Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit
            <sup>+</sup>
            Cardiac Stem Cells As Regenerative Therapy for Heart Failure)

Bolli, Roberto; Hare, Joshua M.; March, Keith L.; Pepine, Carl J.; Willerson, James T.; Perin, Emerson C.; Yang, Phillip C.; Henry, Timothy D.; Traverse, Jay H.; Mitrani, Raul D.; Khan, Aisha; Schulman, Ivonne Hernandez; Taylor, Doris A.; DiFede, Darcy L.; Lima, João A.C.; Chugh, Atul R.; Loughran, John; Vojvodic, Rachel W.; Sayre, Shelly L.; Bettencourt, Judy; Cohen, Mark H.; Moyé, Lem; Ebert, Ray F.; Simari, Robert D.

doi:10.1161/circresaha.118.312978

Cited by 98 publications

(66 citation statements)

References 55 publications

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“…Combinatorial approaches harnessing beneficial attributes of multiple adult cell types are gaining acceptance as a method to enhance biological properties and efficacy based upon the tenets that: (1) no single cell population possesses all the requisite attributes for effective repair, and (2) both cardiomyogenic and non-cardiomyogenic cells contribute to myocardial repair and regeneration. Combining multiple cell types with complementary roles more efficiently mediates repair in preclinical experimental animal models of heart failure [18][19][20][21] and is currently being assessed in the CONCERT clinical trial with patients receiving mixtures of MSCs and cardiac progenitor cells 71 . Similarly, induced pluripotent stem cell-derived cardiomyocytes combined with vascular cells 72 or MSCs 73 potentiates myocardial repair, likely due to enhanced stimulation of endogenous repair mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Enhancing myocardial repair with CardioClusters

et al. 2020

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Cellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such 'next generation' implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit + cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed Cardi-oClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.

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Section: Discussionmentioning

confidence: 99%

Enhancing myocardial repair with CardioClusters

et al. 2020

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“…Multiple translational failures led researchers to return to the benches and develop distinguished approaches, such as combined transplantation of different stem cell types. An ongoing clinical study (CONCERT-HF) is evaluating the feasibility, safety, and effect of a combination of MSCs and c-kit(+) cardiac stem cells on heart failure (NCT02501811) 21 .…”

Section: Discussionmentioning

confidence: 99%

Adjuvant role of macrophages in stem cell-induced cardiac repair in rats

et al. 2018

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Bone marrow-derived mesenchymal stem cells (BMMSCs) are used extensively for cardiac repair and interact with immune cells in the damaged heart. Macrophages are known to be modulated by stem cells, and we hypothesized that priming macrophages with BMMSCs would enhance their therapeutic efficacy. Rat bone marrow-derived macrophages (BMDMs) were stimulated by lipopolysaccharide (LPS) with or without coculture with rat BMCs. In the LPS-stimulated BMDMs, induction of the inflammatory marker iNOS was attenuated, and the anti-inflammatory marker Arg1 was markedly upregulated by coculture with BMMSCs. Myocardial infarction (MI) was induced in rats. One group was injected with BMMSCs, and a second group was injected with MIX (a mixture of BMMSCs and BMDMs after coculture). The reduction in cardiac fibrosis was greater in the MIX group than in the BMC group. Cardiac function was improved in the BMMSC group and was substantially improved in the MIX group. Angiogenesis was better in the MIX group, and anti-inflammatory macrophages were more abundant in the MIX group than in the BMMSC group. In the BMMSCs, interferon regulatory factor 5 (IRF5) was exclusively induced by coculture with macrophages. IRF5 knockdown in BMMSCs failed to suppress inflammatory marker induction in the macrophages. In this study, we demonstrated the successful application of BMDMs primed with BMMSCs as an adjuvant to cell therapy for cardiac repair.

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“…A more recent approach is treatment using combinations of stem cells, which may provide greater therapeutic efficacy than a single cells type, as was observed with MSCs+CSCs in preclinical studies in porcine models of ICM. [76][77][78] These porcine studies formed the basis of the ongoing phase II CONCERT-HF trial (Combination of Mesenchymal and C-kit + Cardiac Stem Cells as Regenerative Therapy for Heart Failure), 79 which is assessing if the combination of MSCs plus CSCs provides greater cardiac repair in humans than either cell type alone. Other clinical 80 and preclinical 77,81 studies have also demonstrated a positive effect of combination stem cell therapy.…”

Section: Chronic Ischemic Cardiomyopathymentioning

confidence: 99%

Clinical-based Cell Therapies for Heart Disease—Current and Future State

Turner¹,

Rieger²,

Balkan³

et al. 2020

Rambam Maimonides Med J

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Hare reports having a patent for cardiac cell-based therapy. He holds equity in Vestion Inc. and maintains a professional relationship with Vestion Inc. as a consultant and member of the Board of Directors and Scientific Advisory Board. Dr Hare is the Chief Scientific Officer, a compensated consultant, and advisory board member for Longeveron and holds equity in Longeveron. Dr Hare is also the co-inventor of intellectual property licensed to Longeveron. The other authors report no conflicts.

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Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit ⁺ Cardiac Stem Cells As Regenerative Therapy for Heart Failure)

Abstract: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811.

Cited by 98 publications

References 55 publications

Enhancing myocardial repair with CardioClusters

Enhancing myocardial repair with CardioClusters

Adjuvant role of macrophages in stem cell-induced cardiac repair in rats

Clinical-based Cell Therapies for Heart Disease—Current and Future State

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Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit + Cardiac Stem Cells As Regenerative Therapy for Heart Failure)

Abstract: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811.

Cited by 98 publications

References 55 publications

Enhancing myocardial repair with CardioClusters

Enhancing myocardial repair with CardioClusters

Adjuvant role of macrophages in stem cell-induced cardiac repair in rats

Clinical-based Cell Therapies for Heart Disease—Current and Future State

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Product

Resources

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Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit ⁺ Cardiac Stem Cells As Regenerative Therapy for Heart Failure)