Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes.

Understanding pathways controlling cardiac development may offer insights that are useful for stem cell-based cardiac repair. Developmental studies indicate that the Wnt/β-catenin pathway negatively regulates cardiac differentiation, whereas studies with pluripotent embryonal carcinoma cells suggest that this pathway promotes cardiogenesis. This apparent contradiction led us to hypothesize that Wnt/β-catenin signaling acts biphasically, either promoting or inhibiting cardiogenesis depending on timing. We used inducible promoters to activate or repress Wnt/β-catenin signaling in zebrafish embryos at different times of development. We found that Wnt/β-catenin signaling before gastrulation promotes cardiac differentiation, whereas signaling during gastrulation inhibits heart formation. Early treatment of differentiating mouse embryonic stem (ES) cells with Wnt-3A stimulates mesoderm induction, activates a feedback loop that subsequently represses the Wnt pathway, and increases cardiac differentiation. Conversely, late activation of β-catenin signaling reduces cardiac differentiation in ES cells. Finally, constitutive overexpression of the β-catenin-independent ligand Wnt-11 increases cardiogenesis in differentiating mouse ES cells. Thus, Wnt/β-catenin signaling promotes cardiac differentiation at early developmental stages and inhibits it later. Control of this pathway may promote derivation of cardiomyocytes for basic research and cell therapy applications.

https://www.pnas.org/content/pnas/104/23/9685.full.pdf

Biphasic role for Wnt/β-catenin signaling in cardiac specification in zebrafish and embryonic stem cells

Background— Induced pluripotent stem (iPS) cells are a novel stem cell population induced from mouse and human adult somatic cells through reprogramming by transduction of defined transcription factors. However, detailed differentiation properties and the directional differentiation system of iPS cells have not been demonstrated. Methods and Results— Previously, we established a novel mouse embryonic stem (ES) cell differentiation system that can reproduce the early differentiation processes of cardiovascular cells. We applied our ES cell system to iPS cells and examined directional differentiation of mouse iPS cells to cardiovascular cells. Flk1 (also designated as vascular endothelial growth factor receptor-2)-expressing mesoderm cells were induced from iPS cells after ≈4-day culture for differentiation. Purified Flk1+ cells gave rise to endothelial cells and mural cells by addition of vascular endothelial growth factor and serum. Arterial, venous, and lymphatic endothelial cells were also successfully ...

Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells

Several applications of pluripotent stem cell (PSC)-derived cardiomyocytes require elimination of undifferentiated cells. A major limitation for cardiomyocyte purification is the lack of easy and specific cell marking techniques. We found that a fluorescent dye that labels mitochondria, tetramethylrhodamine methyl ester perchlorate, could be used to selectively mark embryonic and neonatal rat cardiomyocytes, as well as mouse, marmoset and human PSC-derived cardiomyocytes, and that the cells could subsequently be enriched (>99% purity) by fluorescence-activated cell sorting. Purified cardiomyocytes transplanted into testes did not induce teratoma formation. Moreover, aggregate formation of PSC-derived cardiomyocytes through homophilic cell-cell adhesion improved their survival in the immunodeficient mouse heart. Our approaches will aid in the future success of using PSC-derived cardiomyocytes for basic and clinical applications.

Nongenetic method for purifying stem cell–derived cardiomyocytes

There is provided a nuclear reprogramming factor for a somatic cell, which comprises a gene product of each of the following three kinds of genes: an Oct family gene, a Klf family gene, and a Myc family gene, as a means for inducing reprogramming of a differentiated cell to conveniently and highly reproducibly establish an induced pluripotent stem cell having pluripotency and growth ability similar to those of ES cells without using embryo or ES cell.

Nuclear reprogramming factor

Embryonic stem (ES) cells are a promising source of cardiomyocytes, but clinical application of ES cells has been hindered by the lack of reliable selective differentiation methods. Differentiation into any lineage is partly dependent on the regulatory mechanisms of normal early development. Although several signals, including bone morphogenetic protein (BMP), Wnt and FGF, are involved in heart development, scarce evidence is available about the exact signals that mediate cardiomyocyte differentiation. While investigating the involvement of BMP signaling in early heart formation in the mouse, we found that the BMP antagonist Noggin is transiently but strongly expressed in the heart-forming region during gastrulation and acts at the level of induction of mesendoderm to establish conditions conducive to cardiogenesis. We applied this finding to develop an effective protocol for obtaining cardiomyocytes from mouse ES cells by inhibition of BMP signaling.

/pdf/transient-inhibition-of-bmp-signaling-by-noggin-induces-14t78m1xig.pdf

Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells.

For a method of inducing differentiation of cardiomyocytes from stem cells, a method is provided to induce efficiently and selectively differentiation of cardiomyocytes by such a method in which the stem cells are cultured to induce differentiation into cardiomyocytes in the presence of a substance that inhibits BMP signaling.

Method of inducing the differentiation of stem cells into myocardial cells

Nat. Biotechnol. 23, 607–611 (2005) The order of the authors is incorrect. The correct order is: Shinsuke Yuasa, Yuji Itabashi, Uichi Koshimizu, Tomofumi Tanaka, Keijiro Sugimura, Masayoshi Kinoshita, Fumiyuki Hattori, Shin-ichi Fukami, Takuya Shimazaki, Satoshi Ogawa, Hideyuki Okano & Keiichi Fukuda.

Correction: Corrigendum: Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells

L'invention concerne une methode propre a induire une differenciation de cellules souches en cellules myocardiques, caracterisee en ce que cette differenciation s'obtient par culture des cellules souches en presence d'une substance qui inhibe le transfert du signal BMP, ce qui permet d'induire efficacement et selectivement la differenciation en cellules myocardiques.

Methode d'induction d'une differenciation de cellules souches en cellules myocardiques

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Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells.

Method of inducing the differentiation of stem cells into myocardial cells

Correction: Corrigendum: Transient inhibition of BMP signaling by Noggin induces cardiomyocyte differentiation of mouse embryonic stem cells

Methode d'induction d'une differenciation de cellules souches en cellules myocardiques