Mesenchymal stromal cells pretreated with pro-inflammatory cytokines promote skin wound healing through VEGFC-mediated angiogenesis

Abstract

Skin is the largest organ of the human body. Skin wound is one of the most common forms of wound. Mesenchymal stromal cells (MSCs) have been used to aid skin wound healing via their paracrine factors. Because the secretome of MSCs can be greatly enriched and amplified by treatment with IFN-γ and TNF-α (IT), we here tested whether supernatant derived from MSCs pretreated with IT, designated as S-MSCs-IT, possesses improved wound healing effect by using a murine model of cutaneous excision, S-MSCs-IT was found to be more potent in promoting angiogenesis, constricting collagen deposition and accelerating wound closure than control supernatant (S-MSCs) during the healing of skin wound. VEGFC, but not VEGFA, was greatly upregulated by IT and was found to be a key factor in mediating the improved wound healing effect of S-MSCs-IT. Our results indicate that the beneficial paracrine effect of MSCs on wound healing can be enhanced by pretreatment with inflammatory cytokines. IT treatment may represent a new strategy for optimizing the therapeutic effect of MSCs on skin injuries.

TNF-α-Inhibition Improves the Biocompatibility of Porous Polyethylene Implants In Vivo

“…Vascular ingrowth is critical for successful biomaterial integration since nutrition of cells within the implant via diffusion is limited to 150–200 μm [ 28 , 29 ], and any pro-angiogenic effects are supportive. TNFα-inhibition is not commonly associated with pro-angiogenic effects; in fact, in certain environments, TNFα-stimulation has been shown to promote angiogenesis via vascular endothelial growth factor, in particular [ 30 , 31 ]. While we used Matrigel which is known for its pro-angiogenic potential as a carrier for Etanercept which is currently available for systemic application in humans, it is important to keep in mind that we used a growth-factor reduced version of Matrigel.…”

Preconditioning mesenchymal stromal cells with flagellin enhances the anti‑inflammatory ability of their secretome against lipopolysaccharide‑induced acute lung injury

“…Following stimulation of TLR5-expressing cells with flagellin, a signaling cascade is triggered, which involves phosphorylation of IL-1 receptor-associated kinase 1, leading to activation of mitogen-activated protein kinase kinases and inhibitor of NF-κB kinases, ultimately activating inflammatory protein production via NF-κB and p38 mitogen-activated protein kinase ( 24 ). However, most previous studies have focused on the beneficial effects of ADSCs activated by cytokines such as TNF-α, IL-1β and IFN-γ ( 17 , 19 , 34 ). Thus, limited information is available regarding the immunomodulatory properties of flagellin-exposed ADSCs.…”

The Role of MSC Therapy in Attenuating the Damaging Effects of the Cytokine Storm Induced by COVID-19 on the Heart and Cardiovascular System

“…In mouse, rat and in vitro cell model studies, MSCs have been found to be potently angiogenic ( 192 , 212 – 221 ). As outlined previously, MSCs most likely promote angiogenesis via paracrine means, such as secretion of angiogenic factors; vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor beta (TGF-β), and platelet-derived growth factor (PDGF) ( 222 , 223 ), which are promoted under hypoxic conditions ( 224 ).…”