Blin, G, Nury, D, Stefanovic, S, Neri, T, Guillevic, O, Brinon, B et al.. A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates. J Clin Invest 120: 1125-1139

INSERM U633, Avenir Program, Embryonic Stem Cells and Cardiogenesis, Evry, France.
The Journal of clinical investigation (Impact Factor: 13.22). 03/2010; 120(4):1125-39. DOI: 10.1172/JCI40120
Source: PubMed


Cell therapy holds promise for tissue regeneration, including in individuals with advanced heart failure. However, treatment of heart disease with bone marrow cells and skeletal muscle progenitors has had only marginal positive benefits in clinical trials, perhaps because adult stem cells have limited plasticity. The identification, among human pluripotent stem cells, of early cardiovascular cell progenitors required for the development of the first cardiac lineage would shed light on human cardiogenesis and might pave the way for cell therapy for cardiac degenerative diseases. Here, we report the isolation of an early population of cardiovascular progenitors, characterized by expression of OCT4, stage-specific embryonic antigen 1 (SSEA-1), and mesoderm posterior 1 (MESP1), derived from human pluripotent stem cells treated with the cardiogenic morphogen BMP2. This progenitor population was multipotential and able to generate cardiomyocytes as well as smooth muscle and endothelial cells. When transplanted into the infarcted myocardium of immunosuppressed nonhuman primates, an SSEA-1+ progenitor population derived from Rhesus embryonic stem cells differentiated into ventricular myocytes and reconstituted 20% of the scar tissue. Notably, primates transplanted with an unpurified population of cardiac-committed cells, which included SSEA-1- cells, developed teratomas in the scar tissue, whereas those transplanted with purified SSEA-1+ cells did not. We therefore believe that the SSEA-1+ progenitors that we have described here have the potential to be used in cardiac regenerative medicine.

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    • "As discussed above, relatively few studies have used PSCs to investigate cardiac regeneration in large animal models. Rhesus monkeys have been used to study the ability of allogeneic NHP ESC derived cardiovascular progenitors transplantation to regenerate infarcted hearts, with (Bel et al., 2010) and without the addition of BM derived MSC (Blin et al., 2010). Recently, human iPSC derived CM have been used in a swine model of MI investigating whether CM cell-sheets induce cardiac regeneration (Kawamura et al., 2012). "
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    ABSTRACT: Pluripotent stem cells (PSCs) have indisputable cardiomyogenic potential and therefore have been intensively investigated as a potential cardiac regenerative therapy. Current directed differentiation protocols are able to produce high yields of cardiomyocytes from PSCs and studies in small animal models of cardiovascular disease have proven sustained engraftment and functional efficacy. Therefore, the time is ripe for cardiac regenerative therapies using PSC derivatives to be tested in large animal models that more closely resemble the hearts of humans. In this review, we discuss the results of our recent study using human embryonic stem cell derived cardiomyocytes (hESC-CM) in a non-human primate model of ischemic cardiac injury. Large scale remuscularization, electromechanical coupling and short-term arrhythmias demonstrated by our hESC-CM grafts are discussed in the context of other studies using Adult Stem Cells for cardiac regeneration.
    Full-text · Article · Nov 2014 · Stem Cell Research
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    • "Assessment of maturity was often discussed in connection with hPSC cardiac differentiation but is not widely standardized. Immature phenotype can be excluded by the use of pluripotency and mesenchymal markers such as stage-specific antigen 1 (SSEA1) and mesoderm posterior 1 (MESP1) [133] or cardiac progenitor markers LIM, homeodomain transcription factor Isl1 [131] and homeobox protein Nkx-2.5 [134]. "
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    ABSTRACT: Human pluripotent stem cells (hPSCs), namely, embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), with their ability of indefinite self-renewal and capability to differentiate into cell types derivatives of all three germ layers, represent a powerful research tool in developmental biology, for drug screening, disease modelling, and potentially cell replacement therapy. Efficient differentiation protocols that would result in the cell type of our interest are needed for maximal exploitation of these cells. In the present work, we aim at focusing on the protocols for differentiation of hPSCs into functional cardiomyocytes in vitro as well as achievements in the heart disease modelling and drug testing on the patient-specific iPSC-derived cardiomyocytes (iPSC-CMs).
    Full-text · Article · Apr 2014
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    • "Indeed, Isl1+ multipotent CPs from mouse and human iPSCs were shown to spontaneously differentiate into all three cardiovascular lineages after transplantation in the left ventricular wall of nude mice, without teratoma formation [115]. Engraftment of ESC-derived early population of CPs in myocardial infarcted nonhuman primate has also been demonstrated [116]. The early multipotent CP population is characterized by expression of OCT4, SSEA-1, and MESP1, and has the potential to differentiate into CMs as well as smooth muscle and endothelial cells. "
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    ABSTRACT: Heart diseases remain a major cause of mortality and morbidity worldwide. However, terminally differentiated human adult cardiomyocytes (CMs) possess a very limited innate ability to regenerate. Directed differentiation of human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) into CMs has enabled clinicians and researchers to pursue the novel therapeutic paradigm of cell-based cardiac regeneration. In addition to tissue engineering and transplantation studies, the need for functional CMs has also prompted researchers to explore molecular pathways and develop strategies to improve the quality, purity and quantity of hESC-derived and iPSC-derived CMs. In this review, we describe various approaches in directed CM differentiation and driven maturation, and discuss potential limitations associated with hESCs and iPSCs, with an emphasis on the role of epigenetic regulation and chromatin remodeling, in the context of the potential and challenges of using hESC-CMs and iPSC-CMs for drug discovery and toxicity screening, disease modeling, and clinical applications.
    Full-text · Article · Aug 2013 · Stem Cell Research & Therapy
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