Desmosomes in Cell Fate Determination: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Hoda Moazzen.

Desmosomes play a vital role in providing structural integrity to tissues that experience significant mechanical tension, including the heart. Deficiencies in desmosomal proteins lead to the development of arrhythmogenic cardiomyopathy (AC). The limited availability of preventative measures in clinical settings underscores the pressing need to gain a comprehensive understanding of desmosomal proteins not only in cardiomyocytes but also in non-myocyte residents of the heart, as they actively contribute to the progression of cardiomyopathy.

  • desmosome
  • cardiogenesis
  • cell fate determination

1. Cardiogenesis and Mechanical Cues

Cardiogenesis is the orchestrated act of cell proliferation, differentiation, and migration that results in the formation of a resilient and durable contractile organ. The uninterrupted rhythmic contractions and the specific arrangement of cardiomyocytes and non-cardiomyocytes are the essential pillars of cardiac function. Deviation from cardiac cell identity and the canonical cell arrangement therefore not only alters cardiac morphogenesis but also impairs heart function. OurThe knowledge about the key genes that drive cardiogenesis comes from decades of animal studies [1]. It is increasingly recognized that the genetic profile and signaling molecules are not the only regulators of cardiac cell biology, but that mechanical cues also play a definitive role [2]. For example, the stiffness of the extracellular matrix modulates signaling in cardiomyocytes during development and disease [3][4]. Such multifactorial pathogenesis has been discussed in various cardiomyopathies including the still poorly understood genetic heart disease arrhythmogenic cardiomyopathy (AC).
Fifty percent of AC cases have been linked to mutations in genes that contribute to the formation of desmosomes, which are prominent cell–cell adhesion sites between cardiomyocytes [5][6]. Disease hallmarks are arrhythmia, loss of cardiomyocytes, and progressive formation of fibro–fatty structures, which lead to impairment of heart function and ultimately to heart failure [7]. Several transgenic animal models have been created to study AC pathogenesis [6]. The emerging insights categorize AC as a multifaceted disease involving disruption of mechanical and signaling pathways and a surge of immune responses [8]. This preseaperrch does not intend to provide a comprehensive review of AC pathogenesis and its clinical outcomes. Readers are referred to recent excellent reviews [9][10][11][12]. Instead, wresearchers will focus on the much less investigated and poorly understood functions of desmosomes in embryogenesis.
Desmosomal proteins are indispensable for early embryogenesis [13][14][15] and cardiogenesis [16][17]. Desmosomal proteins are enriched in intercalated discs of cardiomyocytes, but have been detected at low levels also in non-cardiomyocytes such as epicardial cells [18][19][20] and cardiac mesenchymal cells [21][22][23]. Importantly, cardiac mesenchymal cells also express desmosomal proteins [24] and desmosomal protein deficiency can enhance differentiation of these cells into fibrous or adipose tissue. In a recent study, a role of desmosomes has been suggested in regulation of cardiac mesenchymal cell fate by direct modulation of Ca2+ signaling at the level of gene expression [25].
During the last decades, research in the AC field was dominated by investigating the role of desmosomal proteins in adult cardiomyocytes [8][26]. It, however, remains to be explored whether desmosomal deficiency triggers “primary events” for the renewal or differentiation of cardiac progenitors both in the developing and mature heart. Of note, molecular pathways that are activated during embryonic development can be reactivated in pathological conditions [27].

2. Molecular Structure of Desmosomes

Desmosomes are specialized structures, which support the physical stability and integrity of epithelial and heart tissue. Cardiac desmosomes are formed by clustering of the Ca2+-dependent adhesion molecules (cadherins) desmoglein 2 (Dsg2) and desmocollin 2 (Dsc2) in the plasma membrane. They interact with each other via their extracellular domains to link neighboring cells. Intracellularly, the clustered desmosomal cadherins are connected to plakophilin 2 (Pkp2) and plakoglobin (PG), both of which contain multiple copies of the 42 amino acid-long armadillo repeat. They serve not only as structural linkers in desmosomes but fulfill additional cellular functions impacting adherens junctions, cytoskeletal organization, and gene transcription. The functions of the large cytolinker desmoplakin (Dsp), on the other hand, are much more restricted to desmosomes. Dsp is essential for the linkage between the clustered desmosomal cadherins with their associated armadillo-repeat proteins and the intermediate filament cytoskeleton, which consists of desmin polypeptides in cardiomyocytes (Figure 1A) [28][29]. Although the molecular composition of desmosomes is the same in the embryonic and adult heart, the arrangement of desmosomes differs. A distinctive characteristic of mammalian adult cardiomyocytes is their maturation process, which is initiated postnatally. Round-shaped embryonic cardiomyocytes initially form independent adherens junctions and desmosomes with neighboring cells throughout their entire borders. Concurrent with myofibril elongation and organization, desmosomes and adherens junctions concentrate at the apical surfaces of cardiomyocytes where they serve important mechanical functions [30]. Postnatally, the junctions amalgamate forming hybrid junctions that are composed of tightly integrated desmosomes and adherens junctions, which are in close apposition to gap junctions and membrane channels. This supercomplex has been referred to as area composita and connexome [31][32]. It was suggested that the maturation phase is essential to ensure life-long contraction of cardiomyocytes [31][33].
Figure 1. Desmosomes in the heart. (A) Scheme of the molecular desmosome structure. PM: plasma membrane. (B) Fluorescence microscopy detecting desmoplakin (Dsp; red) and nuclei (blue) in embryonic (left) and adult murine heart (right). CM: compact myocardium, Epi: Epicardium. Scale bars: 20 μm. (C) Electron micrographs of cardiomyocytes in embryonic (left) and adult murine hearts (right). Asterisks point to sarcomeres, arrows to actin-anchoring adherens junctions, and arrowheads to desmin-anchoring desmosomes. TM: trabecular myocardium; CM: compact myocardium; m, mitochondrion. Scale bar: 1 μm.

3. Cardiogenesis

3.1. Contribution of Different Heart Fields

Lineage tracing and anatomical studies revealed that Mesp1+ cardiac progenitors appear in the anterior splanchnic mesoderm layer at the lateral sides of the primitive streak [34]. The cardiac progenitor cells are arranged in two different heart fields, i.e., the first heart field (FHF) and the second heart field (SHF). They develop in a temporally and spatially distinct manner and participate in the formation of discrete parts of the heart [35], each with a unique gene profile [36][37]. The FHF comprises cardiac progenitors, which appear first and differentiate rapidly. These fast-differentiating cells express the transcription factors NKX2-5, Tbx5, Hand1, and GATA4 as well as the chromatin regulatory factor BAF60c. Together, these factors drive the expression of sarcomeric proteins [38]. Morphologically, the cells in the lateral regions of the FHF migrate toward the midline and form a tubular heart at embryonic day (E) 8 in mice and during the third week of gestation in humans. Slowly differentiating but rapidly proliferating cardiac progenitors appear posterior to the FHF to form the SHF. They express the transcription factors Isl-1 and TBX-1 [39][40][41]. Following heart tube formation, the SHF cells migrate into the heart tube from the atrial and venous poles. The coordinated movement of SHF and FHF cells is facilitated via receptor-ligand interaction and leads to the elongation of the heart tube and the formation of the right ventricle and outflow tract [42]. The lumen of the heart is lined by endocardial cells, which are a unique type of endothelial cells, both in terms of their origin and differentiation capacities [43]. Endocardial cells appear at the same time as cardiac progenitors with whom they share a common origin [44]. The endocardial and myocardial cell layers are separated by an extracellular matrix, which is composed of hyaluronic acid, fibronectin, collagen IV, and proteoglycans [45][46][47][48]. Endocardial cells can undergo endothelial-to-mesenchymal transition and transform into mesenchymal endocardial cushion cells, which subsequently remodel to form cardiac valves and separate the outflow track into the pulmonary artery and aorta. Endocardial cells exhibit remarkable plasticity differentiating into various lineages including endothelial cells of the capillary network, adipocytes, fibroblasts, and hematopoietic cells [44][49]. At mid-gestation (E10.5), two types of cardiomyocytes are present in the ventricular myocardium. The majority (86%) are immature cardiomyocytes, which are primarily located in the compact myocardium [50]. They have a spherical shape and contain little cytoplasm with loosely arranged myofilaments. The remaining cardiomyocytes (14%) are elongated and have regularly arranged sarcomeres [50]. They are generated from the compact myocardium by proliferation and delamination of cells and make up the trabecular myocardium [51]. Adherens and desmosomal junctions are present in both cardiomyocyte types. But the spherical-shaped myocytes contain intercellular junctions along all sides whereas the trabecular myocytes restrict the junctions to intercalated discs for the most part (Figure 1B,C).

3.2. Development of Epicardium and Epicardial-Derived Cells

Epicardial cells emerge from cell clusters that are referred to as the proepicardium (PE). The PE is located close to the liver primordium and sinus venosus. PE cells migrate toward the looped heart tube around E9.5, attach to the myocardium, and form the epicardial cell layer [52]. Prior to the attachment of epicardial cells to the myocardium at E9.5, the outer layer of cardiomyocytes is covered by a thin and patchy layer of fibronectin, laminin, and collagen IV, generating a basement membrane-like structure [53]. Epicardial cells initially contact myocytes directly through their α4 integrin receptor (CD49d), which binds VCAM-1 on adjacent cardiomyocytes [54]. Later, an extracellular matrix builds up between both cell layers. After formation of the epicardial layer, around E12 some epicardial cells undergo epithelial to mesenchymal transition (EMT), migrate into the sub-epicardial space and subsequently into the myocardium, where they can differentiate into fibroblasts, endothelial cells, and the smooth muscle cells surrounding arteries [55][56] as well as into mesenchymal stem cells [57]. At the same time, paracrine communication between epicardial and myocardial cells promotes myocardial growth [58]. In accordance, co-culture of embryonic epicardium-derived cells enhances the proliferation, maturation, and alignment of cardiomyocytes in vitro. This cross-talk involves increased expression of Cx43, N-cadherin, focal adhesion kinase, and sarcoplasmic reticulum Ca2+ ATPase [59]. Similarly, the promotion of structural and metabolic maturation of cardiomyocytes has been observed in co-cultures of cardiac fibroblasts (the derivatives of epicardial cells) with cardiomyocytes [60].

3.3 Development of Intercellular Junctions in Embryonic Cardiomyocytes

N-cadherin is the main cadherin of classical adherens junctions that are formed in cardiac progenitors as they appear in the cardiac crescent [61][62]. Immature and spherical cardiomyocytes establish multiple contacts with neighboring cells through N-cadherin-based junctions and maintain them as they are required for cardiomyocyte differentiation and organization [30][63][64][65]. During cardiogenesis, the localization of N-cadherins to intercalated discs is closely followed by the appearance of desmosomes [66]. The formation of adherens junctions is a prerequisite for desmosome formation. Loss of N-cadherin, therefore, destabilizes intercalated discs and desmosomes in adult cardiomyocytes [67]. It is even more detrimental during cardiogenesis inducing the formation of a disorganized myocardium with adhesion-deficient cardiomyocytes, reduced trabeculation, loss of cell polarity, and outward migration of cardiomyocytes to the pericardial cavity [51][68]. After the establishment of adherens junctions, the spherical cardiomyocytes of the compact myocardium establish additional contact points by forming desmosomal adhesions with neighboring cardiomyocytes. Desmosomal proteins such as Pkp2 and Dsp can be identified in cardiomyocytes as early as embryonic day 9.5 [17][62]. This goes along with prominent shape changes from spheroidal to elongated. After the appearance of desmosomes, gap junctions are formed and expanded in the plasma membrane [62]. In mature cardiomyocytes of the adult, desmosomes are clustered together with other junctions in the intercalated disc region leaving the lateral membranes desmosome-free.

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