Retinoic Acid Accelerates Embryonic Stem Cell-Derived Cardiac Differentiation and Enhances Development of Ventricular Cardiomyocytes

Wobus, Anna M.; Guan, Kaomei; Shan, Jin; Wellner, M C; Rohwedel, Jürgen; Guanju, Ji; Fleischmann, Bernd K.; Katus, Hugo A.; Hescheler, Jürgen; Franz, Wolfgang-Michael

doi:10.1006/jmcc.1997.0433

Cited by 387 publications

(258 citation statements)

References 2 publications

Supporting

Mentioning

242

Contrasting

Unclassified

Order By: Relevance

“…Our results demonstrate that the activation or inhibition of retinoid signals instructs the atrial versus ventricular specification of differentiating hESCs, respectively. By contrast, a previous study demonstrated that RA enhances the development of ventricular cardiomyocytes derived from mESCs [33]. This result could represent differences between the differentiation culture systems used in the two studies, the embryoid body procedure versus the flat culture system, or the timing of RA administration.…”

Section: Discussionmentioning

confidence: 68%

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

et al. 2010

View full text Add to dashboard Cite

Although myocyte cell transplantation studies have suggested a promising therapeutic potential for myocardial infarction, a major obstacle to the development of clinical therapies for myocardial repair is the difficulties associated with obtaining relatively homogeneous ventricular myocytes for transplantation. Human embryonic stem cells (hESCs) are a promising source of cardiomyocytes. Here we report that retinoid signaling regulates the fate specification of atrial versus ventricular myocytes during cardiac differentiation of hESCs. We found that both Noggin and the panretinoic acid receptor antagonist BMS-189453 (RAi) significantly increased the cardiac differentiation efficiency of hESCs. To investigate retinoid functions, we compared Noggin+RAi-treated cultures with Noggin+RA-treated cultures. Our results showed that the expression levels of the ventricular-specific gene IRX-4 were radically elevated in Noggin+RAi-treated cultures. MLC-2V, another ventricular-specific marker, was expressed in the majority of the cardiomyocytes in Noggin+RAi-treated cultures, but not in the cardiomyocytes of Noggin+RA-treated cultures. Flow cytometry analysis and electrophysiological studies indicated that with 64.7 ± 0.88% (mean ± s.e.m) cardiac differentiation efficiency, 83% of the cardiomyocytes in Noggin+RAi-treated cultures had embryonic ventricular-like action potentials (APs). With 50.7 ± 1.76% cardiac differentiation efficiency, 94% of the cardiomyocytes in Noggin+RA-treated cultures had embryonic atrial-like APs. These results were further confirmed by imaging studies that assessed the patterns and properties of the Ca 2+ sparks of the cardiomyocytes from the two cultures. These findings demonstrate that retinoid signaling specifies the atrial versus ventricular differentiation of hESCs. This study also shows that relatively homogeneous embryonic atrial-and ventricular-like myocyte populations can be efficiently derived from hESCs by specifically regulating Noggin and retinoid signals.

show abstract

Section: Discussionmentioning

confidence: 68%

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

et al. 2010

View full text Add to dashboard Cite

show abstract

“…The scalable expansion of ESC into cardiac-like cells can also be accomplished by exposing undifferentiated ESC to a number of specific proteins or low-molecular weight compounds [60][61][62]. For example, the TGF-beta family of secreted factors has been shown to induce mesodermal differentiation of ESC [63,64].…”

Section: Embryonic Stem Cells (Esc)mentioning

confidence: 99%

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

Gillum

Sarvazyan

2008

Cardiovasc Toxicol

View full text Add to dashboard Cite

Cell-transplantation therapy is a promising treatment option that is being actively explored as a way to repair cardiac muscle. The ultimate goal is to reconstitute the architecture of the cardiac muscle and to reestablish electrical propagation, while avoiding hypertrophy and scar formation. In this review, we focus on recent advances in the field as well as the difficulties encountered when the engraftment of cells into the host tissue is to be confirmed and functionally characterized. This is critical since incomplete or partial engraftment of transplanted cells within the host cardiac network exacerbates the heterogeneity already present in the injured myocardium and increases its propensity to arrhythmia. We conclude with a brief discussion of how the modulation of cell adhesion via modification of coupling proteins within transplanted cells may facilitate engraftment and alleviate the arrhythmogenic potential of cardiac grafts.

show abstract

“…For example, retinoic acid (Wobus et al 1997) has been shown to accelerate differentiation, although it was not clear if there was an overall enhancement of total cardiomyocyte yield. Interestingly, treatment with retinoic acid resulted in an increase in cardiomyoblast differentiation toward the ventricular lineage in EBs cultured under high serum conditions (Wobus et al 1997;Hidaka et al 2003), with a concomitant reduction in differentiation toward the atrial lineage. Paradoxically, depletion of retinoic acid in low serum cultures enhanced cardiomyogenic differentiation (Gajovic et al 1997), presumably due to effects on other cell lineages.…”

Section: Identification Of Factors That Enhance Cardiomyogenic Differmentioning

confidence: 99%

Cardiac Repair by Embryonic Stem-Derived Cells

Rubart

Field

2006

Stem Cells

View full text Add to dashboard Cite

Cell transplantation approaches offer the potential to promote regenerative growth of diseased hearts. It is well established that donor cardiomyocytes stably engraft into recipient hearts when injected directly into the myocardial wall. Moreover, the transplanted donor cardiomyocytes participate in a functional syncytium with the host myocardium. Thus, transplantation of donor cardiomyocytes resulted in at least partial restoration of lost muscle mass. It is also well established that embryonic stem (ES) cells differentiate into cells of ecto-, endo-, and mesodermal lineages when cultured under appropriate conditions in vitro. Robust cardiomyogenic differentiation was frequently observed in spontaneously differentiating ES cultures. Cellular, molecular and physiologic analyses indicated that ES-derived cells were bona fide cardiomyocytes, with in vitro characteristics typical for cells obtained from early stages of cardiac development. Thus, ES-derived cardiomyocytes constitute a viable source of donor cells for cell transplantation therapies.

show abstract

Retinoic Acid Accelerates Embryonic Stem Cell-Derived Cardiac Differentiation and Enhances Development of Ventricular Cardiomyocytes

Cited by 387 publications

References 2 publications

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

Direct differentiation of atrial and ventricular myocytes from human embryonic stem cells by alternating retinoid signals

Adhesion Proteins, Stem Cells, and Arrhythmogenesis

Cardiac Repair by Embryonic Stem-Derived Cells

Contact Info

Product

Resources

About