**1. Introduction**

The mesenchymal stem cell (MSC) therapies offer new opportunities for confronting diseases that lack curative treatments through the properties of multipotentiality, self-renewal, and the secretion of paracrine factors derived from exosomes (cytokines, growth factors, microRNAs, and proteases), which act as mediators of intracellular communication and induce the repair and regeneration of organs and tissues [1].

Cell therapy with MSCs is safe and effective in the treatment of degenerative and traumatic diseases; they are found *in vivo* in minimal quantities throughout the body and they have the ability to differentiate into bone, cartilage, and adipose tissue through stimuli and in culture. The MSCs are located in the perivascular environment, activating and creating a regenerative microenvironment, with the secretion of molecules to regulate the immune response; however, the therapeutic effects through paracrine interactions of the MSCs are of short duration. The response to changes in the environment is attributed to MSCs through the transcriptional regulation of mediators that control inflammation, remodeling, repair, and cellular recruitment. The repair process involves the regulation of extracellular matrix (ECM) deposition, collagen synthesis, fibroblast proliferation, platelet activation, fibrinolysis, and angiogenesis; the immune process suppresses T-cells, activates macrophages, and recruits neutrophils [2].

Cell differentiation and replacement is attributed to cellular secretions that function as therapeutic inducers. The secretions of extracellular vesicles (EV) are both local and systemic. To determine the functions of the factors secreted by the MSCs in regeneration, it is necessary to identify precisely the molecular profile of the secretome of the MSC constituted by growth factors (GF), cytokines and chemokines, proteases, ECM, hormones, and lipid mediators, and so on [3].

The secretome of MSCs contains multiple overlapping elements that make it difficult to identify them. The *in vivo* examination of the secretome of MSCs and the strategies to modulate it and the result of the analysis are essential for the design of the next generation of regenerative therapies without cells. In this way, questions arise about the regulatory function of the secretome of the MSC, such as (i) what are the most effective approaches to study the secretome both *in vitro* and *in vivo* and are new technologies necessary to achieve it? (ii) how do the properties of the secretome change or become manageable, and after the transplant how does it evolve in the local microenvironment? (iii) what are the best methods to achieve the sustainability of the secretome and the control in the transplant? [4].
