Bone marrow-derived mesenchymal stem cells have innate procoagulant activity and cause microvascular obstruction following intracoronary delivery: amelioration by antithrombin therapy

Autor: Frank Barry, Sujith Kumar, M. Gopala-Krishnan Pillai, Birgitta M. Gleeson, Alessia Stocca, Derek Whelan, Kenneth Martin, Mohammed T. Ali, John F. O'Sullivan, Noel M. Caplice, Arun H.S. Kumar, Timothy O'Brien, Wisam Khider
Rok vydání: 2015
Předmět:
Swine
coronary flow reserve
030204 cardiovascular system & hematology
Pharmacology
Biology
heparin
Mesenchymal Stem Cell Transplantation
Thromboplastin
03 medical and health sciences
Tissue factor
randomized-trial
0302 clinical medicine
Fibrinolytic Agents
Bone Marrow
medicine
Animals
Humans
acute myocardial-infarction
Platelet
cardiovascular diseases
Blood Coagulation
Cells
Cultured
030304 developmental biology
stromal cells
0303 health sciences
mesenchymal stem cells
model
ischemic cardiomyopathy
cardiac-function
Antithrombin
Mesenchymal stem cell
percutaneous coronary intervention
Cell Biology
Heparin
tissue factor
Coronary Vessels
medicine.anatomical_structure
myocardial infarction
transendocardial injection
mediated induction
Microvessels
Immunology
Molecular Medicine
Female
Bone marrow
Fibrinolytic agent
Developmental Biology
medicine.drug
Popis: Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 106 MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI. Stem Cells 2015;33:2726–2737
Databáze: OpenAIRE
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