Abstract
The role of the mesenchymal stromal cell- (MSC-) derived secretome is becoming increasingly intriguing from a clinical perspective due to its ability to stimulate endogenous tissue repair processes as well as its effective regulation of the immune system, mimicking the therapeutic effects produced by the MSCs. The secretome is a composite product secreted by MSC in vitro (in conditioned medium) and in vivo (in the extracellular milieu), consisting of a protein soluble fraction (mostly growth factors and cytokines) and a vesicular component, extracellular vesicles (EVs), which transfer proteins, lipids, and genetic material. MSC-derived secretome differs based on the tissue from which the MSCs are isolated and under specific conditions (e.g., preconditioning or priming) suggesting that clinical applications should be tailored by choosing the tissue of origin and a priming regimen to specifically correct a given pathology. MSC-derived secretome mediates beneficial angiogenic effects in a variety of tissue injury-related diseases. This supports the current effort to develop cell-free therapeutic products that bring both clinical benefits (reduced immunogenicity, persistence in vivo, and no genotoxicity associated with long-term cell cultures) and manufacturing advantages (reduced costs, availability of large quantities of off-the-shelf products, and lower regulatory burden). In the present review, we aim to give a comprehensive picture of the numerous components of the secretome produced by MSCs derived from the most common tissue sources for clinical use (e.g., AT, BM, and CB). We focus on the factors involved in the complex regulation of angiogenic processes.
Highlights
Mesenchymal stromal cells (MSCs) were described for the first time in 1970 by Alexander Friedenstein as a “population of bone marrow stromal cells capable of mesodermal differentiation and trophic support of hematopoiesis” [1, 2]
MSCs release in the extracellular space a plethora of angiogenic factors including basic fibroblast growth factor, VEGF, transforming growth factor-beta (TGF-β), plateletderived growth factor (PDGF), ANG-1, placental growth factor (PIGF), IL-6, hepatocyte growth factor (HGF), and monocyte chemoattractant protein 1 (MCP-1), which stimulate angiogenesis in vitro and in vivo [9, 107]
It has been reported throughout the literature that conditions such as exposure to tumor necrosis factor- (TNF-) α, interferon- (IFN-) γ, or hypoxia are able to modulate the composition of the mesenchymal stromal cell- (MSC-)derived secretome, a method generally referred to as priming
Summary
Mesenchymal stromal cells (MSCs) were described for the first time in 1970 by Alexander Friedenstein as a “population of bone marrow stromal cells capable of mesodermal differentiation and trophic support of hematopoiesis” [1, 2]. MSCs have been shown to play an important role in decreasing tissue damage and accelerating repair through the promotion of vascularization, the use of MSC-based therapies is restricted by their low level of persistence in targeted tissues and their limited capabilities of transdifferentiation in vivo [16,17,18,19,20,21,22]. The MSC-derived secretome is very tissue- and/or individual cell-specific and is subject to fluctuations related to physiological states or pathological conditions. The appropriate therapeutic use of the MSC secretome as an active pharmaceutical ingredient as well as a drug delivery system [32] relies on the systematic quantitative and functional assessment of the MSC-secreted effectors from the perspective of specific clinical settings, e.g., macroareas such as angiogenesis, bone regeneration, and immune suppression. The elements of the secretome of MSCs derived from the most common tissue sources for clinical use (e.g., AT, BM, and CB) will be explored in further detail addressing their roles in the angiogenic modulation (Figure 1), and data will be compared where available
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