PDGFRα/Sca-1 Sorted Mesenchymal Stromal Cells Reduce Liver Injury in Murine Models of Hepatic Ischemia-Reperfusion Injury

Abstract

Liver transplantation is an effective therapy, but increasing demand for donor organs has led to the use of marginal donor organs with increased complication rates. Mesenchymal stromal cells (MSC) pleiotropically modulate aberrant immune-mediated responses and represent a potential therapy to target the inflammation seen post-transplant with marginal donor livers. To avoid the confounding effects of xenotransplantation seen in studies with human MSC, a PDGFRα/Sca-1 (PaS) sorted MSC population was used which was analogous to human MSC populations (LNGFR +Thy-1 +VCAM-1 Hi). PaS MSC are a well-described population which demonstrate MSC properties without evidence of clonal mutation during expansion. We demonstrate their anti-inflammatory properties herein through their suppression of T lymphocyte proliferation in vitro and secretion of anti-inflammatory cytokines (Il-10 and OPG) after stimulation (p=0.004 and p=0.003). The MDR2 -/- model of biliary injury and hepatic ischaemia-reperfusion (HIR) injury models were used to replicate the non-anastomotic biliary complications seen following liver transplant. Systemic MSC therapy in MDR2 -/- mice led to reduced liver injury with an increase in restorative macrophages (5913±333.9 vs 12597±665.8, p=0.002, n=7) and a change in lymphocyte ratios (3.55±0.37 vs 2.59±0.139, p=0.023, n=17), whereas subcutaneous administration of MSC showed no beneficial effect. MSC also reduced cell death in the HIR model assessed by PAS staining (91.7% ± 2.8 vs 80.1% ± 4.6, p=0.03). Systemically administered quantum dot labelled MSC were tracked using single cell resolution CryoViz TM imaging which demonstrated their sequestration in lungs alongside retention/redistribution to injured liver tissue. MSC represent a potential novel therapy in marginal organ transplantation which warrants further study.

dCas9-Based PDGFR–β Activation ADSCs Accelerate Wound Healing in Diabetic Mice through Angiogenesis and ECM Remodeling

“…Numerous previous studies have demonstrated the importance of endogenous PDGFR–β signaling in vascular development and tissue repair, whereas the function of PDGFR–β signaling in exogenous transplanted therapeutic cells remains poorly understood. Andrew Owen et al reported that PDGFR–α positive MSCs had a better therapeutic effect on a rat model of hepatic ischemia-reperfusion [ 36 ], and Wang Feng et al demonstrated that PDGFR–α positive BMSCs can secrete more mir–6924–5p, which can better treat osteolysis and improve healing intensity during tendon bone healing [ 37 ]. Consequently, as a member of the PDGFRs family, what effect does PDGFR–β signaling have on the function and therapeutic potential of ADSCs?…”

Isolation, culture, and delivery considerations for the use of mesenchymal stem cells in potential therapies for acute liver failure

“…Tail vein ( 165 , 166 ), hepatic vein ( 167 ) and peripheral vein ( 168 ) injection of MSCs in an ischaemia-reperfusion injury animal model showed that MSC infusion can reduce liver damage and cell death ( 165 , 167 ), improve the levels of ALT and AST ( 166 – 168 ) and mainly decrease oxidative stress caused by liver excision and ischaemia-reperfusion injury ( 169 ). MSCs also inhibit the production of proinflammatory cytokines (TNF-α, IL-1β and iNOS), macrophage activation and neutrophil recruitment and promote anti-inflammatory cytokine secretion (IL-10), which is beneficial for recovery from liver injury and inflammatory responses ( 167 ).…”