Mesenchymal Stem/Stromal Cells and Their Paracrine Activity—Immunomodulation Mechanisms and How to Influence the Therapeutic Potential

Abstract

With high clinical interest to be applied in regenerative medicine, Mesenchymal Stem/Stromal Cells have been widely studied due to their multipotency, wide distribution, and relative ease of isolation and expansion in vitro. Their remarkable biological characteristics and high immunomodulatory influence have opened doors to the application of MSCs in many clinical settings. The therapeutic influence of these cells and the interaction with the immune system seems to occur both directly and through a paracrine route, with the production and secretion of soluble factors and extracellular vesicles. The complex mechanisms through which this influence takes place is not fully understood, but several functional manipulation techniques, such as cell engineering, priming, and preconditioning, have been developed. In this review, the knowledge about the immunoregulatory and immunomodulatory capacity of MSCs and their secretion products is revisited, with a special focus on the phenomena of migration and homing, direct cell action and paracrine activity. The techniques for homing improvement, cell modulation and conditioning prior to the application of paracrine factors were also explored. Finally, multiple assays where different approaches were applied with varying success were used as examples to justify their exploration.

Effects of Olfactory Mucosa Stem/Stromal Cell and Olfactory Ensheating Cells Secretome on Peripheral Nerve Regeneration

“…Thus, the application of the secretome as a cell-free therapeutic approach may have benefits in promoting nerve regeneration, with clinical effects that involve immunomodulation at the site of injury, pro-vasculogenic effects, modulation of the different phases of Wallerian degeneration, increase in the thickness of the myelin sheaths, increase in the number and organization of nerve fibers, and decrease in the phenomena of fibrosis and exuberant scarring [ 22 ]. In addition to its potential direct effects on the promotion of peripheral nerve regeneration, the use of secretome as a therapeutic option has several technical advantages over the direct administration of cells: there are no concerns or limitations associated with the survival of MSCs after transplantation; the absence of proteins present on the cell surface decreases the immunogenic potential and the rejections after administration; the secretome can be stored for long periods of time as a ready-to-use and off-the-shelf product, and can be used when necessary without the need to expand large amounts of cells that can undergo phenotypic changes and lose therapeutic potential along the passages, in addition to not requiring the use of potentially toxic cryoprotectants; large amounts of secretome can be faster produced in bioreactors, increasing the efficiency of the process; the secretome can be modified and adapted for each clinical need [ 8 , 22 , 34 ]. Thus, there is a great clinical and scientific interest in developing regenerative therapies based on the administration of the cell secretome, as a whole or based on its constituent components, such as microvesicles and exosomes [ 35 ].…”

“…Among the mechanisms of action described, MSCs are able to replace damaged and lost tissues and cells, to differentiate into target tissue cells, to secrete bioactive factors such as homing and signaling molecules, and also to directly influence the remyelination processes, essential for the functional and structural recovery of the injured nerve. In addition, MSCs are considered to be immune-privileged, almost never causing immune and rejection reactions after allogeneic transplantation, greatly increasing their range of applicability [ 8 ].…”

“…Recent studies, however, demonstrate that, regardless the method of administration, only a small percentage of the administered cells manage to survive after transplantation. The main mechanisms of loss are systemic dilution and cell death after exposure to the hostile environment around the lesion [ 8 ]. Although the application of NGCs and the administration of MSCs inside their lumen allow to reduce the occurrence of these deleterious phenomena, the mechanical microaggressions that can occur during the administration of the cells can also lead to their death and even to the development of neuromas in the nerve under regeneration [ 20 ].…”

“…Several recent studies have demonstrated that MSCs can act and influence the surrounding environment not only through cell-to-cell interactions but also through paracrine signaling processes [ 21 ]. Through these mechanisms, and after being activated after contact with inflammatory biofactors, MSCs are able to produce and secrete a set of soluble molecules, including growth factors, cytokines, chemokine, growth factors, and extracellular vesicles that directly influence the inflammatory and regenerative processes in a way similar to the administered cells [ 8 ]. This fact creates an alternative therapeutic approach that allows using all the medicinal benefits of MSCs without the limitations associated with their direct administration.…”

“…For instance, through in vitro priming methods, it is possible, by modifying the culture conditions, to indirectly influence the expression of MSCs’ genes and also their secretion products, thus manipulating the immunomodulatory behavior of the cell and allowing the production of a secretome oriented towards the regeneration of a certain tissue. A common priming approach is to manipulate the cell secretome by supplementing the culture medium with soluble factors such as cytokines [ 8 ].…”