Severe burns remain a life-threatening local and general inflammatory condition often with serious sequelae, despite remarkable progress in their treatment over the past three decades. Cultured epidermal autografts, the first and still most up-to-date cell therapy for burns, plays a key role in that progress, but drawbacks to this need to be reduced by using cultured dermal-epidermal substitutes. This review focuses on what could be, in our view, the next major breakthrough in cell therapy of burns -use of mesenchymal stromal cells (MSCs). After summarizing current knowledge, including our own clinical experience with MSCs in the pioneering field of cell therapy of radiation-induced burns, we discuss the strong rationale supporting potential interest in MSCs in treatment of thermal burns, including limited but promising pre-clinical and clinical data in wound healing and acute inflammatory conditions other than burns. Practical options for future therapeutic applications of MSCs for burns treatment, are finally considered. Severe burns and their treatmentBurns are traumatic destruction of the skin and sometimes underlying tissues, usually caused by a heat source, less often by electricity or chemicals and rarely by ionizing radiation.1 Necrosis-triggered release of inflammatory mediators and in situ formation of toxic lipid-protein complexes generate local inflammation. In the most severe cases, potentially lethal acute toxaemia with systemic inflammatory response (SIR) and organ dysfunction, with a threshold around 20-30% total body surface area burnt, and dose (burn depth and extension)-dependent severity (1). Severe burns evolve in three phases:• In the early shock phase, hyperinflammation causes intense plasma leakage into the interstitium, organ dysfunction and injury aggravation. • In the following hypermetabolic phase, a long-lasting inflammatory status sustains organ dysfunctions and slows the wound-healing process, while cell-mediated immunity is impaired. • In the late local remodelling phase, cell ⁄ matrix interactions promote fibrotic, hypertrophic and ⁄ or retractile scarring.Besides aggressive supportive therapy, treating burns demands that the toxic eschar be quickly removed and that structure and function of the destroyed skin be restored. This is usually achieved through surgical eschar excision and split thickness autografts from healthy skin areas of the same patient. Despite providing epidermis and also a thin layer of dermal tissue, that technique cannot restore fully functional dermis nor epidermal appendages, and its applicability is limited by available amounts of healthy skin still present. Thus, burn treatment strategies often involve a combination of mesh expanded epidermal autografts, temporary or preparative skin substitutes including skin allografts and bio-engineered products (2), topical treatments and techniques to improve wound healing, and cell therapy in selected cases. Cell therapy for burns: background

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By using a high internal phase emulsion process, elastomeric poly(ε-caprolactone urethane) (PCLU) scaffolds were designed with pores size ranging from below 150 μm to 1800 μm and a porosity of 86% making them suitable for bone tissue engineering applications. Moreover, the pores appeared to be excellently interconnected, promoting cellularization and future bone ingrowth. This study evaluated the in vitro cytotoxicity of the PCLU scaffolds towards human mesenchymal stem cells (hMSCs) through the evaluation of cell viability and metabolic activity during extract test and indirect contact test at the beginning of the scaffold lifetime. Both tests demonstrated that PCLU scaffolds did not induce any cytotoxic response. Finally, direct interaction of hMSCs and PCLU scaffolds showed that PCLU scaffolds were suitable for supporting the hMSCs adhesion and that the cells were well spread over the pore walls. We conclude that PCLU scaffolds may be a good candidate for bone tissue regeneration applications using hMSCs.

Mesenchymal stromal cell (MSC)-based cell therapy has received great interest in regenerative medicine. Priming the cells during the culture phase can improve their efficacy and/or survival after injection. The literature suggests that MSC extracellular vesicles (EV) can recapitulate a substantial part of the beneficial effects of the cells they originate from, and that micro-RNAs (miRNAs) are important players in EV biological action. Here, our aim was to determine if two classical priming methods of MSC, interferon-gamma (IFNγ) and hypoxia (HYP), could modify their EV miRNA content. Human bone marrow MSCs (BM-MSCs) from five healthy donors were cultured with IFNγ or in HYP or in control (CONT) conditions. The conditioned media were collected after 48 h in serum-free condition and EV were isolated by ultracentrifugation. Total RNA was isolated, pools of CONT, IFN, and HYP cDNA were prepared, and a miRNA profiling was performed using RT-qPCR. Then, miRNAs were selected based on their detectability and measured on each individual EV sample. Priming had no effect on EV amount or size distribution. A set of 81 miRNAs was detected in at least one of the pools of EVs. They were measured on each individual sample; 41 miRNAs were detected in all samples. The principal component analysis (PCA) failed to discriminate the groups. HYP induced a significant decrease in EV hsa-miR-34a-3p content and IFN induced a significant increase in five miRNAs (hsa-miR-25-3p, hsa-miR-106a-5p, hsa-miR-126-3p, hsa-miR-451a, and hsa-miR-665). Taken together, we found only limited alterations in the miRNA landscape of MSC EV with a high inter-individual variability.