Heparin Disrupts the CXCR4/SDF-1 Axis and Impairs the Functional Capacity of Bone Marrow–Derived Mononuclear Cells Used for Cardiovascular Repair

Seeger, Florian; Rasper, Tina; Fischer, Ariane; Muhly-Reinholz, Marion; Hergenreider, Eduard; Leistner, David M.; Sommer, Katharina; Manavski, Yosif; Henschler, Reinhard; Chavakis, Emmanouil; Aßmus, Birgit; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1161/circresaha.112.265678

Cited by 85 publications

(62 citation statements)

References 41 publications

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“…13,38,42 Heparin has been reported to negatively affect cellular homing by impairment of the SDF-1α/CXCR4 axis. 40 We cannot exclude that the use of heparin in our isolation procedure could have reduced the potency of our product. Contamination of erythrocytes in the BMMNC product may Figure 3.…”

Section: Discussionmentioning

confidence: 99%

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Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia

Teraa¹,

Sprengers²,

Schutgens³

et al. 2015

Circulation

153

103

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Background— Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow–derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results— The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62–3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63–3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22–2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions— Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00371371.

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Section: Discussionmentioning

confidence: 99%

“…[39][40][41] We used Lymphoprep for BMMNC isolation and included heparin in our isolation protocol, which is similar to previous studies that showed potential clinical effects. 13,38,42 Heparin has been reported to negatively affect cellular homing by impairment of the SDF-1α/CXCR4 axis.…”

Section: Discussionmentioning

confidence: 99%

Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia

Teraa¹,

Sprengers²,

Schutgens³

et al. 2015

Circulation

153

103

View full text Add to dashboard Cite

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“…Heparin, has been observed recently to exert detrimental effects on the functionality of BM-MNCs by interacting with the CXCR4/SDF-1 axis. [62,63] The CCTRN-trials have been performed using an automated cell-sorting system for the isolation of BM-MNCs. [64,65] However, whether these cells are efficient in an experimental myocardial infarction model in vivo has not been reported.…”

Section: Potential Impact Of Cell Isolation Procedures and Impaired Fmentioning

confidence: 99%

Current Status of Cell-Based Therapy for Heart Failure

Jakob

Landmesser

2013

Curr Heart Fail Rep

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In the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies. However, despite these advances, there is a substantial unmet need for novel therapies, ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults. In this respect, cardiac cell-based therapies have gained substantial attention and have entered clinical feasibility and safety studies a decade ago. Different cell-types have been used, including bone marrow-derived mononuclear cells, bone marrow-derived mesenchymal stem cells, mobilized CD34+ cells, and more recently cardiac-derived c-kit+ stem cells and cardiosphere-derived cells. Some of these studies have suggested a potential of cell-based therapies to reduce cardiac scar size and to improve cardiac function in patients with ischemic cardiomyopathy. While first clinical trials examining the impact of cardiac cell-based therapy on clinical outcome have now been initiated, improved understanding of underlying mechanisms of action of cell-based therapies may lead to strategies for optimization of the cardiac repair potential of the applied cells. In experimental studies, direct in vivo reprogramming of cardiac fibroblasts towards cardiomyocytes, and microRNA-based promotion of cardiomyocyte proliferation and cardiac repair have recently been reported that may represent novel therapeutic approaches for cardiac regeneration that would not need cell-administration but rather directly stimulate endogenous cardiac regeneration. This review will focus mainly on recently completed clinical trials (within the last 2 years) investigating cardiac cell-based therapies and the current status of experimental studies for cardiac cell-based repair and regeneration with a potential for later translation into clinical studies in the future. AbstractIn the last two decades, morbidity and mortality of patients with chronic heart failure could be further reduced by improved pharmacological and cardiac device therapies.However, despite these advances, there is a substantial unmet need for novel therapies ideally specifically addressing repair and regeneration of the damaged or lost myocardium and its vasculature, given the limited endogenous potential for renewal of cardiomyocytes in adults.In this respect, cardiac cell-based therapies have gained substantial attention and

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“…This inhibition was not seen when an alternative anticoagulant -the thrombin inhibitor bivalirudin -was used. Given that the homing and engraftment of cells delivered as part of a therapeutic strategy is the key to a successful outcome in cardiac repair, this finding has important implications for the choice of anticoagulant when designing future clinical trials (Seeger et al, 2012). Other potentially negative interactions between cardiovascular drugs and cell therapy are not just confined to i.v.…”

Section: Figurementioning

confidence: 99%