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A purified population of multipotent cardiovascular progenitors derived from primate pluripotent stem cells engrafts in postmyocardial infarcted nonhuman primates
Guillaume Blin, … , Philippe Menasché, Michel Pucéat
Guillaume Blin, … , Philippe Menasché, Michel Pucéat
Published March 24, 2010
Citation Information: J Clin Invest. 2010;120(4):1125-1139. https://doi.org/10.1172/JCI40120.
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Research Article Article has an altmetric score of 24

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

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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.

Authors

Guillaume Blin, David Nury, Sonia Stefanovic, Tui Neri, Oriane Guillevic, Benjamin Brinon, Valérie Bellamy, Catherine Rücker-Martin, Pascal Barbry, Alain Bel, Patrick Bruneval, Chad Cowan, Julia Pouly, Shoukhrat Mitalipov, Elodie Gouadon, Patrice Binder, Albert Hagège, Michel Desnos, Jean-François Renaud, Philippe Menasché, Michel Pucéat

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Figure 4

BMP2-induced SSEA-1+ primate cardiac progenitors differentiate in mature cardiomyocytes.

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BMP2-induced SSEA-1+ primate cardiac progenitors differentiate in mature...
Immunostaining of actin promoter EGFP SSEA-1+ ORMES cells cultured on (A and B) both cardiac fibroblasts and myocytes. (A) Anti-GFP and anti-actinin, with merged image on the right. (B) Anti-GFP immunostaining and DAPI staining of nuclei of SSEA-1+ cells; z-stack of images was acquired in a laser-scanning confocal microscope, with the green and blue channels together with differential interference contrast images. The merged image of a 200-nm focal plane is shown. (C) Merged image of anti-actinin (red), anti-GFP (green), and Cx43 (white) immunostaining. (D) Actin promoter EGFP SSEA-1+ ORMES cells cultured on cardiomyocytes only and (E) fibroblasts only (GFP, green; actinin, red; CX43 or phosphorylated P-CX43, white). (F) Actin promoter EGFP SSEA-1+ ORMES cells cultured on both cardiac fibroblasts and myocytes immunostained with the anti-GFP (green), anti-actinin (red), and anti-MLC2v (blue) antibodies. These images are representative of 3 coculture experiments. Original magnification, ×100 (inset). (G) Actin promoter EGFP SSEA-1+ ORMES cells were cultured for 2 weeks on matrigel in the presence of filtered conditioned medium of a mix of fibroblasts and cardiomyocytes and actin stained with phalloidin. Original magnification, ×63 (inset). (H) Actin promoter EGFP SSEA-1+ ORMES cells cultured on both cardiac fibroblasts and myocytes immunostained with the anti–β-MHC (red) and anti-GFP (green). Merged image is shown on the right. The sarcomeric staining of GFP is due to its binding to myosin (60).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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