Molecular basis of the effect of atorvastatin pretreatment on stem cell therapy in chronic ischemic diseases – critical limb ischemia

Abstract

Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.

Effect of Atorvastatin on Angiogenesis-Related Genes VEGF-A, HGF and IGF-1 and the Modulation of PI3K/AKT/mTOR Transcripts in Bone-Marrow-Derived Mesenchymal Stem Cells

“…The phosphatidylinositol 3-kinase (PI3K) and the downstream target AKT belong to a conserved family of signal transduction enzymes with roles in cell proliferation, transformation, paracrine function and processes of angiogenesis and apoptosis [ 9 ]. Therefore, an understanding of the mechanism of the activation or modulation of PI3K/AKT pathway by statins in MSCs culture is warranted, as we already discussed in the review article [ 10 ]. In addition, statins can affect the expression of several growth factors, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), insulin-like growth factor (IGF) and hepatocyte growth factor (HGF), which play important roles in the activation of the PI3K/AKT pathway.…”

Adipose-derived stem cell/FGF19-loaded microfluidic hydrogel microspheres for synergistic restoration of critical ischemic limb

“…Among these approaches, stem cell therapy stands out as an emerging strategy due to its self-renewal ability, paracrine secretion, and multilineage differential potential [ 13 , 14 ]. For example, adipose-derived stem cells (ADSCs) could not only directly differentiate into vascular endothelial cells to realize neovascularization, but also secrete miRNA-containing or cytokine-containing vesicles in a paracrine manner to regulate the proliferation, differentiation and immunomodulation of neighboring cells [ [15] , [16] , [17] , [18] , [19] , [20] , [21] ]. For instance, Madonna et al directly injected ADSCs suspension into the ischemic lesions and established neovascularization, as ADSC can mediate the hypoxia-induced release of cytokines (VEGF and related growth factors) and give rise to angiogenesis [ 22 ].…”