectively) harvested from tissues discarded after elective abdominoplasties [5, 7, 20]. We have shown that both DSCs and ASCs share the general MSC immunophenotype (CD73+, CD90+, CD105+, CD34−, and CD45−) and mesodermal differentiation potential (adipogenic, osteogenic, and chondrogenic). Both have similar self-renewal capacity and remain genetically stable over time in culture with a low frequency of nuclear alterations. However, while the isolation procedure for ASCs recovers a higher initial number of cells, the DSCs show shorter doubling time/faster proliferation and quicker closure of in vitro wounds as evaluated by cell scratch assay [7]. We also tested DSCs and ASCs’ potential to promote skin wound healing in a mouse model, using a commercially available collagen-based dermal template (Integra bilayer wound dressing, Integra LifeSciences) as a delivery system. We showed that animals treated with either DSC or ASC have accelerated wound closure in comparison to controls (empty scaffold).