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Published on: January 28, 2020
Quantitative assessment of initial retention of bone marrow mononuclear cells injected into the coronary arteries
Satsuki Fukushima1, Niall G Campbell, Steven R Coppen
1Harefield Heart Science Centre, Imperial College London, London, UK.
Insights
Bone marrow mononuclear cell retention in the heart after injection is poor. Ischemia-reperfusion injury significantly enhances cell retention through P-selectin interactions, improving potential cell therapy for heart disease.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Cell Biology
Background:
- Intracoronary injection of bone marrow mononuclear cells (BMMNC) is a standard cell transplantation method for heart disease.
- Poor engraftment of donor BMMNC in the heart limits therapeutic efficacy.
- Initial BMMNC retention (adherence/extravasation) is critical for engraftment but poorly understood.
Purpose of the Study:
- Quantify BMMNC retention after intracoronary injection.
- Assess the impact of ischemia-reperfusion injury on BMMNC retention efficiency.
- Elucidate mechanisms of BMMNC retention, focusing on adhesion molecules.
Main Methods:
- Injected 1 million GFP-transgenic mouse BMMNC into syngeneic wild-type mouse hearts via Langendorff perfusion.
- Quantified retention efficiency by measuring GFP-positive cells in coronary effluent.
- Utilized immunoconfocal microscopy and adhesion molecule inhibition (anti-P-selectin, anti-ICAM-1, anti-VCAM-1).
Main Results:
- Normal hearts retained only 13.3% of injected BMMNC.
- Ischemia-reperfusion (30 min ischemia/30 min reperfusion) increased retention to 36.5% (p < 0.05).
- Enhanced retention was reduced by anti-P-selectin antibody but unaffected by anti-ICAM-1 or anti-VCAM-1.
Conclusions:
- BMMNC retention is poor in isolated, crystalloid-perfused murine hearts.
- Global ischemia-reperfusion significantly enhances BMMNC retention.
- P-selectin-dependent BMMNC-endothelial interactions mediate improved retention after ischemia-reperfusion.
Background:
Intracoronary injection of bone marrow mononuclear cells (BMMNC) is a common clinical protocol of cell transplantation for heart disease, but poor engraftment of donor cells in the heart, which will limit its therapeutic efficacy, is a major issue. Initial "retention" (endothelial adherence and/or extravasation) of BMMNC immediately after intracoronary injection is a key step toward successful engraftment; however, this event has not been fully characterized. The aim of this study is to quantitatively clarify the frequency of "retention" of BMMNC after intracoronary injection, determine the impact of prior induction of ischemia-reperfusion injury on "retention" efficiency, and elucidate the underlying mechanisms focusing on adhesion molecule-mediated cell-cell interactions.
Methods:
One million BMMNC collected from green fluorescent protein (GFP)-transgenic mice were injected into the coronary arteries of syngeneic wild-type mouse hearts under Langendorff perfusion. Retention efficiency was quantitatively estimated from the GFP-positive cell number flushed out into the coronary effluent.
Results:
Whereas only 13.3 ± 1.2% of injected BMMNC were retained into normal hearts, prior induction of 30-minute ischemia and 30-minute reperfusion increased the retention efficiency to 36.5 ± 1.6% (p < 0.05, n = 8). Immunoconfocal observation further confirmed this enhanced retention after ischemia-reperfusion. Noticeably, the enhanced retention efficiency after ischemia-reperfusion treatment was diminished by administration of anti-P-selectin antibody (8.3 ± 0.8%, p < 0.05), but was not affected by inhibiting intercellular adhesion molecule-1 (39.6 ± 3.3%) or vascular cell adhesion molecule-1 (43.9 ± 2.9%).
Conclusions:
Retention efficiency of intracoronary-injected BMMNC was poor in a model of isolated, crystalloid-perfused murine hearts. An antecedent period of global ischemia-reperfusion increased the retention via P-selectin-dependent BMMNC-endothelial interaction.
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