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Circ Res. 2012 Sep 14;111(7):876-81. doi: 10.1161/CIRCRESAHA.112.270272. Epub 2012 Aug 7.

A Nodal-to-TGFβ cascade exerts biphasic control over cardiopoiesis.

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1
Muscle Development and Regeneration Program, Sanford-Burnham Medical Research Institute, 10901 N Torrey Pines Rd, La Jolla, CA 92037, USA.

Abstract

RATIONALE:

The transforming growth factor-β (TGFβ) family member Nodal promotes cardiogenesis, but the mechanism is unclear despite the relevance of TGFβ family proteins for myocardial remodeling and regeneration.

OBJECTIVE:

To determine the function(s) of TGFβ family members during stem cell cardiogenesis.

METHODS AND RESULTS:

Murine embryonic stem cells were engineered with a constitutively active human type I Nodal receptor (caACVR1b) to mimic activation by Nodal and found to secrete a paracrine signal that promotes cardiogenesis. Transcriptome and gain- and loss-of-function studies identified the factor as TGFβ2. Both Nodal and TGFβ induced early cardiogenic progenitors in embryonic stem cell cultures at day 0 to 2 of differentiation. However, Nodal expression declines by day 4 due to feedback inhibition, whereas TGFβ persists. At later stages (days 4-6), TGFβ suppresses the formation of cardiomyocytes from multipotent Kdr(+) progenitors while promoting the differentiation of vascular smooth muscle and endothelial cells.

CONCLUSIONS:

Nodal induces TGFβ, and both stimulate the formation of multipotent cardiovascular Kdr(+) progenitors. TGFβ, however, becomes uniquely responsible for controlling subsequent lineage segregation by stimulating vascular smooth muscle and endothelial lineages and simultaneously blocking cardiomyocyte differentiation.

PMID:
22872153
PMCID:
PMC3766357
DOI:
10.1161/CIRCRESAHA.112.270272
[Indexed for MEDLINE]
Free PMC Article
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