Limits...
Building and repairing the heart: what can we learn from embryonic development?

Freire AG, Resende TP, Pinto-do-Ó P - Biomed Res Int (2014)

Bottom Line: Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease.Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration.The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal ; Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA ; Faculdade de Engenharia da Universidade do Porto (FEUP), Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal.

ABSTRACT
Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs) in vitro model system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.

Show MeSH

Related in: MedlinePlus

Signaling events in murine heart development and cardiac ESC differentiation. In both systems, mesodermal induction from the epiblast is regulated by Wnt/β-catenin, Nodal/Activin, and BMP signaling pathways and correlates with Brachyury upregulation. Further commitment of mesodermal progenitors to cardiac mesoderm and consequent first heart field (FHF) formation require the inhibition of Wnt signaling and expression of BMPs. Similarly, in ESCs system, Notch pathway inhibits Wnt/β-catenin signaling and activates BMP to specify cardiac fates. Wnt/β-catenin signaling is then activated to allow proliferation and maintenance of the SHF, both in embryo and ESCs. Further differentiation from the cardiac crescent stage to the following morphogenic phases of embryonic heart development and, in parallel, the expression of cardiomyocyte differentiation genes in ESCs require inhibition of Wnt/β-catenin. In the embryo and ESCs, this is achieved by Notch and noncanonical Wnt signaling, which inhibit the effect of Wnt/β-catenin and instruct progenitor cells within the SHF to leave the proliferative state and start differentiating. ⊣ represents inhibitory effect; ⤾ represents maintenance of a proliferative state.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4016833&req=5

fig1: Signaling events in murine heart development and cardiac ESC differentiation. In both systems, mesodermal induction from the epiblast is regulated by Wnt/β-catenin, Nodal/Activin, and BMP signaling pathways and correlates with Brachyury upregulation. Further commitment of mesodermal progenitors to cardiac mesoderm and consequent first heart field (FHF) formation require the inhibition of Wnt signaling and expression of BMPs. Similarly, in ESCs system, Notch pathway inhibits Wnt/β-catenin signaling and activates BMP to specify cardiac fates. Wnt/β-catenin signaling is then activated to allow proliferation and maintenance of the SHF, both in embryo and ESCs. Further differentiation from the cardiac crescent stage to the following morphogenic phases of embryonic heart development and, in parallel, the expression of cardiomyocyte differentiation genes in ESCs require inhibition of Wnt/β-catenin. In the embryo and ESCs, this is achieved by Notch and noncanonical Wnt signaling, which inhibit the effect of Wnt/β-catenin and instruct progenitor cells within the SHF to leave the proliferative state and start differentiating. ⊣ represents inhibitory effect; ⤾ represents maintenance of a proliferative state.

Mentions: In embryo development, gastrulation is a key event through which the three germ layers (endoderm, mesoderm, and ectoderm) are formed. Cellular fates are specified during gastrulation by both time of recruitment to the primitive streak (PS) and perceived morphogenetic information [4, 5]. Mesodermal induction is regulated by the interaction of distinct signaling pathways including bone morphogenetic proteins (BMPs), Nodal/Activin, and Wnt (reviewed in [6]). Mesodermal cells ingressing through the PS express the T-box transcription factor brachyury (Bry, also T), a direct target of the Wnt pathway [7]. β-catenin, a central player in Wnt signaling, has been shown to be essential for mesoderm formation since in β-catenin deficient mice no mesodermal or head structures are formed and Bry is not expressed [8]. These early embryonic events are also observed in ESCs, in which mesodermal commitment is defined by the upregulation of the Bry gene within 48 hours after the onset of differentiation (Figure 1) [9]. Mesoderm is then patterned and specified to originate distinct mesodermal subsets, characterized by differential expression of fetal liver kinase-1 (Flk1, also Vegfr2) and platelet-derived growth factor receptor-alpha (Pdgfra, also CD140a) [10]. Concomitantly, Bry expression in these cells decreases [11] and other transcription factors are activated. One key gene in both mouse embryo and mESCs is mesoderm posterior 1 (Mesp1) that has been correlated with definite cardiac commitment by activating the cardiogenic transcriptional network in a context-dependent manner (reviewed in [12, 13]). The conjunction of knowledge acquired from studying embryonic development and ESCs system led to the optimization of chemically defined cocktails that efficiently drive ESCs differentiation in the absence of serum (reviewed in [1]). Different studies have demonstrated that a tight balance between canonical Wnt and members of the transforming growth factor-β (TGF-β) superfamily, including Nodal/Activin and BMP signaling pathways, regulates the specification of the anterior and posterior regions of PS in mouse [14, 15] and human ESCs [16]. In fact, the combination of Activin A and BMP4 has been shown to direct mESCs into a mesodermal fate [17] whereas inhibition of the Nodal/Activin pathway drives human ESCs (hESCs) towards a neuroectoderm path [18]. Balanced levels of Nodal and BMPs determine mesoderm patterning: increased levels of Activin A favor FLK1+PDGFRα+ cardiogenic progenitors while high doses of BMP4 promote the FLK1+PDGFRα− hematopoietic reservoir [19]. Importantly, activation of Notch pathway in differentiating mESCs has been shown to block the emergence of FLK1+ mesodermal progenitors [20].


Building and repairing the heart: what can we learn from embryonic development?

Freire AG, Resende TP, Pinto-do-Ó P - Biomed Res Int (2014)

Signaling events in murine heart development and cardiac ESC differentiation. In both systems, mesodermal induction from the epiblast is regulated by Wnt/β-catenin, Nodal/Activin, and BMP signaling pathways and correlates with Brachyury upregulation. Further commitment of mesodermal progenitors to cardiac mesoderm and consequent first heart field (FHF) formation require the inhibition of Wnt signaling and expression of BMPs. Similarly, in ESCs system, Notch pathway inhibits Wnt/β-catenin signaling and activates BMP to specify cardiac fates. Wnt/β-catenin signaling is then activated to allow proliferation and maintenance of the SHF, both in embryo and ESCs. Further differentiation from the cardiac crescent stage to the following morphogenic phases of embryonic heart development and, in parallel, the expression of cardiomyocyte differentiation genes in ESCs require inhibition of Wnt/β-catenin. In the embryo and ESCs, this is achieved by Notch and noncanonical Wnt signaling, which inhibit the effect of Wnt/β-catenin and instruct progenitor cells within the SHF to leave the proliferative state and start differentiating. ⊣ represents inhibitory effect; ⤾ represents maintenance of a proliferative state.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4016833&req=5

fig1: Signaling events in murine heart development and cardiac ESC differentiation. In both systems, mesodermal induction from the epiblast is regulated by Wnt/β-catenin, Nodal/Activin, and BMP signaling pathways and correlates with Brachyury upregulation. Further commitment of mesodermal progenitors to cardiac mesoderm and consequent first heart field (FHF) formation require the inhibition of Wnt signaling and expression of BMPs. Similarly, in ESCs system, Notch pathway inhibits Wnt/β-catenin signaling and activates BMP to specify cardiac fates. Wnt/β-catenin signaling is then activated to allow proliferation and maintenance of the SHF, both in embryo and ESCs. Further differentiation from the cardiac crescent stage to the following morphogenic phases of embryonic heart development and, in parallel, the expression of cardiomyocyte differentiation genes in ESCs require inhibition of Wnt/β-catenin. In the embryo and ESCs, this is achieved by Notch and noncanonical Wnt signaling, which inhibit the effect of Wnt/β-catenin and instruct progenitor cells within the SHF to leave the proliferative state and start differentiating. ⊣ represents inhibitory effect; ⤾ represents maintenance of a proliferative state.
Mentions: In embryo development, gastrulation is a key event through which the three germ layers (endoderm, mesoderm, and ectoderm) are formed. Cellular fates are specified during gastrulation by both time of recruitment to the primitive streak (PS) and perceived morphogenetic information [4, 5]. Mesodermal induction is regulated by the interaction of distinct signaling pathways including bone morphogenetic proteins (BMPs), Nodal/Activin, and Wnt (reviewed in [6]). Mesodermal cells ingressing through the PS express the T-box transcription factor brachyury (Bry, also T), a direct target of the Wnt pathway [7]. β-catenin, a central player in Wnt signaling, has been shown to be essential for mesoderm formation since in β-catenin deficient mice no mesodermal or head structures are formed and Bry is not expressed [8]. These early embryonic events are also observed in ESCs, in which mesodermal commitment is defined by the upregulation of the Bry gene within 48 hours after the onset of differentiation (Figure 1) [9]. Mesoderm is then patterned and specified to originate distinct mesodermal subsets, characterized by differential expression of fetal liver kinase-1 (Flk1, also Vegfr2) and platelet-derived growth factor receptor-alpha (Pdgfra, also CD140a) [10]. Concomitantly, Bry expression in these cells decreases [11] and other transcription factors are activated. One key gene in both mouse embryo and mESCs is mesoderm posterior 1 (Mesp1) that has been correlated with definite cardiac commitment by activating the cardiogenic transcriptional network in a context-dependent manner (reviewed in [12, 13]). The conjunction of knowledge acquired from studying embryonic development and ESCs system led to the optimization of chemically defined cocktails that efficiently drive ESCs differentiation in the absence of serum (reviewed in [1]). Different studies have demonstrated that a tight balance between canonical Wnt and members of the transforming growth factor-β (TGF-β) superfamily, including Nodal/Activin and BMP signaling pathways, regulates the specification of the anterior and posterior regions of PS in mouse [14, 15] and human ESCs [16]. In fact, the combination of Activin A and BMP4 has been shown to direct mESCs into a mesodermal fate [17] whereas inhibition of the Nodal/Activin pathway drives human ESCs (hESCs) towards a neuroectoderm path [18]. Balanced levels of Nodal and BMPs determine mesoderm patterning: increased levels of Activin A favor FLK1+PDGFRα+ cardiogenic progenitors while high doses of BMP4 promote the FLK1+PDGFRα− hematopoietic reservoir [19]. Importantly, activation of Notch pathway in differentiating mESCs has been shown to block the emergence of FLK1+ mesodermal progenitors [20].

Bottom Line: Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease.Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration.The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.

View Article: PubMed Central - PubMed

Affiliation: Instituto de Engenharia Biomédica (INEB), Universidade do Porto, Rua do Campo Alegre 823, 4150-180 Porto, Portugal ; Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, NY 10029, USA ; Faculdade de Engenharia da Universidade do Porto (FEUP), Rua Dr. Roberto Frias, s/n, 4200-465 Porto, Portugal.

ABSTRACT
Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs) in vitro model system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.

Show MeSH
Related in: MedlinePlus