Stem-cell extracellular vesicles and lung repair

Abstract

Four out of the ten leading causes of morbidity and mortality worldwide are lung diseases. Despite advances in comprehending the pathophysiological mechanisms involved in these disorders, for several respiratory diseases, there is still no effective treatment able to stop their natural history or reverse the morphological and functional damage they cause. In this context, recent research has supported a potential role of cell therapy for lung diseases and critical illness. The anti-inflammatory, antifibrotic, and microbicidal effects of stem cells are mainly attributed to their secretome, which contains proteins, lipids, microRNAs, and mRNAs. These are secreted in the conditioned medium and are also present in extracellular vesicles (EVs). This review will provide a detailed discussion of the role of EVs produced by mesenchymal stromal cells in preclinical experimental models of pulmonary disorders and critical illness, as well as in ongoing clinical trials.

Immunoregulatory role of exosomes derived from differentiating mesenchymal stromal cells on inflammation and osteogenesis

“…Therefore, instead of discussing naïve MSCs, osteogenically primed MSCs, and exosomes as stand‐alone isolated phenomena, they should be viewed as the whole dynamic environment in which the exosome‐mediated intercellular communication has long been ignored. The beneficial effect of BMSC‐derived exosomes on tissue regeneration has been extensively studied previously in acute lung injury (Cruz & Rocco, ), drug‐induced liver injury (Tan et al, ), and acute kidney injury (Lv et al, ). A recent in vitro study on an osteoblast cell line stimulated with MSC‐derived exosomes uncovered greater osteoblast proliferation and cell cycle promotion (Zhao, Xiao, Peng, Qian, & Huang, ).…”

Efficacy of erythropoietin-pretreated mesenchymal stem cells in murine burn wound healing: possible in vivo transdifferentiation into keratinocytes

“…Also, murine MSCs were injected intradermally in a rat burn model resulting in an increase in anti-inflammatory cytokines TGF-b and IL-10 in the blood and reduction of CD4+ and CD8+ cells in the spleen as compared to control PBS-treated rats [3]. MSCs had been shown to possess a paracrine action by secretion of "secretomes" or extracellular vesicles [6]. These secretomes can cause profound immunomodulatory effects when studied in vitro experiments by downregulating IL-6 and nitric oxide synthase, promoting M1 (pro-inflammatory) to M2 (anti-inflammatory) polarisation of macrophages, increase IL-10 concentrations, and increase adenosine triphosphate [6].…”

“…MSCs had been shown to possess a paracrine action by secretion of "secretomes" or extracellular vesicles [6]. These secretomes can cause profound immunomodulatory effects when studied in vitro experiments by downregulating IL-6 and nitric oxide synthase, promoting M1 (pro-inflammatory) to M2 (anti-inflammatory) polarisation of macrophages, increase IL-10 concentrations, and increase adenosine triphosphate [6].…”

The effect of allogenic human Wharton's jelly stem cells seeded onto acellular dermal matrix in healing of rat burn wounds

“…The anti‐inflammatory role of MSCs in burn skin tissues can be explained by downregulation of inflammatory markers, upregulation of anti‐inflammatory markers and a local increase in anti‐inflammatory cytokines . The immunomodulatory effect of MSCs was shown to be due to secretion of “secretomes” or extracellular vesicles that further downregulate the IL‐6 and nitric oxide synthase, and increase the IL‐10 and ATP . Liu et al by intravenous application of human UC‐MSCs on burn wounds of rats reported a decrease in inflammatory cell infiltrates, interleukin‐1 and 6, and TNF alpha, and a higher ratio of collagen types I/III, vascularization, neo‐angiogenesis, and keratinization leading to a faster wound healing …”

“…36 The immunomodulatory effect of MSCs was shown to be due to secretion of "secretomes" or extracellular vesicles that further downregulate the IL-6 and nitric oxide synthase, and increase the IL-10 and ATP. 37 In porcine model with contact burns using allogeneic MSCs with a fibrin matrix, a statistically reduced burn wound size was noted. 39 There were several limitations in our study including the use of the rat model for studying human wound healing as histologic structures and healing characteristics in human are different from rats.…”