Taking advantage of the potential of mesenchymal stromal cells in liver regeneration: Cells and extracellular vesicles as therapeutic strategies

Figure 1 Mesenchymal stem/stromal cells clinical trials in liver disease. A: MSCs clinical trials classified by cell source; B: MSCs clinical trials classified by transplant type; C: MSCs clinical trials classified by liver disease treated. Data from http//www.clinicaltrial.gov. n: Number of clinical trials; MSCs: Mesenchymal stem/stromal cells; BM: Bone marrow; UC: Umbilical cord; AT: Adipose tissue.

Figure 2 Extracellular vesicles as paracrine mediator in liver disease and therapeutics potential of mesenchymal stem/stromal cells. After ischemia reperfusion injury (I/R) or hepatectomy, hepatocytes (1) HPCs (2) release EVs with the ability to induce hepatocyte proliferation. (3) HPC-derived EVs stimulate LSECs and macrophages production of proliferative cytokines such as IL25 and IL17B. (4) On the other hand, free fatty acids induce the production of hepatocyte-derived EVs that result in the activation of quiescent HeSCs and pro-inflammatory macrophages (M1). (5) During chronic hepatitis C virus infection, EVs secreted by HCV-infected hepatocytes induce activation of HeSCs. (6) EVs secreted by hepatocytes after alcohol injury (containing CD40L and miRNAs) induce activation of monocytes and HeSCs. It seems to be a balance between EVs derived from active or quiescent HeSCs that promotes or inhibits fibrogenesis. Activated HeSC-derived EVs induce activation of quiescent HeSCs trough CCN2 (7) and quiescent HeSCs inhibit activated HeSCs transferring Twist1 or miRNA199a-5p (8). LSEC-derived EVs could also regulate HeSC activation (9). MSC-EVs induce hepatocyte proliferation, reduce oxidative stress and apoptosis, and modulate inflammatory response by carrying GPX1 or SK2 (10). Engineered MSC-EVs transferring miRNA-122, miRNA 181 5p and miRNA-223 have potential effects. The effects of MSC-EVs on HeSCs, hepatic macrophages, LSEC and infiltrated cells populations remain poorly explored. Green arrows: Inactivation of HeSCs; Red arrows: Activation of HeSCs; Blue arrow: Proliferative effect; Colors spots represent EVs from different cell origin; NCDase: Neutral ceramidase; SK2: Sphingosine kinase 2; S1P: Sphingosine-1-phosphate; IL: Interleukin; SK1: Sphingosine kinase 1; CCN2: Connective tissue growth factor; Twist1: Basic helix-loop-helix transcription factor; GPX1: Glutathione peroxidase 1; HCV: Hepatitis C virus; EVs: Extracellular vesicles.