Human Amnion-Derived Mesenchymal Stromal/Stem Cells Pre-Conditioning Inhibits Inflammation and Apoptosis of Immune and Parenchymal Cells in an In Vitro Model of Liver Ischemia/Reperfusion

Abstract

Ischemia/reperfusion injury (IRI) represents one of the leading causes of primary non-function acute liver transplantation failure. IRI, generated by an interruption of organ blood flow and the subsequent restoration upon transplant, i.e., reperfusion, generates the activation of an inflammatory cascade from the resident Kupffer cells, leading first to neutrophils recruitment and second to apoptosis of the parenchyma. Recently, human mesenchymal stromal/stem cells (hMSCs) and derivatives have been implemented for reducing the damage induced by IRI. Interestingly, sparse data in the literature have described the use of human amnion-derived MSCs (hAMSCs) and, more importantly, no evidence regarding hMSCs priming on liver IRI have been described yet. Thus, our study focused on the definition of an in vitro model of liver IRI to test the effect of primed hAMSCs to reduce IRI damage on immune and hepatic cells. We found that the IFNγ pre-treatment and 3D culture of hAMSCs strongly reduced inflammation induced by M1-differentiated macrophages. Furthermore, primed hAMSCs significantly inhibited parenchymal apoptosis at early timepoints of reperfusion by blocking the activation of caspase 3/7. All together, these data demonstrate that hAMSCs priming significantly overcomes IRI effects in vitro by engaging the possibility of defining the molecular pathways involved in this process.

Role of Mesenchymal Stem/Stromal Cells in Modulating Ischemia/Reperfusion Injury: Current State of the Art and Future Perspectives

“…The MSC secretome, containing biological factors that include EVs enriched in proteins and miRNAs, has been shown to be strongly involved in the modulation of the IRI phenotype for several reasons. First, it contains immunomodulatory factors, as well as pro-angiogenic and tissue repair properties, which by themselves seem to account for the majority of the therapeutic effects [ 20 , 22 , 252 , 253 , 254 ]. Second, because of the MSC secretome requirement for resolution of IRI, its use has recently been proposed instead of MSC transplantation.…”

“…Scientific evidence has revealed that both cellular and acellular therapies based on the use of mesenchymal stem/stromal cells (MSCs), represent promising approaches to mitigate IRI-related pathological processes [ 19 , 20 , 21 , 22 ]. MSCs have been found in different tissues, including umbilical cord (UC-MSCs) [ 23 ], bone marrow (BM-MSCs) [ 24 ], adipose tissue (Ad-MSCs) [ 25 ], and placenta (AM-MSCs) [ 26 ], where they participate in the maintenance of stem cell niches and tissue homeostasis [ 27 , 28 ].…”

“…Finally, our group recently showed that 3D and IFN-γ priming of human amnion-derived MSCs (AMSCs) are able to modulate IRI damage in an in vitro model of IRI carried out on primary macrophages and hepatocytes. We found that several bioactive factors, including HGF, IL-10, IL-1RA, and BDNF, selectively inhibit inflammation of primary macrophages and apoptosis of IRI hepatocytes in vitro [ 22 ].…”

Human Umbilical Cord Mesenchymal Stem Cells Attenuate Severe Burn-Induced Multiple Organ Injury via Potentiating IGF-1 and BCL-2/BAX Pathway

“…Therefore, the hUCMSCs could better protect the organ structures and functions at early stage post severe burn. And other preclinical studies also have shown hMSCs therapeutic value in studies of myocardial infarction, diabetes, sepsis, hepatic failure, acute renal failure, and acute lung injury (ALI) [35][36][37][38][39]. But administered hUCMSCs do not massively integrate into the injured tissues, so we speculated reasonably the main mechanism by which hUCMSCs play a role in repairing damaged tissues by paracrine protective cytokines.…”

Stem cells for treatment of liver fibrosis/cirrhosis: clinical progress and therapeutic potential

“…IFN-γ pre-treatment and 3D culture of MSC showed increased production of both growth and immunoregulatory factors. Furthermore, these modified MSCs strongly reduced M1-induced inflammation [ 145 ]. Pre-activation of in vitro cultured MSCs with patient serum allows MSCs to have specific host-related functions and properties, thus allowing for individualized management strategies.…”