A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates.

INSERM U633, Avenir Program, Embryonic Stem Cells and Cardiogenesis, Evry, France.
The Journal of clinical investigation (Impact Factor: 15.39). 03/2010; 120(4):1125-39. DOI: 10.1172/JCI40120
Source: PubMed

ABSTRACT 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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    ABSTRACT: Background Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. This study tested the long-term effects of their combination. Methods and Results Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks thereafter, those with an echocardiographically-measured ejection fraction (EF) ≤55% were reoperated on and randomly allocated to receive a cell-free fibrin patch (n=25), a fibrin patch loaded with 700,000 human embryonic stem cell (ESC) pre-treated to promote early cardiac differentiation (SSEA1+ progenitors [n=30]) or to serve as sham-operated animals (n=25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for the assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the qPCR-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed blindly. The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p=0.002 for EF; p=0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p=0.006) which yielded the lowest heart failure score (p=0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma either. Conclusion A fibrin scaffold loaded with ESC-derived cardiac progenitors results in sustained improvement of contractility and attenuation of remodelling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.
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Guillaume Blin