Abstract
Mesenchymal stem/stromal cells (MSCs) are multipotent cells residing in the stromal tissues of the body and capable of promoting tissue repair and attenuating inflammatory processes through their immunomodulatory properties. Preclinical and clinical observations revealed that not only direct intercellular communication mediates MSC properties; in fact, a pivotal role is also played by the release of soluble and bioactive factors, such as cytokines, growth factor and extracellular vesicles (EVs). EVs are membrane-coated vesicles containing a large variety of bioactive molecules, including lipids, proteins, and nucleic acids, such as RNA. EVs release their contents into target cells, thus influencing cell fate through the control of intracellular processes. In addition, MSC-derived EVs can mediate modulatory effects toward different effector cells belonging to both innate and adaptive immunity. In this review, we will discuss the literature data concerning MSC-derived EVs, including the current standardized methods for their isolation and characterization, the mechanisms supporting their immunoregulatory properties, and their potential clinical application as alternative to MSC-based therapy for inflammatory reactions, such as graft-versus-host disease (GvHD).
Highlights
Mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin described in bone marrow (BM) for the first time by Alexander Friedenstein in 1966 (Friedenstein et al, 1966)
MSCs are capable of stimulating cytokine release and proliferation of innate lymphoid cells, affecting dendritic cell (DC) maturation and activation (Zhang et al, 2004), suppressing natural killer (NK) cell activity and proliferation (Spaggiari et al, 2008), supporting the expansion of myeloid-derived suppressor cells (MDSCs) (Yen et al, 2013), and regulating B cell proliferation and activation (Fan et al, 2016) as well as T cell activity, balance between T helper (Th)1 and Th2 lymphocytes and expansion of T regulatory (Treg) cells (Haddad and Saldanha-Araujo, 2014; Gao et al, 2016)
The biological activity of MSC was ascribed to their ability to home within the injury site; only a small fraction of MSCs is capable of reaching the damaged tissues after systemic administration (Kraitchman et al, 2005; Yukawa et al, 2012; Scarfe et al, 2018), while the majority of them are rapidly cleared through phenomena of efferocytosis, polarizing macrophages toward an inhibitory phenotype (Galleu et al, 2017)
Summary
Mesenchymal stromal cells (MSCs) are multipotent stem cells of mesodermal origin described in bone marrow (BM) for the first time by Alexander Friedenstein in 1966 (Friedenstein et al, 1966). MSCs were identified in a large number of tissues, including fat, umbilical cord, amniotic fluid, placenta, skin, dental pulp, and many others (Riekstina et al, 2008; Marquez-Curtis et al, 2015; Camilleri et al, 2016; Ventura Ferreira et al, 2018; Caseiro et al, 2019; Fukutake et al, 2019). In 2006, the International Society for Cellular Therapy (ISCT) established the minimal criteria to define human MSCs, i.e., (i) plastic-adherence when maintained in standard culture conditions; (ii) surface expression of CD105, CD73 and CD90 antigens while lacking CD45, CD34, CD14 or CD11b, CD79α or CD19, and HLA-DR molecules; (iii) in vitro differentiation into three mesodermal lineages (osteoblasts, adipocytes, and chondrocytes) (Dominici et al, 2006)
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