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First published online December 21, 2007
doi: 10.1242/10.1242/dev.001883

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Islet1 cardiovascular progenitors: a single source for heart lineages?

¹ Massachusetts General Hospital - Cardiovascular Research Center, Charles River Plaza/CPZN 3208, 185 Cambridge Street, Boston, MA 02114, USA.
² Klinikum rechts der Isar und Deutsches Herzzentrum - Technische Universität München, I. Medizinische Klinik - Molekulare Kardiologie, Ismaninger Strasse 22, 81675 München, Germany.
³ Department of Stem Cell and Regenerative Biology, Harvard University and the Harvard Stem Cell Institute, Cambridge, MA 02138, USA.

View larger version (81K): [in this window] [in a new window]   Fig. 1. Origin and lineage relationship of cardiac cell types. (A) Contribution of the three populations of embryonic heart progenitors, cardiogenic mesoderm (red), cardiac neural crest (purple) and proepicardial organ (yellow) to different heart compartments during cardiac morphogenesis in the mouse. Progenitors of the cardiogenic mesoderm are first recognizable under the head folds (HFs) of the embryo at E7.5, then move ventrally to the midline (ML) and form initially the linear heart tube and ultimately the four chambers of the heart. After the looping of the heart tube (E8.5), cardiac neural crest progenitors migrate from the dorsal neural tube to engulf the aortic arch arteries and contribute to vascular smooth muscle cells of the outflow tract (OFT) around E10.5. At the same time in mouse development, the proepicardial organ precursors contact the surface of the developing heart, give rise to the epicardial mantle (yellow) and contribute later to the coronary vasculature. In the fetal heart (E14), the chambers separate due to septation and are connected to the pulmonary trunk (PT) and aorta (Ao). Cranial (Cr)-caudal (Ca), right (R)-left (L), and dorsal (D)-ventral (V) axes are indicated. (B) Cardiac cell types that arise through the lineage diversification of the three embryonic precursor pools in the mouse heart. Whereas the contribution of the proepicardium to the smooth muscle cells of the coronary system and to the mesenchymal cells of the heart is well accepted, the origin of the endothelial lineage in the coronary vasculature is still controversial. AA, aortic arch; IVS, interventricular septum; LA, left atrium; LV, left ventricle; PhA, pharyngeal arches; PLA, primitive left atrium; PRA, primitive right atrium; RA, right atrium; RV, right ventricle.

View larger version (70K): [in this window] [in a new window]   Fig. 2. First and second heart fields and their contributions to the developing heart. (A) The upper drawings show the relative position, movement and contribution of the second heart field progenitors (green) relative to the first heart field cells (red) from the cardiac-crescent through to the looping stages of mouse heart development. The dashed lines indicate the position of the corresponding sections shown in the lower panels. (B) Location (upper) and contribution (beneath) of the second heart field progenitors (blue) to the outflow tract in the chick embryo. Cranial (Cr)-caudal (Ca), right (R)-left (L), and dorsal (D)-ventral (V) axes are indicated. DOFT, distal outflow tract; HFs, head folds; LA, left atrium; LV, left ventricle; ML, midline; PhA, pharyngeal arches; OFT, outflow tract; POFT, proximal outflow tract; RA, right atrium; RV, right ventricle.

View larger version (5K): [in this window] [in a new window]   Fig. 3. Regulatory networks within the second heart field lineage. The model presents an Isl1-dependent transcriptional network for the development of the second heart field lineage. The LIM-homeodomain transcription factor Isl1 (blue) functions as an early regulator of a core network that determines right ventricle and outflow tract development. The solid lines indicate that direct in vivo activation of regulatory sequences has been demonstrated. Dotted lines indicate genetic data or in vitro activation. Fgf8/10, fibroblast growth factor 8 and 10; Foxa2, forkhead box a2; Foxc1/2, forkhead box c1/2; Foxh1, forkhead box h1; Gata, GATA-binding proteins; Hand2, heart and neural crest derivatives expressed transcript 2; Isl1, insulin gene enhancer protein; Mef2c, myocyte enhancer factor 2C; Nkx2-5, NK2 transcription factor related, locus 5; Smyd1, SET and MYND domain containing 1; Tbx1/20, T-box 1 and 20.

View larger version (102K): [in this window] [in a new window]   Fig. 4. Isl1+ progenitor cells during cardiovascular development. β-gal expression was analyzed in Isl1-nlacZ knock-in mouse embryos at the indicated days of development and in the postnatal heart at day 3 (PN 3d) by X-Gal staining. Representative sections at each developmental stage from E8.5-14.5 are shown (left), as are the corresponding heart structures that express Isl1 (middle) and the lineage markers used to identify the different cell types (right). Cranial (Cr)-caudal (Ca), right (R)-left (L), and dorsal (D)-ventral (V) axes are indicated. A, atrial cavity; Ao, aorta; AS, atrial septum; AVN, atrioventricular node; CG, cardiac ganglia; Hcn4, hyperpolarization-activated cyclic nucleotide-gated K+ 4; LA, left atrium; LV, left ventricle; MF20, antibody recognizing sarcomeric myosin; OFT, outflow tract; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SAN, sinoatrial node; SM, smooth muscle; sm-actin, smooth muscle actin; V, ventricle cavity. Parts of the figure are reproduced with permission (Sun et al., 2007).

View larger version (50K): [in this window] [in a new window]   Fig. 5. Cell lineage tracing of Isl1+ cardiac progenitors and lineage contribution to the adult heart. Lineage tracing utilizing the Isl1-IRES-Cre mouse crossed with the indicator R26R line to mark all cells that once expressed Isl1 during development. The boxes represent magnifications of different regions of the coronary tree (black boxes) and of the aorta/pulmonary artery (red boxes), where β-gal-positive cells have been detected. (A) Contribution of Isl1+ progenitors (blue) to the coronary vasculature, the valves and the pulmonary artery/aorta. The contribution of Isl1+ cells to the endothelial (purple) and smooth muscle (yellow) cell layers is limited to the proximal area of the great vessels and progressively declines from the proximal to the distal parts of the coronary tree. β-gal+ cells were also detected in connective tissue structures of the aortic and pulmonary leaflets, indicating that components of the conotruncal cushions, which have an endocardial origin, are derived from Isl1+ progenitors. (B) Contribution of Isl1+ progenitors (blue) to the atrial/ventricular myocardium (red), the conduction system (white) and cardiac ganglia (green). In the conduction system, most genetically marked cells were detected in the sino-atrial nodal (SAN) region. AS, atrial septum; AVN, atrioventricular node; CAs, coronary arteries; LA, left atrium; LCA, left coronary artery; LV, left ventricle; RA, right atrium; RCA, right coronary artery; RV, right ventricle; VS, ventricular septum.

View larger version (38K): [in this window] [in a new window]   Fig. 6. Cellular hierarchy of cardiac progenitors and their lineage specification. The expression of the lineage markers shown is based on previous studies (Kattman et al., 2006; Moretti et al., 2006; Wu et al., 2006). The divergence of endothelial and haematopoietic lineages from the myocardial lineage precedes the expression of Nkx2-5 in the precardiac mesoderm (tissue-specific markers are shown in blue). Bry, brachyury (T); MLC2a, atrial myosin light chain 2 (also known as Myl7); MLC2v, ventricular myosin light chain 2 (Myl2); cTnT, cardiac troponin T (Tnnt2); Hcn4, hyperpolarization-activated cyclic nucleotide-gated K+ 4; sm-actin, smooth muscle actin; SM-MHC, smooth muscle myosin heavy chain; VE-Cadh, VE-cadherin.

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