Mesenchymal Stromal Cell Secretome: Influencing Therapeutic Potential by Cellular Pre-conditioning

Abstract

Mesenchymal stromal cells (MSCs) are self-renewing, culture-expandable adult stem cells that have been isolated from a variety of tissues, and possess multipotent differentiation capacity, immunomodulatory properties, and are relatively non-immunogenic. Due to this unique set of characteristics, these cells have attracted great interest in the field of regenerative medicine and have been shown to possess pronounced therapeutic potential in many different pathologies. MSCs' mode of action involves a strong paracrine component resulting from the high levels of bioactive molecules they secrete in response to the local microenvironment. For this reason, MSCs' secretome is currently being explored in several clinical contexts, either using MSC-conditioned media (CM) or purified MSC-derived extracellular vesicles (EVs) to modulate tissue response to a wide array of injuries. Rather than being a constant mixture of molecular factors, MSCs' secretome is known to be dependent on the diverse stimuli present in the microenvironment that MSCs encounter. As such, the composition of the MSCs' secretome can be modulated by preconditioning the MSCs during in vitro culture. This manuscript reviews the existent literature on how preconditioning of MSCs affects the therapeutic potential of their secretome, focusing on MSCs' immunomodulatory and regenerative features, thereby providing new insights for the therapeutic use of MSCs' secretome.

Keywords: MSCs (Mesenchymal Stromal Cells); immunomodulation; pre-conditioning; regeneration; secretome; therapeutic potential.

Figure 1

MSCs phenotype, differentiation potential, and immunological properties. Schematic representation of MSCs phenotype and immunological profile. (A) MSCs capacity of differentiation into osteogenic, chondrogenic and adipogenic lineages. (B) MSCs phenotype accordingly with the International Society for Stem Cell Research (ISSCR). (C) MSCs immunological profile. (D) Soluble factors families produced by MSCs and profile of interaction with immune cells.

Figure 2

The effect of different preconditioning stimuli in the MSCs response. Schematic representation of known effects of highly studied preconditioning factors—hypoxia (in blue), 3D culture (in blue), specific soluble factors (green), and inflammatory cytokines (red)—in the MSCs response. Blue pathway presents the effect of a hypoxic environment on the cells, which is mediated by specific signaling pathaways (Akt, ERK, p38MAPK) and culminates in the stimulation of the above signaled effects. Tridimensional culture is also represented in blue. MSCs preconditioning with specific soluble factors (SDF-1, TGF-α, and melatonin) seems to stimulate the same signaling pathways as a hypoxic environment and, thus, elicit the same general response from these cells. The use of inflammatory cytokines to influence the MSC response, as represented in red, besides promoting the specific above shown effects, also stimulates the production of factors that seem to be common to all the other preconditioning factors. The pathways that mediate this activity are still to be determined.