Fig. 1.

Comparative biological impact between MSCs and MSC-derived mitochondria on target cells. Immunomodulation by MSC, involves a paracrine secretion of factors such as indoleamine 2,3-dioxygenase (IDO), transforming growth factor beta (TGF-β) and histocompatibility locus antigen G (HLA-G5), promoting inhibition of T cell proliferation. In addition, transfer or MSC-derived mitochondria has shown to induce regulatory T cells (Treg) differentiation, the involved mechanisms and pathways are still to be unraveled. MSCs exert anti-inflammatory effects also by the secretion of factors, such as prostaglandin E2 (PGE2) and tumor necrosis factor-stimulated gene 6 (TSG-6). PGE2 secreted by MSCs bind to EP2 and EP4 receptors expressed by macrophage inducing cyclic AMP upregulation (cAMP) promoting polarization to M2 phenotype. TSG-6 secreted by MSC inhibits activation of M1 macrophages. Mechanisms and pathways of anti-inflammatory effects from mitochondrial transfer are yet to be confirmed. The anti-apoptotic effect of MSCs is due to the enhancement of B cell lymphoma 2 (Bcl-2) expression. Likewise mitochondrial transfer also has anti-apoptotic effects in target cells, by increased expression of Bcl-2 and reduced activity of Bcl-2-associated X (Bax) and Caspase-3 (Casp3) (unpublished data). MSCs have shown the ability to regulate oxidative stress by increasing levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Similarly mitochondrial transfer exhibits oxidative stress regulation by the enhanced expression of mitochondrial superoxide dismutase 2 (SOD-2)