The pulmonary microvasculature entraps induced vascular progenitor cells (<scp>iVPC</scp>s) systemically delivered after cardiac ischemia‐reperfusion injury: Indication for preservation of heart function via paracrine effects beyond engraftment

Ziegler, Melanie; Haigh, Katharina; Nguyen, Thao M.; Wang, Xiaowei; Lim, Bryan; Yap, May Lin; Eddy, Eleanor; Haigh, Jody J.; Peter, Karlheinz

doi:10.1111/micc.12493

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…demonstrated <2.6% retention of unselected BM-derived cells in ST-segment elevation MI patients when delivered 5–10 days after stenting. Pulmonary entrapment is a common feature of cellular therapy 36 , 37 which we also noted in the current study.…”

Section: Discussionsupporting

confidence: 83%

“…Bone marrow-derived stem and progenitor cells can secrete a rich and potent combination of growth factors and anti-inflammatory cytokines that act in a paracrine manner on neighbouring cells 40 , 41 . Even without retention in the heart, these factors may be released systemically from remote sites and confer vasculoprotection in the heart 36 . Indeed, remote transplantation of MSCs into the interscapular region protected the IRI heart 42 .…”

Section: Discussionmentioning

confidence: 99%

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Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells

Kavanagh

Lokman

Neag

et al. 2019

Cardiovascular Research

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AimsAdequate microcirculatory perfusion, and not just opening of occluded arteries, is critical to salvage heart tissue following myocardial infarction. However, the degree of microvascular perfusion taking place is not known, limited primarily by an inability to directly image coronary microcirculation in a beating heart in vivo. Haematopoietic stem/progenitor cells (HSPCs) offer a potential therapy but little is known about their homing dynamics at a cellular level and whether they protect coronary microvessels. This study used intravital microscopy to image the anaesthetized mouse beating heart microcirculation following stabilization.Methods and resultsA 3D-printed stabilizer was attached to the ischaemia–reperfusion injured (IRI) beating heart. The kinetics of neutrophil, platelet and HSPC recruitment, as well as functional capillary density (FCD), was imaged post-reperfusion. Laser speckle contrast imaging (LSCI) was used for the first time to monitor ventricular blood flow in beating hearts. Sustained hyperaemic responses were measured throughout reperfusion, initially indicating adequate flow resumption. Intravital microscopy confirmed large vessel perfusion but demonstrated poor transmission of flow to downstream coronary microvessels. Significant neutrophil adhesion and microthrombus formation occurred within capillaries with the latter occluding them, resulting in patchy perfusion and reduced FCD. Interestingly, ‘patrolling’ neutrophils were also observed in capillaries. Haematopoietic stem/progenitor cells readily trafficked through the heart but local retention was poor. Despite this, remarkable anti-thromboinflammatory effects were observed, consequently improving microvascular perfusion.ConclusionWe present a novel approach for imaging multiple microcirculatory perturbations in the beating heart with LSCI assessment of blood flow. Despite deceptive hyperaemic responses, increased microcirculatory flow heterogeneity was seen, with non-perfused areas interspersed with perfused areas. Microthrombi, rather than neutrophils, appeared to be the major causative factor. We further applied this technique to demonstrate local stem cell presence is not a pre-requisite to confer vasculoprotection. This is the first detailed in vivo characterization of coronary microcirculatory responses post-reperfusion injury.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells

Kavanagh

Lokman

Neag

et al. 2019

Cardiovascular Research

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“…Furthermore, enriching induced vascular progenitor cells (iVPCs), pre-incubated with the same tandem scFv antibody against the activated GPIIb/IIIa receptor (Tandem-scFv GPIIb/IIIa-Sca-1 ), demonstrated significant cardiac benefits 28 days after I/R injury. These iVPC treatment-driven effects were paracrine rather than through direct accumulation and differentiation (engraftment) of iVPCs within the infarcted tissue 129 …”

Section: Platelet Targeting and Platelet Activation-inhibiting Thementioning

confidence: 99%

Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target

Ziegler

Wang

Peter

2019

Cardiovascular Research

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“…Anti-platelet therapies targeting platelet COX-1 (aspirin), P 2 Y 12 (clopidogrel, ticagrelor, prasugrel, cangrelor), GPIIbIIIa (abciximab, tirofiban, eptifibatide), GPVI (revacept),p-selectin (fucoidan, inclacumab) can exhibit pleotropic cardioprotective effects [ 5 ]. Novel theranostics in preclinical validation that target activated platelets to enrich delivery of cardioprotective drugs (Targ-CD39) [ 34 , 143 ] or progenitor cells (Tandem-scFv GPIIb/IIIa-Sca-1 ) [ 144 ] effectively combine diagnostic tools [ 145 , 146 ] and therapeutic prospects [ 33 , 34 , 144 ] for myocardial regeneration and functional recovery in murine models. However, these innovative and clinical therapeutics exclusively target platelet receptors, while ACKR3/CXCR7 is broadly expressed in the ischiatic cardiac microenvironment, including infiltrating cells.…”

Section: Therapeutic Implication Of Ackr3/cxcr7 In Platelet-associated Cardiovascular Diseasementioning

confidence: 99%

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

Chatterjee

2022

Cells

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The manifold actions of the pro-inflammatory and regenerative chemokine CXCL12/SDF-1α are executed through the canonical GProteinCoupledReceptor CXCR4, and the non-canonical ACKR3/CXCR7. Platelets express CXCR4, ACKR3/CXCR7, and are a vital source of CXCL12/SDF-1α themselves. In recent years, a regulatory impact of the CXCL12-CXCR4-CXCR7 axis on platelet biogenesis, i.e., megakaryopoiesis, thrombotic and thrombo-inflammatory actions have been revealed through experimental and clinical studies. Platelet surface expression of ACKR3/CXCR7 is significantly enhanced following myocardial infarction (MI) in acute coronary syndrome (ACS) patients, and is also associated with improved functional recovery and prognosis. The therapeutic implications of ACKR3/CXCR7 in myocardial regeneration and improved recovery following an ischemic episode, are well documented. Cardiomyocytes, cardiac-fibroblasts, endothelial lining of the blood vessels perfusing the heart, besides infiltrating platelets and monocytes, all express ACKR3/CXCR7. This review recapitulates ligand induced differential trafficking of platelet CXCR4-ACKR3/CXCR7 affecting their surface availability, and in regulating thrombo-inflammatory platelet functions and survival through CXCR4 or ACKR3/CXCR7. It emphasizes the pro-thrombotic influence of CXCL12/SDF-1α exerted through CXCR4, as opposed to the anti-thrombotic impact of ACKR3/CXCR7. Offering an innovative translational perspective, this review also discusses the advantages and challenges of utilizing ACKR3/CXCR7 as a potential anti-thrombotic strategy in platelet-associated cardiovascular disorders, particularly in coronary artery disease (CAD) patients post-MI.

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The pulmonary microvasculature entraps induced vascular progenitor cells (iVPCs) systemically delivered after cardiac ischemia‐reperfusion injury: Indication for preservation of heart function via paracrine effects beyond engraftment

Cited by 15 publications

References 26 publications

Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells

Imaging the injured beating heart intravitally and the vasculoprotection afforded by haematopoietic stem cells

Platelets in cardiac ischaemia/reperfusion injury: a promising therapeutic target

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

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