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Neural crest development. Neural crest forms at the junction between neural plate and non-neural ectoderm. Inductive signals include wnt, BMP, and FGF signaling. The neural plate border regions are specified by a range of transcription factors that include Msx1, Msx2, Pax3, and Pax7. Subsequently, a group of neural crest specifiers including c-Myc, Snai1, Sox9, and FoxD3 are expressed in migrating neural crest cells, which can self-renew or differentiate to a range of cell types
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Vascular smooth muscle cells (SMCs) arise from multiple origins during development, raising the possibility that differences in embryological origins between SMCs could contribute to site-specific localization of vascular diseases. In this review, we first examine the developmental pathways and embryological origins of vascular SMCs and then discus...
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... development [33] and at approximately the 4th week of human development [34]. The induction of neural crest precursors occurs at the edge of the neural plate and is regulated by multiple signaling pathways including bone morphogenetic protein (BMP), wingless-type MMTv integration family (wnt), fibroblast growth factor (FGF), and notch [35,36] (Fig. 2). Numerous studies have shown that diminished BMP signaling pro- motes neural induction during vertebrate development [37]. to SMCs in the ascending aorta and arch while the descending aorta is derived from the somites. The aortic root base originates from the sec- ondary heart field, a lateral plate mesoderm derivative, while coronary ...
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Citations
... Additionally, the utilization of iPSCs in manufacturing functional and contractile vascular smooth muscle cells has already demonstrated significant value. They not only contain disease-causing mutations but also, in many cases, possess the permissive genetic background required for full disease expression (Ge et al., 2012;Sinha et al., 2014), making iPSCs highly suitable for vascular disease model reconstruction. ...
Craniofacial reconstruction faces many challenges, including high complexity, strong specificity, severe injury, irregular and complex wounds, and high risk of bleeding. Traditionally, the "gold standard" for treating craniofacial bone defects has been tissue transplantation, which involves the transplantation of bone, cartilage, skin, and other tissues from other parts of the body. However, the shape of craniofacial bone and cartilage structures varies greatly and is distinctly different from ordinary long bones. Craniofacial bones originate from the neural crest, while long bones originate from the mesoderm. These factors contribute to the poor effectiveness of tissue transplantation in repairing craniofacial defects. Autologous mesenchymal stem cell transplantation exhibits excellent pluripotency, low immunogenicity, and minimally invasive properties, and is considered a potential alternative to tissue transplantation for treating craniofacial defects. Researchers have found that both craniofacial-specific mesenchymal stem cells and mesenchymal stem cells from other parts of the body have significant effects on the restoration and reconstruction of craniofacial bones, cartilage, wounds, and adipose tissue. In addition, the continuous development and application of tissue engineering technology provide new ideas for craniofacial repair. With the continuous exploration of mesenchymal stem cells by researchers and the continuous development of tissue engineering technology, the use of autologous mesenchymal stem cell transplantation for craniofacial reconstruction has gradually been accepted and promoted. This article will review the applications of various types of mesenchymal stem cells and related tissue engineering in craniofacial repair and reconstruction.
... Progressive aortic wall degeneration, aneurysm, and aortic dissection predominantly in the ascending aorta (Stanford Type A) have been widely attributed to locally elevated hemodynamics, with MFS deemed as a matrix disease 1,2 . However, it is also known that ascending aortic smooth muscle cells (ASMCs) come from a distinct embryologic developmental origin [3][4][5][6] . While ascending-ASMCs are ectodermal derived, descending and other ASMCs are mesodermal derived, with each SMC sub-type occupying a distinct region within the aorta [3][4][5][7][8][9] . ...
... However, it is also known that ascending aortic smooth muscle cells (ASMCs) come from a distinct embryologic developmental origin [3][4][5][6] . While ascending-ASMCs are ectodermal derived, descending and other ASMCs are mesodermal derived, with each SMC sub-type occupying a distinct region within the aorta [3][4][5][7][8][9] . While investigation of the origin-specific differences in ASMCs can improve our understanding of their role in MFS, dissecting their involvement has been challenging with animal models in vivo. ...
Marfan Syndrome (MFS), a connective tissue disorder caused by a mutation in the fibrillin-1 gene, occurs in approximately 1 in 5,000 people worldwide. As an important constituent of the extracellular matrix, mutated fibrillin-1 in Marfan Syndrome leads to aortic medial degeneration, aneurysm, and dissection. TGFβ in the matrix, which is controlled by fibrillin-1, is known to cause pathological effects in smooth muscle cells (SMCs) within the aortic wall during MFS. TGFβ as well as other cytokines have been shown to impact neural crest derived SMCs differently than mesodermal derived SMCs. Furthermore, outcomes of variable cytokine responsiveness of neural crest SMCs are compounded by genetically imposed changes to neural crest SMC integrin distributions in MFS. Thus, it has been hypothesized that neural crest derived SMCs, which give rise to ascending aortic SMCs, are intrinsically mechanically susceptible to aneurysm formation in MFS. This hypothesis has been linked to the clinical observation of aneurysm formation preferentially occurring in the ascending versus descending aorta in MFS. We aim to test the hypothesis that aortic smooth muscle cells (ASMCs) have intrinsic mechanobiological properties which cause cell weakening in Marfan Syndrome. Human induced pluripotent stem cells (hiPSC) from Marfan patients and healthy volunteers were differentiated into either ascending- or descending-ASMCs via their respective developmental lineages, and cultured to either an early (6 days) or late (30 days) stage of post-differentiation maturation. Mass spectrometry-based proteomics of early-stage iPSC-ASMCs revealed an array of depleted proteins unique to MFS ascending-SMCs that were associated with cell mechanics and aortic aneurysm. Targeted examination of the proteomics dataset revealed intracellular proteins (ACTA2, CNN1, TAGLN) were significantly depleted in MFS ascending-ASMCs. The intrinsic, matrix-independent, hiPSC-ASMC stiffness quantified by atomic force microscopy (AFM) revealed that MFS ascending-ASMCs, but not descending-ASMCs, were significantly less stiff than healthy, at the late cell-maturation stage (p<0.0005). Late-stage ascending- and descending-ASMCs also showed clear functional impairments via calcium flux in MFS. AFM revealed a similar mechanical phenotype in early-stage ASMCs, with MFS ascending-ASMCs, but not descending-ASMCs, being significantly less stiff than healthy (p<0.005). In summary, this study supports an emerging hypothesis of ontogenetic predisposition for aneurysm susceptibility in Marfan Syndrome based on locally altered mechanobiology of developmental origin-specific ASMC subtypes. This may lead to new cell-targeted approaches for treating aortic aneurysm in patients with MFS.
... SM is derived from both mesoderm and neural crest cells, and it can have a local common progenitor origin in adult tissue (for example, vascular progenitors) [10]. SM tissue is located throughout the body and is crucial, from a functional standpoint, in a variety of tissues [11]. ...
... At a cellular level, SM is described as a nonstriated muscle, with neural innervations from the autonomic nervous system, and it differs from SkM in many ways, possibly the most functionally significant being its ability to be contracted and controlled involuntarily [11]. SMCs are usually characterized by identification of multiple markers namely smooth muscle actin (α-SMA), smoothelin, calponin, smooth muscle 22 (SM22α), and smooth muscle myosin heavy chain (MYH11) [10,13]. These proteins can also be transiently detected in other cell types, such as α-SMA in activated fibroblasts or myofibroblasts [10]. ...
... SMCs are usually characterized by identification of multiple markers namely smooth muscle actin (α-SMA), smoothelin, calponin, smooth muscle 22 (SM22α), and smooth muscle myosin heavy chain (MYH11) [10,13]. These proteins can also be transiently detected in other cell types, such as α-SMA in activated fibroblasts or myofibroblasts [10]. Therefore, in vitro manufacturing of SMCs needs to take into account the multitude of markers for SMC identity, as well as the ability for contractility. ...
Tissue engineering approaches within the muscle context represent a promising emerging field to address the current therapeutic challenges related with multiple pathological conditions affecting the muscle compartments, either skeletal muscle or smooth muscle, responsible for involuntary and voluntary contraction, respectively. In this review, several features and parameters involved in the bioprocessing of muscle cells are addressed. The cell isolation process is depicted, depending on the type of tissue (smooth or skeletal muscle), followed by the description of the challenges involving the use of adult donor tissue and the strategies to overcome the hurdles of reaching relevant cell numbers towards a clinical application. Specifically, the use of stem/progenitor cells is highlighted as a source for smooth and skeletal muscle cells towards the development of a cellular product able to maintain the target cell’s identity and functionality. Moreover, taking into account the need for a robust and cost-effective bioprocess for cell manufacturing, the combination of muscle cells with biomaterials and the need for scale-up envisioning clinical applications are also approached.
... [68][69][70][71] Furthermore, these differences may underlie vascular disease states, including aortic aneurysms and vascular calcification. [72][73][74] Our studies are valuable because they confirm the indelible role of SMAD4 in cardiac NC cell survival using a different set of reagents. In addition, we discovered that cells of non-NC origin differentiate into smooth muscle cells to compensate for the reduced numbers of NC-derived cells in the arches. ...
Background
During embryogenesis, cardiac neural crest‐derived cells (NCs) migrate into the pharyngeal arches and give rise to the vascular smooth muscle cells (vSMCs) of the pharyngeal arch arteries (PAAs). vSMCs are critical for the remodeling of the PAAs into their final adult configuration, giving rise to the aortic arch and its arteries (AAAs).
Results
We investigated the role of SMAD4 in NC‐to‐vSMC differentiation using lineage‐specific inducible mouse strains. We found that the expression of SMAD4 in the NC is indelible for regulating the survival of cardiac NCs. Although the ablation of SMAD4 at E9.5 in the NC lineage led to a near‐complete absence of NCs in the pharyngeal arches, PAAs became invested with vSMCs derived from a compensatory source. Analysis of AAA development at E16.5 showed that the alternative vSMC source compensated for the lack of NC‐derived vSMCs and rescued AAA morphogenesis.
Conclusions
Our studies uncovered the requisite role of SMAD4 in the contribution of the NC to the pharyngeal arch mesenchyme. We found that in the absence of SMAD4⁺ NCs, vSMCs around the PAAs arose from a different progenitor source, rescuing AAA morphogenesis. These findings shed light on the remarkable plasticity of developmental mechanisms governing AAA development.
... How these findings can be reconciled remains to be determined. Tgfβ signalling can also directly influence SMC differentiation and homeostasis (Sinha et al., 2014;Wang et al., 2015) (Fig. 3). In embryonic stem cells, Tgfb1 contributes to SMC development (Sinha et al., 2004) and further work has identified deltaEF1 (Zeb1) as a transcription factor mediating Tgfβ signalling during SMC differentiation (Nishimura et al., 2006). ...
... The mesothelium, a squamous epithelial cell layer of mesodermal origin gives rise to mural cells in the lung, liver and gut (Armulik et al., 2011;Asahina et al., 2011;Que et al., 2008;Wilm et al., 2005). The major aorta has vascular mural cells from various origins; depending on the location along the aorta, the mural cells investing this vessel have four different developmental origins, including the secondary heart field, neural crest, splanchnic mesoderm and somites (Armulik et al., 2011;Majesky, 2007;Sinha et al., 2014;Sinha and Santoro, 2018). Even within these areas, SMCs of inner and outer regions of the media can be derived from distinct embryonic sources (Sawada et al., 2017). ...
The vasculature consists of vessels of different sizes that are arranged in a hierarchical pattern. Two cell populations work in concert to establish this pattern during embryonic development and adopt it to changes in blood flow demand later in life: endothelial cells that line the inner surface of blood vessels, and adjacent vascular mural cells, including smooth muscle cells and pericytes. Despite recent progress in elucidating the signalling pathways controlling their crosstalk, much debate remains with regard to how mural cells influence endothelial cell biology and thereby contribute to the regulation of blood vessel formation and diameters. In this Review, I discuss mural cell functions and their interactions with endothelial cells, focusing on how these interactions ensure optimal blood flow patterns. Subsequently, I introduce the signalling pathways controlling mural cell development followed by an overview of mural cell ontogeny with an emphasis on the distinguishing features of mural cells located on different types of blood vessels. Ultimately, I explore therapeutic strategies involving mural cells to alleviate tissue ischemia and improve vascular efficiency in a variety of diseases.
... 30 Previous studies reported that VSMC-specific loss of SMAD4 or TEAD1 could lead to embryonic lethality at E11.5 or E12.5 by harnessing the proliferation of VSMCs. 27,31,32 Consistent with these phenotypes caused by VSMC defects, our data also showed that VSMC-specific Ddx24 depletion affected embryonic development as early as E11.5 and resulted in complete lethality at E13.5. The effect of VSMCs in embryonic development is largely due to their impact on vascular development. ...
Background:
The DEAD-box family is essential for tumorigenesis and embryogenesis. Previously, we linked the malfunction of DDX (DEAD-box RNA helicase)-24 to a special type of vascular malformation. Here, we aim to investigate the function of DDX24 in vascular smooth muscle cells (VSMCs) and embryonic vascular development.
Methods:
CMC/VSMC-specific Ddx24 knockout mice were generated by crossing Tagln-Cre mice with Ddx24flox/flox transgenic mice. The development of blood vessels was explored by stereomicroscope photography and immunofluorescence staining. Flow cytometry and cell proliferation assays were used to verify the regulation of DDX24 on the function of VSMCs. RNA sequencing and RNA immunoprecipitation quantitative real-time polymerase chain reaction were combined to investigate DDX24 downstream regulatory molecules. RNA pull-down and RNA stability experiments were performed to explore the regulation mechanism of DDX24.
Results:
CMC/VSMC-specific Ddx24 knockout mice died before embryonic day 13.5 with defects in vessel formation and abnormal vascular remodeling in extraembryonic tissues. Ddx24 knockdown suppressed VSMC proliferation via cell cycle arrest, likely due to increased DNA damage. DDX24 protein bound to and stabilized the mRNA of FANCA (FA complementation group A) that responded to DNA damage. Consistent with the function of DDX24, depletion of FANCA also impacted cell cycle and DNA repair of VSMCs. Overexpression of FANCA was able to rescue the alterations caused by DDX24 deficiency.
Conclusions:
Our study unveiled a critical role of DDX24 in VSMC-mediated vascular development, highlighting a potential therapeutic target for VSMC-related pathological conditions.
... Vasculature smooth muscle and development were found to be at the center of upregulated developmental GO ( Figures 1E and 2A,C). Recent studies showed that lateral plate mesoderm and neural crest contribute to the smooth muscle components of the blood vasculature [38,39], which explains the enrichment of the brain and peripheral nervous system enrichment by the upregulated DEGs (Figure 2A). ...
Carnosic acid (CA) is a phenolic diterpene widely distributed in herbal plants, rosemary and sage. Although its medicinal properties, such as antioxidant, antimicrobial, and neuroprotective effects, have been well-documented, its relevant biochemical processes and molecular targets have not been fully explored yet. In the present study, we conducted an untargeted whole-genome transcriptomics analysis to investigate CA-induced early biological and molecular events in human amniotic epithelial stem cells (hAESCs) with the aim of exploring its multiple tissue-specific functionalities and potential molecular targets. We found that seven days of CA treatment in hAESCs could induce mesoderm-lineage-specific differentiation. Tissue enrichment analysis revealed that CA significantly enriched lateral plate mesoderm-originated cardiovascular and adipose tissues. Further tissue-specific PPI analysis and kinase and transcription factor enrichment analyses identified potential upstream regulators and molecular targets of CA in a tissue-specific manner. Gene ontology enrichment analyses revealed the metabolic, antioxidant, and antifibrotic activities of CA. Altogether , our comprehensive whole-genome transcriptomics analyses offer a thorough understanding of the possible underlying molecular mechanism of CA.
... The rapid hemodynamic force change and higher blood flow shear stress in the proximal thoracic aortic region may hinder the aortic regression caused by aortic wall healing. The differences in embryological origins between SMCs or aortic segments could contribute to site-specific aortic aneurysm pathogenesis (27,28). The specific detailed differences between murine PTAA lesions and descending TAA lesions at the molecular level need to be revealed through genome wide RNA sequencing in the future. ...
Objective
This study was performed to develop a murine model of elastase-induced proximal thoracic aortic aneurysms (PTAAs).Methods
The ascending thoracic aorta and aortic arch of adult C57BL/6J male mice were exposed through a midline incision in the anterior neck, followed by peri-adventitial elastase or saline application. The maximal ascending thoracic aorta diameter was measured with high-resolution micro-ultrasound. Twenty-eight days after the operation, the aortas were harvested and analyzed by histopathological examination and qualitative polymerase chain reaction to determine the basic characteristics of the aneurysmal lesions.ResultsFourteen days after the operation, the dilation rate (mean ± standard error) in the 10-min elastase application group (n = 10, 71.44 ± 10.45%) or 5-min application group (n = 9, 42.67 ± 3.72%) were significantly higher than that in the saline application group (n = 9, 7.37 ± 0.94%, P < 0.001 for both). Histopathological examination revealed aortic wall thickening, degradation of elastin fibers, loss of smooth muscle cells, more vasa vasorum, enhanced extracellular matrix degradation, augmented collagen synthesis, upregulated apoptosis and proliferation capacity of smooth muscle cells, and increased macrophages and CD4+ T cells infiltration in the PTAA lesions. Qualitative analyses indicated higher expression of the proinflammatory markers, matrix metalloproteinase-2 and -9 as well as Collagen III, Collagen I in the PTAAs than in the controls.Conclusion
We established a novel in vivo mouse model of PTAAs through a midline incision in the anterior neck by peri-adventitial application of elastase. This model may facilitate research into the pathogenesis of PTAA formation and the treatment strategy for this devastating disease.
... The SMC of the aortic root derives from the secondary heart field of lateral plate mesoderm, while the brachiocephalic artery SMC comes from neural crest [34]. There is evidence that differences in SMC origin influence the function of the mature vessel and the constituent SMC [35,36]. ...
Introduction:
We previously identified Notch2 in smooth muscle cells (SMC) in human atherosclerosis and found that signaling via Notch2 suppressed human SMC proliferation. Thus, we tested whether loss of Notch2 in SMC would alter atherosclerotic plaque progression using a mouse model.
Methods:
Atherogenesis was examined at the brachiocephalic artery and aortic root in a vascular SMC null (inducible smooth muscle myosin heavy chain Cre) Notch2 strain on the ApoE-/- background. We measured plaque morphology and size, as well as lipid, inflammation, and smooth muscle actin content after Western diet.
Results:
We generated an inducible SMC Notch2 null on the ApoE-/- background. We observed ∼90% recombination efficiency with no detectable Notch2 in the SMC. Loss of SMC Notch2 did not significantly change plaque size, lipid content, necrotic core, or medial area. However, loss of SMC Notch2 reduced the contractile SMC in brachiocephalic artery lesions and increased inflammatory content in aortic root lesions after 6 weeks of Western diet. These changes were not present with loss of SMC Notch2 after 14 weeks of Western diet.
Conclusions:
Our data show that loss of SMC Notch2 does not significantly reduce atherosclerotic lesion formation, although in early stages of plaque formation there are changes in SMC and inflammation.
... In current mice embryological studies, it could be shown that vascular cells within the outer layer of the tunica media of the ascending aorta derive from the 2nd heart field (pharyngeal mesoderm), whereas the inner cell layers form from the neural crest ectomesenchyme. These transition zones ( Figure 2) are referred to as ontogenetic borders and suspected to be predilection sites for vascular pathologies, such as Stanford type A or B aortic dissection and CeAD [27,28]. Multiple dissections might occur predominantly in arterial locations based on embryologic aspects or similarities in vessel wall composition. ...
... the ascending aorta derive from the 2nd heart field (pharyngeal mesoderm), whereas the inner cell layers form from the neural crest ectomesenchyme. These transition zones (Figure 2) are referred to as ontogenetic borders and suspected to be predilection sites for vascular pathologies, such as Stanford type A or B aortic dissection and CeAD [27,28]. Multiple dissections might occur predominantly in arterial locations based on embryologic aspects or similarities in vessel wall composition. ...
Background:
Although patients with multiple arterial dissections in distinct arterial regions rarely present with known connective tissue syndromes, we hypothesized that mild connective tissue abnormalities are common findings in these patients.
Methods:
From a consecutive register of 322 patients with cervical artery dissection (CeAD), we identified and analyzed 4 patients with a history of additional dissections in other vascular beds. In three patients, dermal connective tissue was examined by electron microscopy. DNA from all four patients was studied by whole-exome sequencing and copy number variation (CNV) analysis.
Results:
The collagen fibers of dermal biopsies were pathologic in all three analyzed patients. One patient carried a CNV disrupting the COL3A1 and COL5A2 genes (vascular or hypermobility type of Ehlers-Danlos syndrome), and another patient a CNV in MYH11 (familial thoracic aortic aneurysms and dissections). The third patient carried a missense substitution in COL5A2.
Conclusion:
Three patients showed morphologic alterations of the dermal connective tissue, and two patients carried pathogenic variants in genes associated with arterial connective tissue dysfunction. The findings suggest that genetic testing should be recommended after recurrent arterial dissections, independently of apparent phenotypical signs of connective tissue disorders.
