A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods

Abstract

The mesenchymal stem cell (MSC) is being broadly studied in clinical trials. Contrary to the early paradigm of cell replacement and differentiation as a therapeutic mechanism of action, evidence is mounting that the secretions of the cells are responsible for their therapeutic effects. These secretions include molecules and extracellular vesicles that have both local and distant effects. This review summarizes the up- and down-regulation of MSC anti-inflammatory, immune modulating, anti-tumor, and regenerative secretions resulting from different stimuli including: a) hypoxia, which increases the production of growth factors and anti-inflammatory molecules; b) pro-inflammatory stimuli that induce the secretion of immune modulating and anti-inflammatory factors; and c) 3 dimensional growth which up regulates the production of anti-cancer factors and anti-inflammatory molecules compared to monolayer culture. Finally we review in detail the most important factors present in conditioned medium of MSC that can be considered protagonists of MSC physiological effects including HGF, TGF-b, VEGF, TSG-6, PGE2 and galectins 1, and 9. We conclude that there is potential for the development of acellular therapeutic interventions for autoimmune, inflammatory, and malignant diseases and tissue regeneration from cellular secretions derived from MSCs cultured under the appropriate conditions.

Figure 1

Effects of the hypoxia, inflammation, and 3D culture on MSC in terms of expression and secretion of molecules of interest for cell therapy. a) Hypoxia activates the HIF and the NF-kappa β; increases the expression of several growth factors (inside the square), it also induces IDO activity and enhances stemness (Oct-4 and Rex-1). Also, the hypoxia pre-conditioned MSC, favor the activation of caspase 3, Bcl-2, MTP-2, TGF- β1 on target cells improving apoptosis resistance; improve regenerative capacity of muscle and endothelial cells. b) Inflammation induced by INF-γ increases the expression of anti-inflammatory and regenerative molecules (in the square) and, through TNF-α enhances the production of VEGF and BMP-2 which favor formation of new vessels and osteoblasts respectively. Also MSC exposed to LPS are able to encapsulate mitochondria and deliver them to other cells. c) 3D culture methods such as microcarriers or spheroids induce the production of TSG-6 and increases PGE₂ secretion. Besides, it also favor the secretion of antiapoptotic and anticancer molecules (in the square). Further, MSCs obtained from 3D configurations, inhibit the expression of inflammatory and cancer related molecules in target cells.