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Reprogramming for cardiac regeneration.

Raynaud CM, Ahmad FS, Allouba M, Abou-Saleh H, Lui KO, Yacoub M - Glob Cardiol Sci Pract (2014)

Bottom Line: Treatment of cardiovascular diseases remains challenging considering the limited regeneration capacity of the heart muscle.Developments of reprogramming strategies to create in vitro and in vivo cardiomyocytes have been the focus point of a considerable amount of research in the past decades.The choice of cells to employ, the state-of-the-art methods for different reprogramming strategies, and their promises and future challenges before clinical entry, are all discussed here.

View Article: PubMed Central - PubMed

Affiliation: Qatar Cardiovascular Research Center, Qatar Foundation-Education City, Doha, Qatar.

ABSTRACT
Treatment of cardiovascular diseases remains challenging considering the limited regeneration capacity of the heart muscle. Developments of reprogramming strategies to create in vitro and in vivo cardiomyocytes have been the focus point of a considerable amount of research in the past decades. The choice of cells to employ, the state-of-the-art methods for different reprogramming strategies, and their promises and future challenges before clinical entry, are all discussed here.

No MeSH data available.


Related in: MedlinePlus

Lesson from embryology and factors involved in hPSC cardiac differentiation. (A) During mouse embryonic development at E5.5 gastrulation occurs by the formation of the primitive streak. An epithelial to mesenchymal transition (EMT) of anterior primitive ectoderm allows cells to move laterally between primitive ectoderm and visceral endoderm. At E6.5 cells located proximally to the primitive ectoderm go on to form the extraembryonic mesoderm. Cells adjacent to this zone form heart, blood and mesoderm derivatives. The most distal portion of the primitive streak gives rise to endoderm cells. At E7.0 the lateral plate mesoderm is formed which delaminates to form two layers. Cardiac mesoderm goes on to form the first heart field (FHF) laterally and more ventrally the second heart field (SHF) is formed both by coordinated expression of Dkk1, MESP1, Nodal and WNT signaling. Other cardiogenic signals, such as BMP and FGF, activate cardiac-specific transcription factors such as Nkx2.5, GATA4, HAND2, which coordinate to move both heart fields to the midline. Whereby at E7.5, the FHF progenitors form the heart tube which later contributes to the left ventricle. SHF progenitors join with the CMs of the FHF which leads to the rightward looping of the cardiac tube which eventually progresses towards formation of cardiac chambers. (B) Schematic representation of a family of factors reported to trigger progression from pluripotent state to CM (adapted from Ref.24).
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fig3: Lesson from embryology and factors involved in hPSC cardiac differentiation. (A) During mouse embryonic development at E5.5 gastrulation occurs by the formation of the primitive streak. An epithelial to mesenchymal transition (EMT) of anterior primitive ectoderm allows cells to move laterally between primitive ectoderm and visceral endoderm. At E6.5 cells located proximally to the primitive ectoderm go on to form the extraembryonic mesoderm. Cells adjacent to this zone form heart, blood and mesoderm derivatives. The most distal portion of the primitive streak gives rise to endoderm cells. At E7.0 the lateral plate mesoderm is formed which delaminates to form two layers. Cardiac mesoderm goes on to form the first heart field (FHF) laterally and more ventrally the second heart field (SHF) is formed both by coordinated expression of Dkk1, MESP1, Nodal and WNT signaling. Other cardiogenic signals, such as BMP and FGF, activate cardiac-specific transcription factors such as Nkx2.5, GATA4, HAND2, which coordinate to move both heart fields to the midline. Whereby at E7.5, the FHF progenitors form the heart tube which later contributes to the left ventricle. SHF progenitors join with the CMs of the FHF which leads to the rightward looping of the cardiac tube which eventually progresses towards formation of cardiac chambers. (B) Schematic representation of a family of factors reported to trigger progression from pluripotent state to CM (adapted from Ref.24).

Mentions: In order to achieve cardiac lineage reprogramming and to derive efficient differentiation protocols, investigators took lessons from developmental biology and the mechanisms of cardiac commitment in early embryos. Gastrulation begins with mesoderm induction through Nodal signaling in the primitive ectoderm. Nodal, a cytokine belonging to the TGF-β superfamily, plays a crucial role in the formation of the primitive streak and germ layers. As gastrulation proceeds, cardiac progenitor cells are among the first cell lineages to be established from mesoderm cells emerging from the primitive streak. These cells express mesoderm gene inducers and transcription factors such as BMP4, Wnt3, Brachyury T, and MESP1.65–67 The latter acts as a key regulator of cardiovascular lineage commitment and drives expression of various transcription factors including NKx2.5, Gata4, Mef2c, and Tbx5 for cardiac differentiation and maturation.68,69 MESP-1 also represses early mesoderm induction through direct inhibition of Wnt and Nodal signaling pathways by DKK1 and CER170,71 (Figure 3A). Accordingly, induction of cardiac differentiation of human PSCs can be initiated by sequential stimulation with specific recombinant growth factors such as basic fibroblast growth factor (bFGF), BMP4, Wnt3, and Activin A, followed by addition of DKK1 or other Wnt inhibitors.72–74 Further cytokines have been reported to increase the differentiation efficiency such as the vascular endothelial growth factor (VEGF),74 Noggin75 (BMP antagonist), and IWR-1/IWP-276 (inhibitors of Wnt) among others. Taken together, these findings have led to the establishment of efficient protocols allowing the production of CMs from PSCs with yields close to 90%.16,25 Nevertheless, much effort is still needed to improve purification and maturation of the derived CMs.77,78


Reprogramming for cardiac regeneration.

Raynaud CM, Ahmad FS, Allouba M, Abou-Saleh H, Lui KO, Yacoub M - Glob Cardiol Sci Pract (2014)

Lesson from embryology and factors involved in hPSC cardiac differentiation. (A) During mouse embryonic development at E5.5 gastrulation occurs by the formation of the primitive streak. An epithelial to mesenchymal transition (EMT) of anterior primitive ectoderm allows cells to move laterally between primitive ectoderm and visceral endoderm. At E6.5 cells located proximally to the primitive ectoderm go on to form the extraembryonic mesoderm. Cells adjacent to this zone form heart, blood and mesoderm derivatives. The most distal portion of the primitive streak gives rise to endoderm cells. At E7.0 the lateral plate mesoderm is formed which delaminates to form two layers. Cardiac mesoderm goes on to form the first heart field (FHF) laterally and more ventrally the second heart field (SHF) is formed both by coordinated expression of Dkk1, MESP1, Nodal and WNT signaling. Other cardiogenic signals, such as BMP and FGF, activate cardiac-specific transcription factors such as Nkx2.5, GATA4, HAND2, which coordinate to move both heart fields to the midline. Whereby at E7.5, the FHF progenitors form the heart tube which later contributes to the left ventricle. SHF progenitors join with the CMs of the FHF which leads to the rightward looping of the cardiac tube which eventually progresses towards formation of cardiac chambers. (B) Schematic representation of a family of factors reported to trigger progression from pluripotent state to CM (adapted from Ref.24).
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4352683&req=5

fig3: Lesson from embryology and factors involved in hPSC cardiac differentiation. (A) During mouse embryonic development at E5.5 gastrulation occurs by the formation of the primitive streak. An epithelial to mesenchymal transition (EMT) of anterior primitive ectoderm allows cells to move laterally between primitive ectoderm and visceral endoderm. At E6.5 cells located proximally to the primitive ectoderm go on to form the extraembryonic mesoderm. Cells adjacent to this zone form heart, blood and mesoderm derivatives. The most distal portion of the primitive streak gives rise to endoderm cells. At E7.0 the lateral plate mesoderm is formed which delaminates to form two layers. Cardiac mesoderm goes on to form the first heart field (FHF) laterally and more ventrally the second heart field (SHF) is formed both by coordinated expression of Dkk1, MESP1, Nodal and WNT signaling. Other cardiogenic signals, such as BMP and FGF, activate cardiac-specific transcription factors such as Nkx2.5, GATA4, HAND2, which coordinate to move both heart fields to the midline. Whereby at E7.5, the FHF progenitors form the heart tube which later contributes to the left ventricle. SHF progenitors join with the CMs of the FHF which leads to the rightward looping of the cardiac tube which eventually progresses towards formation of cardiac chambers. (B) Schematic representation of a family of factors reported to trigger progression from pluripotent state to CM (adapted from Ref.24).
Mentions: In order to achieve cardiac lineage reprogramming and to derive efficient differentiation protocols, investigators took lessons from developmental biology and the mechanisms of cardiac commitment in early embryos. Gastrulation begins with mesoderm induction through Nodal signaling in the primitive ectoderm. Nodal, a cytokine belonging to the TGF-β superfamily, plays a crucial role in the formation of the primitive streak and germ layers. As gastrulation proceeds, cardiac progenitor cells are among the first cell lineages to be established from mesoderm cells emerging from the primitive streak. These cells express mesoderm gene inducers and transcription factors such as BMP4, Wnt3, Brachyury T, and MESP1.65–67 The latter acts as a key regulator of cardiovascular lineage commitment and drives expression of various transcription factors including NKx2.5, Gata4, Mef2c, and Tbx5 for cardiac differentiation and maturation.68,69 MESP-1 also represses early mesoderm induction through direct inhibition of Wnt and Nodal signaling pathways by DKK1 and CER170,71 (Figure 3A). Accordingly, induction of cardiac differentiation of human PSCs can be initiated by sequential stimulation with specific recombinant growth factors such as basic fibroblast growth factor (bFGF), BMP4, Wnt3, and Activin A, followed by addition of DKK1 or other Wnt inhibitors.72–74 Further cytokines have been reported to increase the differentiation efficiency such as the vascular endothelial growth factor (VEGF),74 Noggin75 (BMP antagonist), and IWR-1/IWP-276 (inhibitors of Wnt) among others. Taken together, these findings have led to the establishment of efficient protocols allowing the production of CMs from PSCs with yields close to 90%.16,25 Nevertheless, much effort is still needed to improve purification and maturation of the derived CMs.77,78

Bottom Line: Treatment of cardiovascular diseases remains challenging considering the limited regeneration capacity of the heart muscle.Developments of reprogramming strategies to create in vitro and in vivo cardiomyocytes have been the focus point of a considerable amount of research in the past decades.The choice of cells to employ, the state-of-the-art methods for different reprogramming strategies, and their promises and future challenges before clinical entry, are all discussed here.

View Article: PubMed Central - PubMed

Affiliation: Qatar Cardiovascular Research Center, Qatar Foundation-Education City, Doha, Qatar.

ABSTRACT
Treatment of cardiovascular diseases remains challenging considering the limited regeneration capacity of the heart muscle. Developments of reprogramming strategies to create in vitro and in vivo cardiomyocytes have been the focus point of a considerable amount of research in the past decades. The choice of cells to employ, the state-of-the-art methods for different reprogramming strategies, and their promises and future challenges before clinical entry, are all discussed here.

No MeSH data available.


Related in: MedlinePlus