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N-cadherin prevents the premature differentiation of anterior heart field progenitors in the pharyngeal mesodermal microenvironment.

Soh BS, Buac K, Xu H, Li E, Ng SY, Wu H, Chmielowiec J, Jiang X, Bu L, Li RA, Cowan C, Chien KR - Cell Res. (2014)

Bottom Line: The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes.Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM.CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM.

View Article: PubMed Central - PubMed

Affiliation: 1] Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA [3] Stem Cell & Regenerative Medicine Consortium, and the Department of Physiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China [4] Department of Cell and Molecular Biology and Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.

ABSTRACT
The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenvironment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides additional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.

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Schematic summarizing the role of N-cadherin in the maintenance of AHF-CPCs. In wild-type mice, N-cadherin expression by CPCs allows the cells to be properly adhered in the microenvironment of the pharyngeal mesoderm, thereby allowing the cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation. In addition, N-cadherin serves to maintain β-catenin levels by sequestering the molecules at the cell membrane. These allow the AHF-CPCs from wild-type mice to achieve higher Wnt signaling activity as compared to single mutant (AHF-Cre;Cdh2fl/fl), where an overall downregulation of Wnt signaling activity was observed, which consequently resulted in premature differentiation of CPCs to cardiomyocytes in the AHF. Expectedly, activating Wnt signaling by overexpression of β-catenin in the double mutant (AHF-Cre; Cdh2fl/fl ; bCat(e3)fl/+) was able to partially rescue the premature differentiation phenotype of the CPCs observed in Cdh2 single mutant.
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fig5: Schematic summarizing the role of N-cadherin in the maintenance of AHF-CPCs. In wild-type mice, N-cadherin expression by CPCs allows the cells to be properly adhered in the microenvironment of the pharyngeal mesoderm, thereby allowing the cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation. In addition, N-cadherin serves to maintain β-catenin levels by sequestering the molecules at the cell membrane. These allow the AHF-CPCs from wild-type mice to achieve higher Wnt signaling activity as compared to single mutant (AHF-Cre;Cdh2fl/fl), where an overall downregulation of Wnt signaling activity was observed, which consequently resulted in premature differentiation of CPCs to cardiomyocytes in the AHF. Expectedly, activating Wnt signaling by overexpression of β-catenin in the double mutant (AHF-Cre; Cdh2fl/fl ; bCat(e3)fl/+) was able to partially rescue the premature differentiation phenotype of the CPCs observed in Cdh2 single mutant.

Mentions: Since N-cadherin plays a crucial role in cell adhesion and Wnt signaling of AHF-CPCs, a working model is suggested whereby the deletion of the adhesion molecule would inevitably perturb the physical cell adhesion system, proliferation and subsequent differentiation processes that are necessary for the formation of a highly organized organ such as the heart (Figure 5). As one of the early events in cardiogenesis involves the expansion of CPCs in the PM (niche), proper adhesion of the CPCs within the PM would allow the progenitor cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation12. This in turn results in a larger pool of CPCs in the PM, which is critical for proper cardiac development.


N-cadherin prevents the premature differentiation of anterior heart field progenitors in the pharyngeal mesodermal microenvironment.

Soh BS, Buac K, Xu H, Li E, Ng SY, Wu H, Chmielowiec J, Jiang X, Bu L, Li RA, Cowan C, Chien KR - Cell Res. (2014)

Schematic summarizing the role of N-cadherin in the maintenance of AHF-CPCs. In wild-type mice, N-cadherin expression by CPCs allows the cells to be properly adhered in the microenvironment of the pharyngeal mesoderm, thereby allowing the cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation. In addition, N-cadherin serves to maintain β-catenin levels by sequestering the molecules at the cell membrane. These allow the AHF-CPCs from wild-type mice to achieve higher Wnt signaling activity as compared to single mutant (AHF-Cre;Cdh2fl/fl), where an overall downregulation of Wnt signaling activity was observed, which consequently resulted in premature differentiation of CPCs to cardiomyocytes in the AHF. Expectedly, activating Wnt signaling by overexpression of β-catenin in the double mutant (AHF-Cre; Cdh2fl/fl ; bCat(e3)fl/+) was able to partially rescue the premature differentiation phenotype of the CPCs observed in Cdh2 single mutant.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4260345&req=5

fig5: Schematic summarizing the role of N-cadherin in the maintenance of AHF-CPCs. In wild-type mice, N-cadherin expression by CPCs allows the cells to be properly adhered in the microenvironment of the pharyngeal mesoderm, thereby allowing the cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation. In addition, N-cadherin serves to maintain β-catenin levels by sequestering the molecules at the cell membrane. These allow the AHF-CPCs from wild-type mice to achieve higher Wnt signaling activity as compared to single mutant (AHF-Cre;Cdh2fl/fl), where an overall downregulation of Wnt signaling activity was observed, which consequently resulted in premature differentiation of CPCs to cardiomyocytes in the AHF. Expectedly, activating Wnt signaling by overexpression of β-catenin in the double mutant (AHF-Cre; Cdh2fl/fl ; bCat(e3)fl/+) was able to partially rescue the premature differentiation phenotype of the CPCs observed in Cdh2 single mutant.
Mentions: Since N-cadherin plays a crucial role in cell adhesion and Wnt signaling of AHF-CPCs, a working model is suggested whereby the deletion of the adhesion molecule would inevitably perturb the physical cell adhesion system, proliferation and subsequent differentiation processes that are necessary for the formation of a highly organized organ such as the heart (Figure 5). As one of the early events in cardiogenesis involves the expansion of CPCs in the PM (niche), proper adhesion of the CPCs within the PM would allow the progenitor cells to be sufficiently exposed to paracrine factors that promote multipotency and proliferation12. This in turn results in a larger pool of CPCs in the PM, which is critical for proper cardiac development.

Bottom Line: The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes.Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM.CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM.

View Article: PubMed Central - PubMed

Affiliation: 1] Cardiovascular Research Center, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University and Harvard Medical School, 7 Divinity Avenue, Cambridge, MA 02138, USA [3] Stem Cell & Regenerative Medicine Consortium, and the Department of Physiology, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China [4] Department of Cell and Molecular Biology and Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.

ABSTRACT
The cardiac progenitor cells (CPCs) in the anterior heart field (AHF) are located in the pharyngeal mesoderm (PM), where they expand, migrate and eventually differentiate into major cell types found in the heart, including cardiomyocytes. The mechanisms by which these progenitors are able to expand within the PM microenvironment without premature differentiation remain largely unknown. Through in silico data mining, genetic loss-of-function studies, and in vivo genetic rescue studies, we identified N-cadherin and interaction with canonical Wnt signals as a critical component of the microenvironment that facilitates the expansion of AHF-CPCs in the PM. CPCs in N-cadherin mutant embryos were observed to be less proliferative and undergo premature differentiation in the PM. Notably, the phenotype of N-cadherin deficiency could be partially rescued by activating Wnt signaling, suggesting a delicate functional interaction between the adhesion role of N-cadherin and Wnt signaling in the early PM microenvironment. This study suggests a new mechanism for the early renewal of AHF progenitors where N-cadherin provides additional adhesion for progenitor cells in the PM, thereby allowing Wnt paracrine signals to expand the cells without premature differentiation.

Show MeSH
Related in: MedlinePlus