Paracrine Mechanisms of Mesenchymal Stromal Cells in Angiogenesis

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.

Melatonin and Mesenchymal Stem Cells as a Key for Functional Integrity for Liver Cancer Treatment

“…It should be stressed that various molecular mechanisms seem to be involved in therapeutic MSC actions in vivo and increase their regenerative potential [65]. Among others, direct MSC differentiation into cardiac and endothelial cells and the paracrine activity mediated by MSC-derived soluble molecules and vesicles are currently considered as major factors mediating beneficial effects of MSC-based therapies in various viable diseases [65][66][67][68][69]. However, recent studies showed that paracrine function of MSCs is the main mechanism by which these cells participate in tissue repair [68].…”

“…Among others, direct MSC differentiation into cardiac and endothelial cells and the paracrine activity mediated by MSC-derived soluble molecules and vesicles are currently considered as major factors mediating beneficial effects of MSC-based therapies in various viable diseases [65][66][67][68][69]. However, recent studies showed that paracrine function of MSCs is the main mechanism by which these cells participate in tissue repair [68]. Importantly, MSCs can promote normal tissue regeneration through enhancement of angiogenesis, tissue remodeling and activation of endogenous stem cells [70], which endorsed the paracrine actions rather than cell differentiation.…”

TNFR2 Is a Crucial Hub Controlling Mesenchymal Stem Cell Biological and Functional Properties

“…Results are collected from two independent experiments. Beckermann et al, 2008;Batlle et al, 2019;Maacha et al, 2020). Here, we aimed to investigate whether there exists a relation between the TNFR2 expression and the MSC proangiogenic function.…”

Biocompatibility of Bone Marrow-Derived Mesenchymal Stem Cells in the Rat Inner Ear following Trans-Tympanic Administration

“…Future studies employing fluorescent conjugated BM-MSCs will help in addressing this concern. However, it has been demonstrated that BM-MSCs can exert protective effects through their paracrine mechanisms [17,[84][85][86][87]. While previously it was thought that MSCs directly and actively participated in the tissue repair and regeneration process, there is increasing evidence that MSCs do not engraft within tissue [88].…”