Secretome as a Tool to Treat Neurological Conditions: Are We Ready?

Abstract

Due to their characteristics, mesenchymal stem cells (MSCs) are considered a potential therapy for brain tissue injury or degeneration. Nevertheless, despite the promising results observed, there has been a growing interest in the use of cell-free therapies in regenerative medicine, such as the use of stem cell secretome. This review provides an in-depth compilation of data regarding the secretome composition, protocols used for its preparation, as well as existing information on the impact of secretome administration on various brain conditions, pointing out gaps and highlighting relevant findings. Moreover, due to the ability of MSCs to respond differently depending on their microenvironment, preconditioning of MSCs has been used to modulate their composition and, consequently, their therapeutic potential. The different strategies used to modulate the MSC secretome were also reviewed. Although secretome administration was effective in improving functional impairments, regeneration, neuroprotection, and reducing inflammation in brain tissue, a high variability in secretome preparation and administration was identified, compromising the transposition of preclinical data to clinical studies. Indeed, there are no reports of the use of secretome in clinical trials. Despite the existing limitations and lack of clinical data, secretome administration is a potential tool for the treatment of various diseases that impact the CNS.

Keywords: central nervous system; conditioned medium; mesenchymal stem cells; preconditioning; secretome.

Figure 1

Summary of secretome composition and common surface markers of exosomes and microvesicles. IGF-1—insulin-like growth factor type 1; BDNF—brain-derived neurotrophic factor; VEGF—vascular endothelial growth factor; HGF—hepatocyte growth factor 1; NGF—nerve growth factor; LIF—leukemia inhibitory factor; bFGF—basic fibroblast growth factor; EGF—epidermal growth factor; GDNF—glia-derived growth factor; SCF—stem cell factor; CNTF—ciliary beurotrophic factor; PDGF—platelet-derived growth factor; TGF-β—tumor growth factor β; IL—interleukin; IFN-γ—Interferon gamma; TNF-α—tumor necrosis factor α; MCP1—monocyte chemoattractant protein 1; CXCL12—CXC motif chemokine ligand 12; IDO—Indoleamine 2,3-dioxugenase; SOD3—superoxide dismutase; UCHL1—ubiquitin carboxy-terminal hydrolase L1; DJ-1—Deglycase Protein; TRX—thioredoxin; PRDX1—pieroxyredoxin; AS—Albumine serine; HSP—heat shock protein; CyPA—Cyclophilon A; CyPB—Cyclophilon B; Cys C—cystatin C; Gal-1—galectin-1; PAI-1—plasminogen activator inhibitor-1; VCAM—vascular cell adhesion molecule; PGE-2—Prostaglandin E2; mRNAs—Messenger ribonucleic acid; CD—Protein-coding Gene; ESCRT—endosomal sorting complex required for transport; TSG101—tumor susceptibility protein 101; PD-L1—programmed death-ligand 1.

Figure 2

Summary of the main outcomes observed with the administration of secretome or its vesicular fraction for the treatment of neurologic disorders. The arrows indicate an increase (↑) or decrease (↓) in the respective processes or molecules.

Figure 3

Steps required to establish conditions for the clinical use of secretome.Clarification of the impact of the cell donor and tissue of cell source, establishment of protocols for cell culture and secretome preparation, comprehensive characterization of the secretome, identification of markers of therapeutic potency, definition of regulations for the clinical application, and production scale up are all needed.