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.

Keywords: Mesenchymal Stem/Stromal Cells; extracellular vesicles; homing; immunomodulation; regenerative medicine; secretome.

Figure 1

Schematic representation of the Migration and Homing processes, secondary to systemic administration, local administration, or organic mobilization of MSCs. (Adapted with permission from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic Licence. https://smart.servier.com/ accessed on 5 January 2022).

Figure 2

Functional and immunomodulatory influences of MSCs on cells of the Innate and Adaptive Immune System. Red Arrows—Action of MSCs on Immune System cells. Green Arrows—Action of Immune System Cells on MSCs, with activation and retroactive stimulation. (Adapted with permission from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic Licence. https://smart.servier.com/ accessed on 5 January 2022).

Figure 3

Schematic representation of the MSCs paracrine action mechanisms and corresponding therapeutic and immunomodulatory consequences. (Adapted with permission from Servier Medical Art, licensed under a Creative Common Attribution 3.0 Generic Licence. https://smart.servier.com/ accessed on 5 January 2022).