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Review
. 2019 Feb 27;6(1):12.
doi: 10.3390/jcdd6010012.

Functional Morphology of the Cardiac Jelly in the Tubular Heart of Vertebrate Embryos

Jörg Männer  1 , Talat Mesud Yelbuz  2
Affiliations
Review

Functional Morphology of the Cardiac Jelly in the Tubular Heart of Vertebrate Embryos

Jörg Männer et al. J Cardiovasc Dev Dis. .

Abstract

The early embryonic heart is a multi-layered tube consisting of (1) an outer myocardial tube; (2) an inner endocardial tube; and (3) an extracellular matrix layer interposed between the myocardium and endocardium, called "cardiac jelly" (CJ). During the past decades, research on CJ has mainly focused on its molecular and cellular biological aspects. This review focuses on the morphological and biomechanical aspects of CJ. Special attention is given to (1) the spatial distribution and fiber architecture of CJ; (2) the morphological dynamics of CJ during the cardiac cycle; and (3) the removal/remodeling of CJ during advanced heart looping stages, which leads to the formation of ventricular trabeculations and endocardial cushions. CJ acts as a hydraulic skeleton, displaying striking structural and functional similarities with the mesoglea of jellyfish. CJ not only represents a filler substance, facilitating end-systolic occlusion of the embryonic heart lumen. Its elastic components antagonize the systolic deformations of the heart wall and thereby power the refilling phase of the ventricular tube. Non-uniform spatial distribution of CJ generates non-circular cross sections of the opened endocardial tube (initially elliptic, later deltoid), which seem to be advantageous for valveless pumping. Endocardial cushions/ridges are cellularized remnants of non-removed CJ.

Keywords: ballooning; blood flow; cardiac jelly; embryonic heart tube; extracellular matrix; heart skeleton; hydraulic skeleton; non-circular cross sections; trabeculation; valveless pumping.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
These transverse histological sections of a human embryo with 10 pairs of somites (Carnegie stage 10) show the inner architecture of an S-shaped heart tube as seen in routine histological preparations. The heart was fixed in a systolic state so that its lumen is partially obliterated. (A) Section at the level of the proximal outflow (= OF) of the ventricular tube. (B) Section of at the level of the inflow (= IF) of the ventricular tube. (C) Section at the level of the developing–right and left atrial appendages (= RAA, LAA). Note that the myocardium (= M) and endocardium (= E) are separated by an “empty” space, called the myoendocardial space. Note also: (1) The difference in the thickness of the myoendocardial space between the developing atria and ventricles; and (2) the paired character of the myoendocardial space, which reflects the origin of the heart from bilaterally paired heart fields. The dorsal mesocardium (= DM, and indicated by orange asterisks) and the obliterated endocardial tube can be used as anatomical landmarks for the original midsagittal fusion plane of the left- and right-sided heart fields (marked by the dotted line in section C). Light blue asterisks mark the original ventral midline of the heart tube. Further abbreviations: VB = ventricular bend; Pha = pharynx/foregut.
Figure 2
Figure 2
These schematic drawings illustrate Barry’s geometrical analyses on cross sections of hypothetical heart tubes of a large diameter. (A) In a hypothetical heart tube without CJ, physiological shortening of the contracting myocardium (20%) produces a large change (50%) in the cross sectional area of the lumen (= stroke volume), but does not close the lumen. (B) In a hypothetical heart tube with CJ, physiological shortening of the contracting myocardium will produce a large change (100%) in the stroke volume as well as complete closure of the endocardial lumen, if the thickness of the CJ layer is about 45% of the radius of the diastolic lumen. Note that the spatial distribution of CJ in the hypothetical heart tube does not correspond to the non-uniform distribution of CJ (bilaterally paired character) found in real embryonic heart tubes (see Figure 1A).
Figure 3
Figure 3
This schematic drawing illustrates the establishment of the primary wall architecture and initiation of myocardial contractions in the tubular hearts of higher vertebrate embryos as seen in the chick (based on data from Manasek [37] and Sakai et al. [39]). Developmental stages according to Hamburger and Hamilton [36] are indicated as HH-8, etc. The components of the primary heart wall derive from the pre-cardiac mesoderms. These parts of the lateral plate mesoderm harbor: (1) A coelomic epithelium formed by myocardial progenitors (pre-myocardium); (2) endocardial progenitors (pre-endocardium), which are found in close association with the endoderm; and (3) a gelatinous ECM (pre-cardiac ECM), which connects the pre-myocardium and pre-endocardium with each other, and with the endoderm. Note that the pre-cardiac mesoderms do not possess an anatomically well-demarcated myoendocardial space. The appearance of such a space depends on myocardial differentiation and the formation of endocardium-lined tubes. During myocardial differentiation, the discontinuous basal layer of the pre-myocardium becomes transformed into a continuous cell sheet bordered by a basal lamina. Consequently, the developing myocardium becomes an anatomically well-demarcated two-layered epithelium and the pre-cardiac ECM becomes split into two compartments: (1) An intramyocardial ECM (marked by asterisks) and (2) a cell-free myoendocardial ECM (CJ).
Figure 4
Figure 4
These schematic drawings illustrate three subsequent phases in the development of the wall architecture of the median embryonic heart tube of higher vertebrates. Note that, for reasons of simplification, this scheme neglects some developmental changes in the size and 3D-configuration of the heart (e.g., elongation of outflow, complex ventricular looping). (A) Primary wall architecture (red = primary myocardium; light blue = CJ; yellow = primary endocardium). Local variations in the thickness of the CJ layer facilitate the distinction of the two main building units: (1) A sac-shaped venous chamber, which has only a thin CJ layer and represents the primary atrium; and (2) a tube-shaped arterial conduit, which has a thick CJ layer and represents the primary ventricular tube. The presence of a thick CJ layer facilitates complete end-systolic occlusion of the endocardial lumen of all portions of the primary ventricular tube. The paired pattern of CJ accumulation reflects the origin of the ventricular tube from bilaterally paired heart fields. (B) The initial phase of the ventricular tube remodeling is characterized by remodeling of the endocardial tube and CJ along the convexity of the ventricular bend. Endocardial sprouts/protrusions invade the CJ and grow toward the primary myocardium. Consequently, CJ disappears along the convexity of the ventricular bend. (C) The advanced phase of the ventricular tube remodeling is characterized mainly by remodeling of the myocardium along the convexity of the ventricular bend and by remodeling of the CJ in the ventricular inflow (atrio-ventricular canal) and outflow portions. Endocardial protrusions invade the myocardial wall, which starts centrifugal growth (ballooning and trabeculation). The CJ in the atrio-ventricular canal (AVC) and outflow does not disappear, but becomes remodeled into endocardial cushions/ridges due to the invasion of endocardium-derived mesenchymal cells. Abbreviations: eLV = embryonic left ventricle; eRV = embryonic right ventricle; LAA = anlage of left atrial appendage; RAA = anlage of right atrial appendage.
Figure 5
Figure 5
These schematic drawings illustrate the region-specific remodeling of the primary ventricular tube of higher vertebrate embryos as seen in the chick (based on data from Manasek [56] and Icardo and Fernandez-Terán [57]). (A) Remodeling along the outer curvature of the ventricular bend. CJ disappears due to the outgrowth of multiple endocardial pouches from the endocardial tube (initial phase of remodeling). When the endocardial pouches reach the basal layer of the myocardium, they start an invasion of the myocardial wall. Now, remodeling is no longer confined to the endocardium and CJ, but, additionally, changes the wall architecture of the myocardial tube. The initially smooth inner myocardial wall becomes transformed into a trabeculated myocardial wall (advanced phase of remodeling). (B) Remodeling in the inflow and outflow portions of the ventricular tube. CJ does not disappear, but loses its cell-free phenotype due to the invasion of endocardium-derived mesenchymal cells. Cellularized CJ is named endocardial cushions (in the inflow portion) or endocardial ridges (in the outflow portion).
Figure 6
Figure 6
These 3D-images, acquired in vivo by 4D optical coherence tomography (OCT) [73], show various aspects of the wall architecture of the primary ventricular tube of a HH-stage 12/13 chick embryo heart as seen in right lateral views. Pictures show the ventricular bend and outflow in a fully contracted (end-systolic) state. (A) Outer shape of the myocardial tube. (B) 3-D shape of the occluded endocardial tube as shown by virtual removal of parts of the myocardial wall. Note that the collapsed endocardial tube has the shape of a flat band, whose edges are fixed to the original ventral and dorsal midlines of the heart tube (marked by blue and orange asterisks, respectively). (C) Cross-sections of the ventricular tube at the level of the ventricular bend and outflow as depicted by virtual dissection of OCT datasets. Note that the flattened endocardial tube is flanked by paired accumulations of CJ, which have half-moon shaped cross-sections. The paired character of the CJ-layer reflects the origin of the ventricular tube from the bilaterally paired heart fields.
Figure 7
Figure 7
Cardiac cycle-related changes in the cross-sectional shape of the primary ventricular tube as visualized (A) by in vivo 4D OCT imaging of a HH-stage 12/13 chick embryo heart (see Figure 6C); and shown (B) by schematic drawings (same color code as used in Figure 2). Note that, due to the non-uniform spatial distribution of the CJ, the endocardial tube does not show concentric widening and narrowing during the cardiac cycle. The opened endocardial tube has an elliptic cross section, while the collapsed endocardial tube has a slit-shaped cross section. Note also the cyclic changes in the thickness of the CJ layer. The CJ undergoes thinning during relaxation of the surrounding myocardial wall (diastole) and thickening during contraction of the myocardial wall (systole).
Figure 8
Figure 8
These images depict the architecture of the fibrillar components of the CJ as seen on cross-sections of the ventricular tube of embryonic chick hearts (HH-stage 16). (A) Routine histological section (HE staining) at the level of the ventricular bend; and (B,C) scanning electron microscopic pictures of cross-sections at the level of the ventricular bend (B) and ventricular inflow (C). Hearts were fixed at end-systole when the CJ has the greatest thickness during the cardiac cycle. Broken lines mark the closing planes of the collapsed endocardial tubes. Asterisks mark the original ventral midline of the ventricular tube. The CJ fibrils form a delicate network that is anchored to the basal laminae of the primary endocardium and myocardium. Within this network of interconnected fibrils, the principal fiber orientation is perpendicular to the basal surfaces of the endocardial and myocardial tubes. During reopening of the endocardial tube (diastole), the endocardial surfaces curve and the CJ fibrils acquire a principally radial orientation around the center axis of the ventricular tube (not shown).
Figure 9
Figure 9
These pictures show the outer shape of an occluded endocardial tube of an embryonic chick heart during the initial phase of ventricular tube remodeling (HH-stage 14). Images were generated by virtual 3-D reconstructions of OCT data sets from a heart that has been fixed in an artificially induced general contraction. (A) Frontal view. (B) Dorsal view. (C) Cranial view. (D) Caudal view. The outer curvature of the ventricular bend has a folded surface, which is characterized by three folds: (1) A midline fold that corresponds to the original ventral edge of the occluded endocardial tube (marked by lines of blue dots). This fold subdivides the trabecular shields into two halves. (2, 3) A pair of lateral folds that form the lateral borders of the trabecular shields (marked by dotted lines in magenta and green). Abbreviations: eLV = embryonic left ventricle; eRV = embryonic right ventricle; IF = inflow portion of ventricular tube; RAA = anlage of right atrial appendage; RS = right horn of sinus venosus; LS = left horn of sinus venosus; OF = outflow portion of ventricular tube.
Figure 10
Figure 10
These drawings depict the changes in the outer shape of the occluded (systolic) endocardial tube of human embryonic heart tubes during the initial phase of ventricular tube remodeling. Hearts are shown in frontal views within the opened pericardial cavities. The ventral myocardial walls have been removed to facilitate views on the endocardial tubes. (A) The occluded endocardial tube of the primary ventricular tube has the shape of a flat band. Its ventral (blue line) and dorsal (orange line) edges correspond to the original ventral and dorsal midlines of the heart. (B) Due to the formation of trabecular shields, the occluded endocardial tube has a folded surface along its outer curvature. Corresponding to the situation in chick embryonic hearts (Figure 9), the picture is dominated by the presence of three folds: (1) A midline fold that corresponds to the original ventral edge of the occluded endocardial tube (blue line). This fold subdivides the trabecular shields into two halves. (2 + 3) A pair of lateral folds that form the lateral borders of the trabecular shields (magenta and green lines). Drawings are based on Figures 22 and 26 from Davis [4]. Same abbreviations as used in Figure 9.
Figure 11
Figure 11
Initial phase of ventricular tube remodeling. Cardiac cycle-related changes in the cross-sectional shape of the ventricular bend as illustrated (A) by histological sections of HH-stage 16 chick embryonic hearts, which have been fixed in emptied (A1,A3) and filled (A2) states; and shown (B) by schematic drawings (same color code as used in Figure 2). Asterisks mark the original ventral (light blue) and dorsal (orange) midlines of the heart as well as the lateral borders of the trabecular shields (magenta and green). Note that, due to the formation of the trabecular shield, the opened endocardial tube has a bell-shaped or deltoid cross section, while the cross section of the collapsed endocardial tube has the shape of a Latin cross. Note also the cyclic changes in the thickness of the CJ layer.
Figure 12
Figure 12
These images obtained by 4-dimensional in vivo OCT imaging of a HH-stage 15 embryonic chick heart depict the peculiar phenomenon of end-systolic stretching of the cross section of the ventricular bend along the original dorso-ventral axis. Asterisks mark the original ventral (light blue) and dorsal (orange) midlines, which are found along the outer and inner curvatures of the ventricular bend, respectively. Note the striking increase in the thickness of the CJ layer between diastole and early end-systole (indicated by white and blue arrows). Late end-systolic stretching of the cross section of the ventricular bend leads to a slight decrease in the CJ thickness (compare blue and magenta arrows). White lines mark the diastolic length of the original dorso-ventral axis.
Figure 13
Figure 13
These schematic drawings illustrate the centrifugal growth concept of ventricular trabeculation. (A) Initial step of trabeculation. (B) Advanced step of trabeculation. According to this concept, myocardial trabeculae are formed mainly from cardiomyocytes of the middle (reticular) layer of the ventricular myocardium (marked by light red color). The endocardium-lined intertrabecular spaces (it) arise from the sprout-like endocardial protrusions of the trabecular shields. These sprouts penetrate the inner (basal) layer of the ventricular myocardium and start an invasion of the intramyocardial ECM of the reticular layer myocardium (A). Signals from the endocardium of the intertrabecular spaces stimulate growth of the reticular/trabecular myocardium, which leads to expansion (ballooning) of the embryonic ventricles (B). Note that the free edges of the myocardial trabeculae are remnants of the original inner (basal) layer of the primary myocardial tube. Color code: orange asterisks mark the inner curvature of the ventricular bend; dark red = remnants of the inner (basal) layer of primary myocardium; red = derivatives of the outer (apical) layer of the primary myocardium; light red = reticular layer of primary myocardium; light blue = CJ and intramyocardial ECM; yellow = endocardium. Abbreviations: AVC = atrio-ventricular canal; it = intertrabecular spaces; OFT = outflow tract.
Figure 14
Figure 14
These histological sections from embryonic chick hearts depict the changes in the ventricular wall architecture during the advanced phase of ventricular tube remodeling. (A) At the time point of the transition from the initial to the advanced phase of ventricular tube remodeling (HH-stage 16/17), the outer curvature of the ventricular bend lacks a CJ layer and the tips of the endocardial projections of the trabecular shields are in direct contact to the basal layer of the ventricular myocardium (blue asterisks mark the proximal and distal borders of the trabecular shields; orange asterisk marks the inner curvature of the ventricular bend). In the AVC, endocardium-derived mesenchyme has started an invasion of the CJ. Note that the myocardial walls of all portions of the primary ventricular tube have a tubular shape. (B1,B2) HH-stage 21. Due to the formation of trabeculated embryonic ventricles, the outer contour of the ventricular bend has lost its original tubular shape. The AVC and OFT have preserved their original tubular shapes. When looking on the inner structure of the embryonic ventricles, however, it becomes apparent that the original tubular shape of the ventricular bend is still visible if one follows an imaginary line that connects the free edges of the myocardial trabeculae (highlighted by the dark red color in (B2). Note that the free lumen of the embryonic ventricles does not change significantly between HH-stages 17 and 21. Note also the structural similarity between the non-trabeculated, three-layered myocardium of the AVC (inner compact layer, reticular layer, outer compact layer) and the trabeculated myocardium of the embryonic ventricles. Color code used in (B2): dark red = remnants of the inner layer of the primary ventricular myocardium; red = reticular and outer compact myocardium of the AVC; light red = trabeculated and outer compact myocardium of embryonic ventricles, and atrial myocardium; light blue = CJ and intramyocardial ECM; yellow = endocardium. Abbreviations: A = primary atrium; AVC = atrio-ventricular canal; OFT = outflow tract; Tr = trabecular layer of ventricular myocardium; V = free lumen of the primary ventricular tube.
Figure 15
Figure 15
These schematic drawings illustrate the centripetal growth concept of ventricular trabeculation. (A) Initial step of trabeculation. (B) Advanced step of trabeculation. According to this concept, myocardial trabeculae are formed mainly from cardiomyocytes of the inner (basal) layer of the ventricular myocardium (marked by dark red color). Recent data suggest that non-removed remnants of CJ along the outer curvature of the ventricular bend serve as pathways for inward growth of the trabeculae toward the center of the embryonic ventricle. Inward growth of myocardial trabeculae separates endocardium-lined intertrabecular spaces (it) from the free ventricular lumen. Outward growth of endocardial sprouting into the myocardial wall does not significantly contribute to the formation of intertrabecular spaces. Note that inward growth of trabeculae is expected to narrow the free lumen of the embryonic ventricles during the initial step of trabeculation. Note also that the embryonic ventricles expand (ballooning) concomitant with the growth of the trabeculae. Same color code and abbreviations as used in Figure 13.
Figure 16
Figure 16
The modified model of cardiac chamber ballooning as depicted by changes in the outer shape of early embryonic hearts. (A–C) Scanning electron micrographs of embryonic mouse hearts on ED 8.5 (A), ED 9.0 (B), and ED 9.75 (C). Hearts are shown in fronto-caudal views. This facilitates direct imaging of the surface of the outer curvature of the ventricular bend. The black dotted lines mark the original ventral midline of the heart. Note that the inner curvature is not visible. (A1–C1) Schematic illustrations of the situations shown in Figures A–C. (A,A1) The initial steps of externally visible chamber ballooning are characterized by the emergence of bilaterally paired ballooning centers at three levels: (1) The embryonic atrium, (2) the prospective left ventricle, and (3) the prospective right ventricle. The white dotted lines in Figure A mark the ventral borders between the remnant of the primary ventricular tube and the paired ballooning centers of the prospective left ventricle. (B,B1) Due to expansion of the paired ballooning centers of the prospective ventricles, their ventral borders shift toward the original ventral midline of the ventricular bend. (C,C1) The originally paired ballooning centers of the prospective ventricles unite to form single units (embryonic left and right ventricle) that give rise to the apical trabeculated regions of the prospective ventricles. The paired ballooning centers of the embryonic atrium remain separated and give rise to the atrial appendages of the mature heart. Same abbreviations as used in Figure 9.
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