Mesodermal ALK5 controls lung myofibroblast versus lipofibroblast cell fate
Aimin LiShudong MaSusan M. SmithMatt K. LeeAshley FischerZea BorokSavério BellusciChanggong LiParviz Minoo
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Abstract:
Epithelial-mesenchymal cross talk is centerpiece in the development of many branched organs, including the lungs. The embryonic lung mesoderm provides instructional information not only for lung architectural development, but also for patterning, commitment and differentiation of its many highly specialized cell types. The mesoderm also serves as a reservoir of progenitors for generation of differentiated mesenchymal cell types that include αSMA-expressing fibroblasts, lipofibroblasts, endothelial cells and others. Transforming Growth Factor β (TGFβ) is a key signaling pathway in epithelial-mesenchymal cross talk. Using a cre-loxP approach we have elucidated the role of the TGFβ type I receptor tyrosine kinase, ALK5, in epithelial-mesenchymal cross talk during lung morphogenesis. Targeted early inactivation of Alk5 in mesodermal progenitors caused abnormal development and maturation of the lung that included reduced physical size of the sub-mesothelial mesoderm, an established source of specific mesodermal progenitors. Abrogation of mesodermal ALK5-mediated signaling also inhibited differentiation of cell populations in the epithelial and endothelial lineages. Importantly, Alk5 mutant lungs contained a reduced number of αSMApos cells and correspondingly increased lipofibroblasts. Elucidation of the underlying mechanisms revealed that through direct and indirect modulation of target signaling pathways and transcription factors, including PDGFRα, PPARγ, PRRX1, and ZFP423, ALK5-mediated TGFβ controls a process that regulates the commitment and differentiation of αSMApos versus lipofibroblast cell populations during lung development. ALK5-mediated TGFβ signaling controls an early pathway that regulates the commitment and differentiation of αSMApos versus LIF cell lineages during lung development.Keywords:
Cell fate determination
Lateral plate mesoderm
Although fate maps of early embryos exist for nearly all model organisms, a fate map of the gastrulating human embryo remains elusive. Here we use human gastruloids to piece together a rudimentary fate map for the human primitive streak (PS). This is possible because differing levels of BMP, WNT, and NODAL leads to self-organization of gastruloids into homogenous subpopulations of endoderm and mesoderm, and comparative analysis of these gastruloids, together with the fate map of the mouse embryo, allows the organization of these subpopulations along an anterior-posterior axis. We also developed a novel cell tracking technique that detected robust fate-dependent cell migrations in our gastruloids comparable to those found in the mouse embryo. Taken together, our fate map and recording of cell migrations provides a first coarse view of what the human PS may resemble in vivo.
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Cell fate determination
Nodal signaling
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Development of the visceral mesoderm is a critical process in the organogenesis of the gut. Elucidation of function and regulation of genes involved in the development of visceral mesoderm is therefore essential for an understanding of gut organogenesis. One of the genes specifically expressed in the lateral plate mesoderm, and later in its derivative, the visceral mesoderm, is the Fox gene FoxF1. Its function is critical for Xenopus gut development, and embryos injected with FoxF1 morpholino display abnormal gut development. In the absence of FoxF1 function, the lateral plate mesoderm, and later the visceral mesoderm, does not proliferate and differentiate properly. Region- and stage-specific markers of visceral mesoderm differentiation, such as Xbap and alpha-smooth muscle actin, are not activated. The gut does not elongate and coil. These experiments provide support for the function of FoxF1 in the development of visceral mesoderm and the organogenesis of the gut. At the molecular level, FoxF1 is a downstream target of BMP4 signaling. BMP4 can activate FoxF1 transcription in animal caps and overexpression of FoxF1 can rescue twinning phenotypes, which results from the elimination of BMP4 signaling. The cis-regulatory elements of FoxF1 are located within a 2 kb DNA fragment upstream of the coding region. These sequences can drive correct temporal-spatial expression of a GFP reporter gene in transgenic Xenopus tadpoles. These sequences represent a unique tool, which can be used to specifically alter gene expression in the lateral plate mesoderm.
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Intermediate mesoderm
Germ layer
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Abstract Positioning of the limb is one of the important events for limb development. In the early stage of embryogenesis, the lateral plate mesoderm splits into two layers and the dorsal layer (the somatic mesoderm) gives rise to a series of distinct structures along the rostrocaudal axis, including the forelimb bud, flank body wall, and hindlimb bud. To determine whether positional information in the somatic mesoderm for regionalization along the rostrocaudal axis is also inherited by the ventral layer of the lateral plate mesoderm (the splanchnic mesoderm), experiments in which the splanchnic mesoderm was transplanted under the ectoderm in an in ovo chick system were carried out. Transplantation of the wing‐, flank‐, and leg‐level splanchnic mesoderm resulted in the formation of wings, nothing, and legs, respectively. These results suggest that the splanchnic mesoderm possesses the ability to form limbs and that the ability differs according to the position along the rostrocaudal axis. The position‐specific ability to form limbs suggests that there are some domains involved in the formation of position‐specific structures in the digestive tract derived from the splanchnic mesoderm, and results of cell fate tracing supported this possibility. In contrast, analysis of shh expression suggested that the anteroposterior polarity in the limb region seems not to be inherited by the splanchnic mesoderm. We propose that the positioning of limb buds is specified and determined in the very early stage of development of the lateral plate mesoderm before splitting and that the polarity in a limb bud is established after the splitting of the mesoderm. Developmental Dynamics 233:256–265, 2005. © 2005 Wiley‐Liss, Inc.
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Intermediate mesoderm
Paraxial mesoderm
Limb bud
Limb development
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Hematopoietic cells (HPCs) develop from hemogenic endothelial cells (ECs), a specialized type of ECs undergoing hematopoietic transition. However, the mesoderm origin for hemogenic ECs or HPCs has not been clarified. To examine the origin for hemogenic mesoderm, we inactivated Etv2, a master regulator for EC/HPC commitment, in specific regions. Region-specific Etv2 ablation in early mesoderm caused local EC differentiation block, resulting in the loss of specific vascular beds without compensatory migration of residual ECs into avascular area. This feature of local EC/HPC differentiation block was correlated to the hemogenic potential of each mesoderm subset. We found that caudal-lateral mesoderm of E7.5-8.5 embryos represent the pre-committed population critical for generating hemogenic ECs. Etv2 ablation in caudal-lateral mesoderm by Hoxb6 Cre or Hoxb6CreER transgene affected vitelline plexus formation and intra-aortic hematopoietic clusters. In differentiated embryonic stem cells, this mesoderm subset marked by Hoxb6-lateral mesoderm promoter showed enriched T lymphopoietic potential among Flk-1(+) cells, which could be regarded as a characteristic for definitive HPCs. These findings indicate that critical mesoderm precursors possibly for definitive type hemogenic ECs are regionally specified in primitive mesoderm, suggesting that Hoxb6(+) caudal-lateral mesoderm represents the critical source of HPCs, which are potentially useful to enrich definitive HPCs from embryonic stem cells.
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ABSTRACT The role of the ectoderm in the expansion of the mesoderm in the area vasculosa of the chicken embryo was studied. The basement membrane of the ectoderm was found to constitute a substratum for the expansion of both layers of mesoderm, since (a) the somatic mesoderm, particularly at its margin, adheres to the basement membrane, and (b) the somatic and splanchnic mesoderm adhere to each other throughout most of the area opaca. Following removal of the ectoderm from the outer surface of the basement membrane, movement of the underlying mesoderm along its inner surface stopped. Mean expansion of the mesoderm in these cases was zero. Following removal of both ectoderm and basement membrane, expansion of the underlying mesoderm was normal in amount. Experimental changes in the ectodermal substratum can thus stop movement of the associated mesoderm, but the role which the substratum normally plays in mesodermal expansion remains unclear.
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ABSTRACT To determine whether expansion of the splanchnic mesoderm of the area vasculosa is influenced by the entodermal substratum on which it occurs, entoderm was separated from a small area of splanchnic mesoderm. The splanchnic mesoderm then contracted and thickened, decreasing to 7 % of its original area in 16 h. By then entoderm had reattached to most of it, and it expanded, reaching 11 % of its original area by 24 h. It was concluded that attachment to entoderm may be required for expansion of the splanchnic mesoderm, but the small amount of expansion obtained made this conclusion tentative. For technical reasons subsequent investigation was done on mesodermal transplants, which attached to the host’s entoderm in 6 h, by which time they had contracted to 15% of their original area. They then expanded, reaching 30% by 16 h and 49% by 24 h. The onset of their expansion was also accompanied by the formation of connexions between their blood vessels and those of the host, and by the resumption of blood flow in them. To see whether their expansion was due to resumption of blood flow or to attachment to entoderm, other transplants were made in which the middle one-third was separated from the host’s entoderm by a piece of Millipore filter. This portion failed to expand although it became connected to the host’s blood vessels and flow of blood resumed in it, while the two lateral thirds, which regained attachment to entoderm, expanded. Transplants were also rotated so that their splanchnic mesoderm attached to ectoderm instead of entoderm. These transplants also formed connexions with the host’s vessels and blood flow resumed in them, but they expanded only slightly compared to non-rotated controls, in which the splanchnic mesoderm attached to entoderm. It was concluded that while flow of blood undoubtedly promotes splanchnic mesodermal expansion as others have shown, attachment of the splanchnic mesoderm to entoderm is also important, and without it the promotive effect of blood flow does not occur. Evidence was also obtained that attachment to entoderm maintains the thinness of the splanchnic mesoderm, and that a vascular growth stimulus may be produced by the unvascularized entoderm distal to the mesoderm.
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Lateral plate mesoderm
Coelom
Germ layer
Intermediate mesoderm
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The precursors of several organs reside within the lateral plate mesoderm of vertebrate embryos. Here, we demonstrate that the zebrafish hands off locus is essential for the development of two structures derived from the lateral plate mesoderm - the heart and the pectoral fin. hands off mutant embryos have defects in myocardial development from an early stage: they produce a reduced number of myocardial precursors, and the myocardial tissue that does form is improperly patterned and fails to maintain tbx5 expression. A similar array of defects is observed in the differentiation of the pectoral fin mesenchyme: small fin buds form in a delayed fashion, anteroposterior patterning of the fin mesenchyme is absent and tbx5 expression is poorly maintained. Defects in these mesodermal structures are preceded by the aberrant morphogenesis of both the cardiogenic and forelimb-forming regions of the lateral plate mesoderm. Molecular analysis of two hands off alleles indicates that the hands off locus encodes the bHLH transcription factor Hand2, which is expressed in the lateral plate mesoderm starting at the completion of gastrulation. Thus, these studies reveal early functions for Hand2 in several cellular processes and highlight a genetic parallel between heart and forelimb development.
Lateral plate mesoderm
Forelimb
Mesenchyme
Heart development
Brachyury
Pectoral girdle
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Lateral plate mesoderm
Germ layer
Intermediate mesoderm
Histogenesis
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Cardiac tissue in the bird is derived from paired regions of lateral mesoderm within the anterior half of the embryo (Rawles [1943] Physiol. Zool. 16:22–42; Stalsberg and DeHaan [1969] Dev. Biol. 19:128–159). Previously, we reported that WNT11 is expressed in early avian mesoderm in a pattern that overlaps with the precardiac regions. To examine whether this molecule may play a role in promoting cardiogenesis, we cultured tissue explants from microdissected HH stage 4, 5, and 6 quail embryos. The isolated tissue consisted of both the mesoderm and endoderm layers from either anterior precardiac or posterior noncardiogenic regions of the embryo. As a necessary control for examining the ability of WNT11 to convert noncardiogenic mesoderm to cardiac tissue, we compared the cardiogenic potential of anterior and posterior regions. For stages 5 and 6, our results were consistent with what has been previously reported (Rawles [1943] Physiol. Zool. 16:22–42; Sugi and Lough [1994] Dev. Dyn. 200:155–162); as anterior mesoderm becomes contractile, while posterior mesoderm does not produce cardiac tissue. Surprisingly, when we examined stage 4 embryos both anterior and posterior regions gave rise to cardiac tissue in culture. To determine whether WNT11 could promote cardiac differentiation in tissue that was noncardiogenic, this molecule was ectopically expressed or added to mesoderm/endoderm explants obtained from stage 5 or 6 posterior tissue. Transfection of stage 5 posterior tissue with a WNT11 expression plasmid provoked the appearance of cardiomyocytes in 33% of the explants; half of which were contractile. Similarly transfected stage 6 posterior explants did not demonstrate cardiac differentiation. More dramatic results were obtained when noncardiogenic tissue was exposed to conditioned media containing soluble WNT11; as 63% and 33% of posterior stage 5- or stage 6-derived explants underwent cardiac differentiation. Together, these results indicate that WNT11 can promote cardiac development within noncardiac tissue. The expression of WNT11 in anterior mesoderm of early gastrula stage embryos suggests it may play a role in the formation of the vertebrate heart. Dev Dyn 1999;216:45–58. © 1999 Wiley-Liss, Inc.
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Paraxial mesoderm
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