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Comparing different administration routes for mesenchymal stromal cell infusion in an in vivo porcine ischemia-reperfusion injury model

ABSTRACT: Hepatic ischemia-reperfusion injury is a complex pathophysiological process that occurs following reperfusion of blood supply in previously ischemic tissues. This form of injury plays a major role in cell dysfunction and death following hepatic surgery and liver transplantation. Mesenchymal stromal cells (MSC) seem to be a promising option for mitigation of this type of injury, as they possess anti-inflammatory and immune modulating capacities that may stimulate liver regeneration. The aim of this study was to demonstrate safety, feasibility and effectiveness of direct hepatic administration of MSC for treatment of ischemia-reperfusion injury in a pig model. After total vascular exclusion of the liver for 45 minutes, 3x10^6 human bone-marrow derived (BM)-MSC/kg were directly administrated into livers either via the intraportal route or hepatic artery route, whereas the control group did not receive any BM-MSC. Following reperfusion, hepatic blood flow and pulmonary pressures were continuously measured. Samples of blood and tissue of spleen, lung, and liver were taken among groups at the end of follow-up. Injection of BM-MSC did not result in obstruction of hepatic blood flow or increased pulmonary artery pressures. Blood flow in the portal vein was higher following injection BM-MSC in comparison to baseline blood flow. Arterially infused BM-MSC were more equal distributed over the different areas of the liver in comparison to the portal vein infused group (p=0,04). No BM-MSC were detected in pulmonary circulation nor in biopsies of spleen and lung. These results show that infusing therapeutic quantities of BM-MSC directly in the vascular bed of the liver is safe and feasible. Regarding risks of thrombosis or embolism, no differences between the routes of admission was observed.

ORGANISM(S): Sus scrofa

PROVIDER: GSE282013 | GEO | 2025/12/02

REPOSITORIES: GEO

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Project description:Background: Systemic sclerosis (SSc) is a chronic autoimmune disease. We tested the safety of a single intravenous injection of intrafamilial allogeneic bone marrow-derived mesenchymal stromal cells (BM-MSC) to treat severe SSc. Methods: We conducted the first prospective, monocentric, dose-escalation, phase I/II clinical trial investigating the feasibility and safety of a single allogeneic BM-MSC infusion in 20 severe SSc patients who were refractory or had a contraindication to conventional immunosuppressive therapy or autologous hematopoietic stem cell transplant. Patients were assigned to an infusion of either 1x10^6 BM-MSC/kg or 3x10^6 BM-MSC/kg obtained from 20 independent intrafamilial donors. Primary endpoint was the rate of grade ≥ 3 Severe Adverse Events (SAE; NCI Common Terminology Criteria for Adverse Events (v5.0)) in the first 10 days post-BM-MSC infusion. Secondary endpoints included adequacy of BM-MSC production, medium-term SAE, as well as clinical and immunological response. Findings: No Grade 3 ≥ SAE occurred in the first 10 days following MSC infusion in the 20 SSc patients. A significant improvement in modified Rodnan Skin Score (p<0.0001) was observed after BM-MSC infusion, which peaked at 3 months and was sustained for 1 year. No changes in health-related quality of life or pulmonary function were observed. CD8pos T-Cell and NK cell counts slightly increased after infusion (p<0.05) and two patients developed de novo donor-specific anti-HLA. Circulating TGF-β level at baseline was significantly higher in non-responder compared to responder patients (p<0.05). A pattern of low IDO activity, CCL2 production, and HLA-DR expression in BM-MSC batches under in vitro stimulation by IFN-beta was associated with a lack of clinical response in recipient SSc patients. Interpretation: A single infusion of allogeneic BM-MSC transplant was safe in severe SSc patients and triggered short-term disease modifying effects. Clinical response was associated with both the recipients biological features and the functional properties of infused BM-MSC.

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Comparing different administration routes for mesenchymal stromal cell infusion in an in vivo porcine ischemia-reperfusion injury model

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