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Mesenchyme

Mesenchyme is a primordial embryonic connective tissue composed of stellate mesenchymal cells dispersed within a loose, amorphous extracellular matrix rich in glycosaminoglycans and reticular fibers, representing an undifferentiated state from which most connective tissues, including bone, cartilage, tendons, ligaments, and blood, ultimately derive.^[1]^[2] This tissue arises primarily from the mesoderm during gastrulation, though contributions from the neural crest also generate neural crest-derived mesenchyme that contributes to craniofacial structures and the peripheral nervous system.^[3]^[4] In embryonic development, mesenchyme plays a crucial role in morphogenesis by enabling cell migration and differentiation through epithelial-mesenchymal transitions (EMT), where epithelial cells lose polarity and adhesion to adopt a migratory mesenchymal phenotype.^[5] These cells exhibit high plasticity, responding to signaling cues such as those from the transforming growth factor-β (TGF-β) family to form specialized structures like the sclerotome (for vertebrae) or the hematopoietic system.^[6]^[7] Beyond embryogenesis, mesenchymal progenitors persist in adults as multipotent stromal cells in bone marrow and other niches, supporting tissue repair and homeostasis, though aberrant activation can contribute to fibrosis and cancer metastasis.^[8]

Definition and Characteristics

Definition

Mesenchyme is a type of loosely organized embryonic connective tissue composed of undifferentiated multipotent cells embedded within an extracellular matrix rich in proteoglycans and glycosaminoglycans.^[9] These cells, known as mesenchymal cells, exhibit a stellate morphology with elongated processes and are capable of migration and differentiation into various specialized cell types.^[10] In triploblastic animals, mesenchyme primarily originates from the mesoderm germ layer during gastrulation, serving as a precursor to diverse adult tissues such as connective tissues, blood, bone, cartilage, muscle, and adipose.^[11] This developmental role underscores its transient nature in embryos, where it facilitates tissue patterning and organ formation, though remnants persist in adults as mesenchymal stromal cells with regenerative potential.^[12] The term "mesenchyme" was introduced in 1881 by the brothers Oscar Hertwig and Richard Hertwig in their work Die Coelomtheorie, derived from the Greek words mesos (middle) and enchyma (infusion), reflecting its intermediate position and fluid-like embedding of cells.^[13] It is distinct from mesothelium, the simple squamous epithelial lining of body cavities that arises from mesoderm but maintains an epithelial phenotype rather than undergoing mesenchymal differentiation.^[14]

Key Characteristics

Mesenchymal cells exhibit a distinctive stellate or spindle-shaped morphology, often appearing fusiform with multiple slender cytoplasmic processes extending from the cell body, which facilitates their interaction with the surrounding environment. These cells contain large, oval to round nuclei featuring prominent nucleoli and fine, euchromatic chromatin, indicative of their high metabolic and proliferative activity.^[15]^[16] Mesenchymal cells demonstrate high motility, enabling them to migrate extensively through tissues via amoeboid or mesenchymal migration modes, a behavior critical for dynamic processes in embryonic development.^[17]^[18] As undifferentiated progenitors, mesenchymal cells possess multipotent differentiation potential, allowing them to give rise to diverse lineages including fibroblasts, osteoblasts, chondrocytes, adipocytes, and hematopoietic cells, thereby contributing to the formation of connective tissues and blood elements.^[2]^[19] This plasticity underscores their role as a foundational embryonic tissue capable of adapting to various developmental cues. Mesenchyme displays a loose, gel-like organization, with cells dispersed in an amorphous ground substance interspersed with minimal collagen and elastic fibers, devoid of tight junctions or other adherens structures that maintain epithelial polarity.^[2]^[17] This arrangement supports fluid cell movement and rapid tissue remodeling during embryogenesis, contrasting sharply with the rigid architecture of differentiated tissues. Biochemically, mesenchymal cells are marked by strong expression of vimentin, an intermediate filament protein essential for cytoskeletal integrity and motility, while exhibiting absence of epithelial markers like E-cadherin, which reinforces their mesenchymal identity.^[20]^[21]

Structure

Cellular Components

Mesenchyme consists primarily of undifferentiated mesenchymal progenitor cells, often referred to as mesenchymal stem cells (MSCs) in their multipotent state, which serve as the core cellular population capable of self-renewal and differentiation into various connective tissue lineages.^[4] These progenitors exhibit a spindle-shaped morphology and are interspersed with more committed cells such as fibroblasts, which contribute to the production of connective tissue fibers, and transient populations including neural crest-derived cells that migrate into mesenchymal regions during early development.^[9] Neural crest cells, for instance, integrate into cranial mesenchyme to support skeletogenesis and other structures.^[9] At the ultrastructural level, mesenchymal cells display an elongated cytoplasm with prominent pseudopods, such as filopodia and lamellipodia, facilitating active migration through the embryonic environment.^[22] These cells typically feature a high nucleus-to-cytoplasm ratio, characterized by pale, euchromatic nuclei with one or two nucleoli, indicative of elevated transcriptional activity and rapid proliferation potential.^[22] Adhesion to the surrounding matrix is mediated by integrins, transmembrane receptors that enable dynamic interactions essential for cell positioning and signaling during tissue remodeling.^[23] Mesenchyme exhibits significant cellular heterogeneity, with subpopulations defined by their embryonic origin and developmental potency. For example, paraxial mesenchyme, derived from somites, includes progenitors committed to axial skeletal and muscular lineages, while lateral plate mesenchyme gives rise to limb, cardiovascular, and visceral structures, reflecting distinct transcriptional profiles and migration patterns.^[24] In early embryogenesis, these cells often display multipotent characteristics, allowing broad lineage potential that narrows with progression; this variability underscores the tissue's adaptability in organ formation.^[24] During embryogenesis, mesenchymal cells maintain high proliferation rates to support tissue expansion, with cell cycle dynamics typically featuring shortened G1 phases to enable rapid division synchronized with migratory behaviors.^[25] In neural crest-derived mesenchyme, for instance, proliferation peaks during active migration phases, ensuring sufficient cell numbers for target tissue colonization, though rates decline as cells commit to differentiation.^[25]

Extracellular Matrix

The extracellular matrix (ECM) of mesenchyme is composed primarily of fibrous proteins, glycoproteins, and glycosaminoglycans that create a loose, hydrated scaffold essential for embryonic tissue organization. Key components include collagens types I and III, which provide tensile strength as interstitial fibrils; fibronectin and laminin, which mediate cell adhesion and assembly; hyaluronic acid, a non-sulfated glycosaminoglycan that contributes to hydration and viscosity; and proteoglycans such as biglycan, decorin, and perlecan, which regulate matrix assembly and growth factor binding. These elements collectively form a gel-like, amorphous ground substance interspersed with sparse fibers, distinguishing mesenchymal ECM from denser matrices in mature connective tissues.^[26]^[27]^[28] This ECM supports mesenchymal cell migration by undergoing continuous remodeling, primarily through the secretion of matrix metalloproteinases (MMPs) by the cells themselves. MMPs, including MMP-1, MMP-2, and MMP-9, degrade specific ECM components like collagen and fibronectin, creating pathways for cell movement and preventing excessive matrix accumulation that could impede motility. Hyaluronic acid within the ECM further enhances this process by upregulating MMP expression and activity, facilitating the invasive behavior characteristic of mesenchymal cells during development. Such remodeling is tightly regulated to balance degradation and deposition, ensuring directional migration in response to developmental cues.^[29]^[30] Biomechanically, the mesenchymal ECM is characterized by low stiffness, typically in the range of 0.1–1 kPa, which permits high cell motility and process extension while resisting shear forces in fluid embryonic environments. This softness arises from the high water content of hyaluronic acid and proteoglycans, forming a compliant network that allows mesenchymal cells to exert traction without rigid constraints. Stiffness gradients within the ECM can further direct differentiation; for instance, softer regions promote adipogenic lineages in mesenchymal stem cells, whereas incrementally stiffer areas favor myogenesis or osteogenesis by modulating mechanotransduction pathways like YAP/TAZ signaling.^[31]^[32]^[33] Mesenchymal cells serve as the principal synthesizers of the ECM, secreting its components via exocytosis and assembling them extracellularly through integrin-mediated interactions. This production is dynamically regulated during embryogenesis, with increased deposition during phases of tissue expansion and rapid turnover via MMP-mediated degradation to accommodate morphogenetic changes. Proteoglycans and hyaluronic acid are particularly rapidly turned over, maintaining the ECM's plasticity and responsiveness to signals like TGF-β, which coordinate synthesis with cellular behavior.^[28]^[29]^[34]

Embryonic Development

Epithelial-Mesenchymal Transition

The epithelial-mesenchymal transition (EMT) is a reversible cellular process in which polarized epithelial cells lose their cell-cell adhesions and apical-basal polarity, acquiring migratory and invasive properties characteristic of mesenchymal cells.^[35] This transition enables epithelial sheets to generate mesenchymal cells that can migrate and contribute to tissue remodeling during development.^[5] The hallmark of EMT includes the downregulation of E-cadherin, a key component of adherens junctions, which disrupts epithelial integrity and promotes individual cell motility.^[35] EMT proceeds through distinct stages: initiation, progression, and resolution. During initiation, epithelial cells exhibit loss of E-cadherin expression and apical-basal polarity, leading to the disassembly of junctional complexes and initial detachment from the epithelial layer.^[5] In the progression stage, cytoskeletal reorganization occurs through dynamic remodeling of actin filaments and myosin contractility, enabling cells to adopt a spindle-like morphology and enhanced migratory capacity.^[5] Resolution involves the potential reversal via mesenchymal-to-epithelial transition (MET), where mesenchymal cells regain epithelial traits, as seen in certain developmental contexts.^[35] Key molecular regulators orchestrate EMT, including transcription factors such as Snail, Slug, and Twist, which repress epithelial genes like E-cadherin while activating mesenchymal programs.^[36] Growth factors, notably TGF-β, FGF, and Wnt signaling pathways, initiate and sustain EMT by activating downstream effectors like Smads and β-catenin that induce these transcription factors.^[36] Additionally, microRNAs, such as the miR-200 family, fine-tune the process by targeting EMT inducers like ZEB1/2, thereby modulating the balance between epithelial and mesenchymal states.^[36] In embryogenesis, EMT occurs at critical junctures, including gastrulation where epiblast cells transition to form mesoderm, neural crest delamination enabling migration of multipotent cells from the neural tube, and heart valve formation involving endocardial cushion cells.^[35] These events highlight EMT's role in generating mesenchymal progenitors essential for organ formation.^[5]

Mesoderm Formation

During gastrulation in vertebrate embryos, the mesoderm germ layer forms through the invagination of cells from the epiblast, which differentiates into the three primary germ layers: ectoderm, mesoderm, and endoderm.^[37] In amniotes such as mammals and birds, this process occurs via the primitive streak, where epiblast cells undergo epithelial-to-mesenchymal transition (EMT) and ingress to generate mesodermal progenitors, including those that will form mesenchyme.^[38] In anamniotes like amphibians and fish, mesoderm arises from cells involuting at the blastopore, leading to the displacement of presumptive mesodermal cells inward and their subsequent migration.^[39] These mesenchymal cells, characterized by their migratory and undifferentiated state, emerge as a key component of the nascent mesoderm during this stage.^[40] Following formation, the mesoderm undergoes regionalization into distinct domains along the anterior-posterior and mediolateral axes, each giving rise to specific mesenchymal populations. The paraxial mesoderm, located adjacent to the neural tube, segments into somites that contribute to skeletal muscle, vertebrae, and dermis through mesenchymal condensations.^[41] The intermediate mesoderm, positioned between the paraxial and lateral domains, develops into mesenchymal derivatives of the urogenital system, such as kidneys and gonads.^[42] Lateral plate mesoderm splits into somatic and splanchnic layers, yielding mesenchymal cells that form connective tissues, cardiovascular structures, and limb mesenchyme.^[43] This spatial organization is established early in gastrulation and ensures the diversification of mesenchymal lineages.^[44] Inductive signals from neighboring tissues and gradients within the embryo specify mesodermal fate and regional identity. Bone morphogenetic protein (BMP) signaling, emanating from the ventral side, promotes ventral mesoderm formation, while its dorsal inhibition by antagonists like Noggin and Chordin allows for paraxial mesoderm development.^[45] Nodal-related factors, expressed in the primitive streak or organizer region, induce mesendoderm and pattern the mesoderm in a dose-dependent manner, with high levels favoring endoderm and intermediate levels specifying mesoderm.^[46] Fibroblast growth factor (FGF) signaling cooperates with these pathways to maintain mesodermal progenitors and drive their migration, particularly in posterior regions.^[47] These gradients transform bipotent ectodermal/endodermal precursors into committed mesodermal cells, including mesenchymal ones.^[48] The formation of mesoderm and its mesenchymal components exhibits evolutionary conservation across bilaterians, reflecting shared developmental mechanisms from a common ancestor. Mesoderm first evolved in early bilaterians as an internal layer for muscle and supportive tissues, with gene regulatory networks involving T-box factors like Brachyury conserved from invertebrates to vertebrates.^[49] Mesenchyme, as a loosely organized derivative, represents a derived feature within this layer, enabling migratory behaviors essential for bilaterian body plans, though its precise origins trace to deuterostome innovations in cell adhesion and signaling.^[50] This conservation underscores the fundamental role of gastrulation in generating mesenchymal diversity across animal phyla.^[51]

Mesenchyme in Vertebrates

Types of Mesoderm-Derived Mesenchyme

In vertebrate embryos, mesenchyme arises during gastrulation from epiblast cells that undergo epithelial-mesenchymal transition and ingression through the primitive streak, forming the mesoderm layer.^[37] These cells contribute primarily to axial structures, including the notochord, which provides midline support and induces neural tube patterning, and the prechordal plate, a rostral mesendodermal region that influences forebrain development and head organizer functions.^[52]^[53] This process occurs in the third week of human gestation, coinciding with the establishment of the trilaminar embryo.^[54] The mesoderm further differentiates into distinct populations, including paraxial mesoderm, which organizes into somites—segmented blocks that give rise to skeletal muscle, vertebrae, and dermis—and intermediate mesoderm, which differentiates into nephrogenic mesenchyme, the precursor for kidney structures such as the nephrons. Lateral plate mesoderm also emerges, contributing to additional mesenchymal populations.^[55]^[56] Mesoderm formation and differentiation extend throughout early organogenesis, from weeks 3 to 8 in human development, allowing progressive segmentation and regional specification along the embryonic axis.^[57] A distinct type, neural crest mesenchyme, originates from the ectoderm rather than mesoderm, arising from neural fold cells that undergo epithelial-mesenchymal transition (EMT) to become migratory mesenchymal cells.^[58] These cells delaminate during neurulation around weeks 3-4 of human gestation and migrate extensively to populate diverse sites, contributing to craniofacial skeleton and connective tissues, as well as elements of the peripheral nervous system, including neurons and glia.^[59]^[60] This ectomesenchymal population underscores the multipotent nature of neural crest cells in vertebrate diversification.

Role in Organogenesis

In vertebrate organogenesis, mesenchyme plays a pivotal role as a multipotent progenitor population that interacts with epithelial components to drive the formation and patterning of diverse organs, including those in the craniofacial region, limbs, reproductive system, and excretory system. Derived primarily from mesoderm such as neural crest or lateral plate mesoderm, it provides structural scaffolding, secretes signaling molecules, and undergoes differentiation to yield connective tissues, vasculature, and skeletal elements essential for organ architecture.^[61] Branchial arch mesenchyme, largely neural crest-derived, is crucial for craniofacial and neck organogenesis. Migrating from the dorsal neural tube, these ectomesenchymal cells populate the pharyngeal arches, where they differentiate into cartilaginous precursors that ossify to form facial bones (e.g., maxilla and mandible from the first arch) and neck structures like the hyoid (second arch).^[61] In the third and fourth arches, neural crest mesenchyme contributes to the connective tissue stroma of the thymus, supporting epithelial cell organization and T-cell maturation during thymic organogenesis.^[62] Limb bud mesenchyme originates from the lateral plate mesoderm and drives appendage formation through reciprocal signaling with the overlying ectoderm. Proliferating mesenchymal cells from the somatic layer form the core of the limb bud, which elongates proximodistally under the influence of fibroblast growth factors (FGFs) secreted by the apical ectodermal ridge (AER). This AER-FGF signaling, particularly FGF8 and FGF10 in a feedback loop, maintains mesenchymal proliferation and survival, while enabling patterning of skeletal elements such as humerus, radius/ulna, and digits through gradients that specify proximodistal identity.^[63]^[64] Extraembryonic mesenchyme supports placental development during embryo implantation by invading nascent chorionic villi to form secondary and tertiary structures, thereby providing a mesenchymal core that stabilizes the trophoblast layer and facilitates its invasion into the uterine endometrium. This mesenchymal influx, derived from extraembryonic mesoderm originating primarily from the epiblast and possibly the primitive endoderm, enables villous branching and vascularization, ensuring nutrient exchange and anchoring the placenta.^[65]^[66]^[67] In kidney development, metanephric mesenchyme induces ureteric bud outgrowth and branching to establish the nephron and collecting system. Condensing around the invading ureteric bud from the Wolffian duct, the mesenchyme secretes glial cell line-derived neurotrophic factor (GDNF), which activates RET receptor signaling in the bud to promote tip cell proliferation and iterative branching morphogenesis, ultimately forming over 20 generations of ducts.^[68] This interaction also triggers mesenchymal-to-epithelial transition in subsets of metanephric cells to generate renal vesicles, the precursors of nephrons.^[69] Gonadal development relies on mesenchyme within the genital ridge to form the stromal framework and support sex-specific organogenesis. The bipotential genital ridge arises from coelomic epithelium overlying intermediate mesoderm-derived mesenchyme, which proliferates to recruit primordial germ cells and differentiate into steroidogenic and supporting cells (e.g., Leydig/Sertoli in testes or theca/granulosa in ovaries), guiding gonad morphogenesis along the cortical-medullary axis.^[70] In vertebrates, PAX2-positive mesenchymal cells contribute to the initial ridge thickening and subsequent sex differentiation, ensuring vascular integration and hormone production essential for reproductive organ function.^[71]

Mesenchyme in Invertebrates

Occurrence in Echinoderms

In echinoderms, mesenchyme plays a pivotal role in embryonic development, particularly in species like sea urchins, where it contributes to larval skeleton formation and other mesodermal structures. Primary mesenchyme cells (PMCs) originate from the micromeres at the vegetal pole, formed during the fourth cleavage division at the 16-cell stage. These cells undergo an epithelial-mesenchymal transition (EMT) in the blastula stage, shortly after hatching (approximately 9-10 hours post-fertilization at 25°C), detaching from the epithelial layer of the vegetal plate and ingressing into the blastocoel cavity.^[72]^[73] During this EMT, micromeres lose epithelial characteristics, such as adhesion to the hyaline layer, and acquire migratory properties through expression of key regulatory genes, including vegf (vascular endothelial growth factor) and ets1 (an ETS family transcription factor homolog). The vegf gene promotes directed migration and patterning of PMCs along the blastocoel wall, while ets1 (known as HpEts in the sea urchin Hemicentrotus pulcherrimus) is essential for PMC specification, differentiation, and filopodial extension during ingression. Following ingression, around the sixth cleavage (64-cell stage) transitioning to the mesenchyme blastula (~250 cells), PMCs migrate to form a ventrolateral ring, where they fuse into syncytia and initiate skeletogenesis by depositing calcium carbonate spicules that support the larval body.^[74]^[75]^[72] PMCs primarily function in providing structural support through the larval skeleton, but echinoderm mesenchyme also exhibits immune capabilities in the larval stage. Secondary mesenchyme cells (SMCs), derived from veg2-tier mesendodermal descendants at the archenteron tip during gastrulation (around 13 hours post-fertilization), delaminate via another EMT event and migrate to contribute to mesodermal derivatives, including pigment cells. These pigment cells, a key SMC lineage, perform immune surveillance by phagocytosing bacteria and responding to microbial challenges in the larva.^[76]^[77]^[72] Comparatively, the EMT process driving mesenchyme formation in echinoderms is conserved with that in chordates, reflecting a shared deuterostome heritage, though echinoderms lack somites and instead utilize mesenchyme for diffuse mesodermal functions like skeletogenesis. As part of the ambulacrarian clade, echinoderm mesenchyme represents an evolutionarily basal system for studying mesodermal diversification predating chordate innovations.^[78]^[73]

Presence in Other Invertebrates

In non-bilaterian invertebrates such as cnidarians, mesenchyme is absent, as these diploblastic organisms lack a true mesodermal layer; mesenchyme emerges evolutionarily with triploblasty in bilaterians, enabling more complex body plans through the development of internal supportive tissues.^[79] In platyhelminthes, or flatworms, mesenchymal cells occupy the parenchyma, a loose connective tissue that fills the space between the outer epidermis and inner gastrodermis, providing structural support for muscles and reproductive organs. These cells are primarily derived from neoblasts, which are pluripotent adult stem cells distributed throughout the mesenchyme and capable of differentiating into various somatic cell types, including muscle fibers and components of the reproductive system.^[80]^[81] Among arthropods, mesenchyme-like tissues appear in the hemocoel, the open body cavity that serves as part of the circulatory system and contains hemolymph with suspended hemocytes, which function in immunity and wound repair but exhibit limited epithelial-mesenchymal transition (EMT) compared to other invertebrates. Hematopoietic organs in arthropods often form as mesenchymal structures associated with the hemocoel lining, producing hemocytes that contribute to tissue maintenance without extensive migratory mesenchymal behaviors.^[82]^[83] In mollusks and annelids, coelomic mesenchyme lines the body wall and septa, originating from mesodermal bands during embryogenesis and supporting organ positioning and movement. In annelids, this mesenchyme has segmental origins, forming peritoneum-like layers around the segmented coelom that aid in locomotion and compartmentalization. Mollusks, with a reduced coelom, retain mesenchymate tissues that integrate with the hemocoel-like spaces, deriving from early mesodermal splits to form supportive matrices for the muscular foot and mantle.^[84]^[85]

Functions and Interactions

Tissue Differentiation

Mesenchyme exhibits multipotent differentiation potential, giving rise to a diverse array of tissues during embryonic development and in adult contexts. This capacity allows mesenchymal progenitors to contribute to both mesodermal and non-mesodermal lineages, guided by specific transcriptional regulators and environmental signals. In vertebrates, mesenchymal stem cells (MSCs) primarily differentiate into mesodermal derivatives such as bone, cartilage, and muscle, while certain subpopulations, like those from the neural crest, can also form ectodermal structures including neurons.^[86]^[87] Key transcription factors orchestrate these lineage commitments. For osteogenesis, Runx2 activates the expression of bone-specific genes, initiating the transition from mesenchymal progenitors to osteoblasts.^[88] In chondrogenesis, Sox9 drives the formation of cartilage by promoting the synthesis of extracellular matrix components like collagen type II.^[89] Myogenesis involves MyoD, which coordinates the fusion of myoblasts into multinucleated muscle fibers.^[86] Non-mesodermal differentiation is exemplified by neural crest-derived mesenchyme, which can generate neurons through pathways involving neural specification factors, highlighting the ectodermal plasticity of these cells.^[90] Differentiation is profoundly influenced by environmental cues, both mechanical and chemical. Mechanical stiffness of the extracellular matrix directs lineage choice: stiff substrates (around 30-40 kPa) promote osteogenesis by enhancing cytoskeletal tension and Runx2 activity, whereas softer matrices (8-17 kPa) favor myogenesis via softer mechanotransduction favoring MyoD expression. Chemically, bone morphogenetic proteins (BMPs), particularly BMP2, induce osteogenic commitment by activating Smad signaling and upregulating Runx2 in mesenchymal cells.^[91] For cartilage formation, Sonic hedgehog (Shh) signaling modulates the somitic mesenchyme, promoting chondrogenic aggregation and Sox9-dependent maturation.^[92] In adults, mesenchymal potency persists in perivascular niches, where MSCs reside as multipotent progenitors. These perivascular cells in bone marrow maintain trilineage potential (osteo-, chondro-, adipogenic) through sustained expression of stemness markers like Sox2.^[93] Similar populations in the umbilical cord's perivascular region exhibit robust multilineage differentiation, including into bone and cartilage, due to their embryonic-like microenvironment.^[94] Adipose tissue-derived perivascular MSCs also retain this potency, supporting tissue repair via osteogenic and myogenic pathways under appropriate stimuli.^[95] In vitro protocols recapitulate these processes to study or expand differentiated cells. For osteogenesis, a standard medium supplemented with dexamethasone (typically 100 nM), ascorbic acid, and β-glycerophosphate induces alkaline phosphatase activity and mineralization in MSCs within 2-3 weeks, mimicking BMP-driven commitment.^[96] This glucocorticoid enhances Runx2 expression while suppressing alternative lineages like chondrogenesis by downregulating Sox9.^[97]

Epithelial-Mesenchymal Signaling

Epithelial-mesenchymal signaling represents a fundamental reciprocal interaction during embryonic development, where mesenchymal cells secrete soluble factors that induce and pattern epithelial structures, while epithelial cells respond with signals that regulate mesenchymal behavior and proliferation. In the developing lung, for instance, mesenchymal-derived fibroblast growth factor 10 (FGF10) promotes epithelial budding and branching morphogenesis by stimulating epithelial cell proliferation and survival.^[98] This mesenchymal signal elicits an epithelial response, including the secretion of Sonic hedgehog (Shh) and bone morphogenetic protein 4 (BMP4), which in turn modulate mesenchymal FGF10 expression and inhibit excessive branching to refine lung architecture.^[99]^[100] Such bidirectional communication ensures coordinated organ formation, with disruptions in these loops leading to impaired morphogenesis.^[101] Several conserved signaling pathways mediate these interactions, providing spatial and temporal cues for tissue patterning. The Wnt/β-catenin pathway, activated in both epithelial and mesenchymal compartments, regulates patterning and differentiation; for example, epithelial Wnt ligands signal to mesenchymal β-catenin to control cartilage and submucosal gland development in the lung.^[102] In limb development, Shh secreted from the posterior limb bud epithelium patterns digit identities by signaling to adjacent mesenchyme, establishing anterior-posterior polarity through concentration-dependent and time-integrated effects.^[103] Similarly, Notch signaling facilitates vascularization by promoting mesenchymal recruitment and differentiation into vascular smooth muscle cells around epithelial-derived vessels, ensuring proper endothelial tube stabilization.^[104]^[105] Feedback loops amplify and refine these signals, particularly in structures like teeth, where mesenchymal-epithelial crosstalk drives cusp formation. In tooth development, the enamel knot—a transient epithelial signaling center—secretes activators such as Shh and BMPs to instruct surrounding mesenchymal proliferation and condensation, while mesenchymal FGFs and Wnts reciprocally maintain knot integrity.^[106]^[107] Disruptions in this loop, such as mutations in EDA or NKX2-3 pathways, impair enamel knot formation and signaling, resulting in tooth agenesis.^[108]^[109] These iterative exchanges highlight the precision required for multicusped tooth morphogenesis. The dynamics of epithelial-mesenchymal signaling evolve temporally, transitioning from early permissive roles—where mesenchymal factors support epithelial survival and basic outgrowth without specifying fate—to later instructive phases that dictate precise patterning and differentiation.^[110] In mammary gland development, initial mesenchymal signals provide permissive cues for bud exit and elongation, shifting to instructive epithelial-directed branching as signaling refines ductal architecture.^[111] This progression ensures developmental flexibility, with early broad permissiveness allowing competence establishment before instructive signals commit cells to specific lineages.^[112]

Clinical and Pathological Aspects

Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs), also known as mesenchymal stromal cells, are multipotent, non-hematopoietic adult stem cells derived from embryonic mesenchyme and found in various tissues including bone marrow, adipose tissue, and Wharton's jelly of the umbilical cord. These cells possess the capacity for self-renewal and differentiation into mesodermal lineages such as osteocytes, chondrocytes, and adipocytes, underscoring their therapeutic potential in regenerative medicine. The International Society for Cell & Gene Therapy (ISCT) defines MSCs by minimal criteria: adherence to plastic under standard culture conditions, expression of CD73, CD90, and CD105 (>95% of cells), absence of hematopoietic markers like CD34, CD45, CD14, CD11b, CD19, CD79a, and HLA-DR, and demonstration of trilineage differentiation potential.^[113]^[114]^[115] Isolation of MSCs typically involves tissue procurement followed by enzymatic digestion or mechanical disruption, with subsequent selection via density gradient centrifugation to enrich for mononuclear cells. Expansion is achieved by culturing these cells on plastic substrates in basal media such as low-glucose Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10-20% fetal bovine serum (FBS), antibiotics, and growth factors, allowing adherence and proliferation while maintaining multipotency. The ISCT's 2006 position statement provides the foundational minimal criteria for identification and quality control during isolation and expansion, with subsequent refinements in 2019 emphasizing nomenclature as "stromal" cells unless multilineage potential is rigorously demonstrated to enhance clinical standardization.^[116]^[117]^[114]^[118] MSCs exert immunomodulatory effects primarily through paracrine secretion of bioactive molecules, including prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO), and transforming growth factor-beta (TGF-β), which inhibit T-cell proliferation, induce regulatory T cells, and suppress inflammatory cytokine production. These properties position MSCs as key players in mitigating immune-mediated tissue damage, with PGE2 and IDO particularly critical for direct suppression of effector T cells in preclinical models of autoimmunity and transplantation.^[119]^[120]^[121] In preclinical applications, MSCs enhance tissue repair by homing to injury sites via the CXCR4/SDF-1 axis, where stromal-derived factor 1 (SDF-1) gradients guide CXCR4-expressing MSCs to damaged areas for paracrine support and regeneration. Updates from 2025 research demonstrate improved homing efficiency through spheroid preconditioning, which upregulates CXCR4 expression, and exosome delivery of SDF-1, yielding superior outcomes in models of bone defects, wound healing, and organ ischemia without adverse effects. These advancements highlight MSCs' scalability for clinical translation in regenerative therapies.^[122]^[113]

Role in Disease

Dysregulation of mesenchymal processes plays a central role in various diseases, particularly through aberrant epithelial-mesenchymal transition (EMT) that enables cancer progression. In metastatic cancers, epithelial tumor cells undergo EMT to gain mesenchymal traits, enhancing motility and invasiveness; this is driven by upregulation of transcription factors like Twist and Snail, which repress epithelial markers and promote mesenchymal ones. For instance, in breast carcinoma, temporal and spatial cooperation between Snail1 and Twist1 during EMT correlates with increased recurrence risk and poor prognosis.^[123] Recent analyses as of 2025 reveal EMT heterogeneity within tumors, where partial or hybrid EMT states—cells retaining both epithelial and mesenchymal features—contribute to intratumor diversity, metastasis, and resistance to therapies, underscoring the spectrum of mesenchymal plasticity in oncology.^[124] Fibrotic disorders exemplify pathological mesenchymal activation, where transforming growth factor-β (TGF-β) signaling induces differentiation of mesenchymal progenitors, such as fibroblasts or pericytes, into contractile myofibroblasts. These cells produce excessive extracellular matrix, leading to tissue stiffening and scarring in organs like the liver (hepatic fibrosis) and lungs (idiopathic pulmonary fibrosis). TGF-β-mediated myofibroblast transition involves Smad-dependent pathways that upregulate α-smooth muscle actin and collagen, perpetuating a fibrogenic cycle; inhibition of this axis, such as via calpain modulation, has shown potential to reverse the process in preclinical models.^[125]^[126] Mesenchymal tumors, known as sarcomas, originate from dysregulated mesenchymal stem cells (MSCs) that lose proliferative controls, giving rise to aggressive neoplasms like osteosarcoma from osteoblastic progenitors. Loss of tumor suppressors such as p53 in MSCs disrupts self-renewal and differentiation, modeling undifferentiated soft tissue sarcomas and promoting tumorigenesis through enhanced stem-like properties. Diagnosis often relies on immunohistochemical markers like vimentin, a intermediate filament protein expressed in these tumors, confirming their mesenchymal lineage and distinguishing them from epithelial malignancies.00097-8)^[127] Congenital diseases highlight mesenchyme's role in developmental pathologies, particularly failures in neural crest-derived mesenchyme. DiGeorge syndrome (22q11.2 deletion syndrome) arises from impaired migration and survival of neural crest cells into pharyngeal mesenchyme, resulting in conotruncal cardiac anomalies, thymic aplasia, and hypoparathyroidism; TGF-β signaling inactivation in these progenitors recapitulates the phenotype in mouse models. Treacher Collins syndrome, caused by TCOF1 mutations, disrupts neural crest contribution to first and second branchial arch mesenchyme, leading to mandibular hypoplasia, ear malformations, and downslanting palpebral fissures through increased apoptosis in pre-migratory crest cells.^[128]^[129]

References

[1]
Anatomy, Connective Tissue - StatPearls - NCBI Bookshelf - NIH
Mar 5, 2023 · [3] Mesenchyme is a loosely organized embryonic connective tissue with undifferentiated cells that produce most of the tissues of the body.
[2]
[PDF] 5.MESODERM FORMATION / SEGMENTATION
Much of the paraxial and lateral plate mesoderm develops into mesenchyme, an embryonic connective tissue. The derivatives of mesenchyme are connective tissue ...Missing: definition | Show results with:definition
[3]
Mesenchymal Stem Cells: Revisiting History, Concepts, and Assays
Mesenchyme, -A primitive embryonic loose connective tissue. -An embryonic subset of mesoderm-derived cells. -Also a subset of neuroectoderm-derived cells ...
[4]
Epithelial Mesenchymal Transition in Embryonic Development ...
This review begins with: (i) a discussion of key concepts involving epithelium and mesenchyme along with an EMT classification; (ii) next, we discuss EMT ...
[5]
Epithelium–Mesenchyme Transitions Are Crucial Morphogenetic ...
The term “mesenchyme” originates from the Greek words Mésos (environment), In (in) and Chymos (juice). A supracellular mesenchymal architecture can be defined ...
[6]
Mesenchymal Stem or Stromal Cells: Toward a Better ... - NIH
Mesenchyme originally describes the embryonic loose connective tissue that is derived from the mesoderm and that develops into hematopoietic and connective ...
[7]
Mesenchyme - an overview | ScienceDirect Topics
Mesenchyme is a type of loose connective tissue, which is derived from all three germ layers and located within the embryo. Mesenchymal cells are capable of ...
[8]
Mesenchyme | Embryo Project Encyclopedia
Sep 14, 2012 · Mesenchyme is a type of animal tissue comprised of loose cells embedded in a mesh of proteins and fluid, called the extracellular matrix.
[9]
Epithelial to mesenchymal transition during gastrulation: An ...
Nov 25, 2008 · Here we discuss, from an embryological perspective, the involvement of EMT in mesoderm formation during gastrulation in triploblastic animals.
[10]
Mesenchymal Stem Cells (MSC): Definitions, Nomenclature, Terms
Rating 5.0 (2) Dec 1, 2024 · Mesenchyme is a form of loose connective tissue within an embryo that contains undifferentiated cells capable of differentiating into bone ...
[11]
MESENCHYME AND MESOTHELIUM - PMC - NIH
Mesothelium is not a differentiated tissue from mesenchyme, but a form transformation of mesenchymal cells, differing only in form, not structure.
[12]
Embryonic Connective Tissue (mesenchyme) - Histology Guide
Mesenchymal Cells - stellate or spindle-shaped (fusiform) cells with round to oval nuclei. Easy to identify when three or more processes are visible. Dental ...
[13]
Phenotypic Characterization and ln Vivo Localization of Human ...
May 14, 2013 · The cells contained large euchromatic nuclei with prominent nucleoli, sparse organelles, abundant free ribosomes, a distended rough endoplasmic ...
[14]
Epithelial-mesenchymal transitions: the importance of changing cell ...
By contrast, mesenchymal cells are nonpolarized and lack intercellular junctions, such that they can move as individual cells throughout the extracellular ...
[15]
Directed migration of mesenchymal cells: where signaling and the ...
Jul 5, 2014 · Amoeboid and mesenchymal motility modes lie at opposite extremes of cell migration phenotypes [16] and reflect the coordinated functions of ...
[16]
Hematopoietic cell differentiation from embryonic and induced ...
Both mouse and human embryonic stem (ES)/induced pluripotent stem (iPS) cells can be differentiated into hematopoietic cells (HCs) from mesodermal cells with ...
[17]
Biomarkers for epithelial-mesenchymal transitions - JCI
A change in expression of E-cadherin is the prototypical epithelial cell marker of EMT. ... A controversial marker of EMT is the intermediate filament vimentin ...
[18]
Significance of E-cadherin and Vimentin as epithelial-mesenchymal ...
Overall, in the EMT process the expression and function of epithelial markers such as E-cadherin decline and mesenchymal markers like Vimentin increase (Ye et ...
[19]
Ultrastructural Analysis of Different Human Mesenchymal Stem Cells ...
This review uses transmission electron microscopy to analyze mesenchymal stem cells, focusing on their ultrastructure, including polymorphic nuclei and rough ...Missing: embryonic | Show results with:embryonic
[20]
The extracellular matrix in development - PMC - NIH
May 29, 2020 · Mesenchymal and lobopodial migration involve extensive integrin-mediated adhesion to surrounding ECM substrates, whereas amoeboid migration can ...
[21]
The developmental basis of mesenchymal stem/stromal cells (MSCs)
Nov 20, 2015 · Mesenchymal Stem/Stromal Cells (MSCs) define a population of progenitor cells capable of giving rises to at least three mesodermal lineages in vitro.
[22]
The neural crest cell cycle is related to phases of migration in the head
Embryonic cells that migrate long distances must critically balance cell division in order to maintain stream dynamics and population of peripheral targets.<|control11|><|separator|>
[23]
Extracellular matrix made by bone marrow cells facilitates ... - PubMed
Results: The marrow cell-derived ECM was made up of collagen types I, III, and V, syndecan-1, perlecan, fibronectin, laminin, biglycan, and decorin, similar to ...
[24]
Extracellular Matrix Degradation and Remodeling in Development ...
In the early limb bud, for example, the mesenchyme is rich in hyaluronic acid and collagen I (Lonai 2003). At the onset of skeletal condensation, hyaluronic ...
[25]
Mesenchymal Stromal Cell-Produced Components of Extracellular ...
The extracellular matrix (ECM) is a complex three-dimensional network of interlaced fibrillar proteins, proteoglycans, multiple matrix protein macromolecules, ...
[26]
Development of Matrix Metalloproteinases-Mediated Extracellular ...
May 9, 2023 · Matrix metalloproteinases (MMPs) are a group of enzymes responsible for ECM degradation and have been accepted as a key regulator in ECM remodeling.
[27]
Mechanochemical Signaling of the Extracellular Matrix in Epithelial ...
Hyaluronic acid increases MMP-2 and MMP-9 ... Mechanical forces regulate the interactions of fibronectin and collagen I in extracellular matrix.
[28]
The Effect of Matrix Stiffness on the Differentiation of Mesenchymal ...
Here we showed that matrix stiffness modulated these differential effects. MSCs on soft substrates had less spreading, fewer stress fibers and lower ...Missing: biomechanical | Show results with:biomechanical
[29]
Extracellular matrix biomechanical roles and adaptation in health ...
Aug 23, 2023 · ECM provides physical cues to cells through its mechanical properties, including stiffness and elasticity. Cells respond to these mechanical ...
[30]
Extracellular matrix and its therapeutic potential for cancer treatment
Apr 23, 2021 · The former include collagen, fibronectin, elastin, and laminin, and the latter mainly consists of hyaluronic acid, chondroitin sulfate, keratan ...
[31]
Extracellular Matrix Synthesis and Remodeling by Mesenchymal ...
Feb 3, 2022 · Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, ...Extracellular Matrix... · 2. Results · 4. Materials And Methods
[32]
Guidelines and definitions for research on epithelial–mesenchymal ...
Apr 16, 2020 · Epithelial–mesenchymal transition (EMT) is a cellular process during which epithelial cells acquire mesenchymal phenotypes and behaviour ...
[33]
Signaling mechanisms of the epithelial-mesenchymal transition - PMC
The epithelial-mesenchymal transition (EMT) is an essential mechanism in embryonic development and tissue repair. EMT also contributes to the progression of ...Tgf-β And Bmp Signaling In... · Fig. 3. Tgf-β Signaling In... · Wnt Signaling In Emt
[34]
Embryology, Gastrulation - StatPearls - NCBI Bookshelf - NIH
Apr 23, 2023 · Gastrulation occurs during week 3 of human development. The process of gastrulation generates the three primary germ layers ectoderm, endoderm, ...
[35]
Decoupling of amniote gastrulation and streak formation reveals a ...
Mesoderm is formed during gastrulation. This process takes place at the blastopore in lower vertebrates and in the primitive streak (streak) in amniotes.
[36]
Reconstruction of distinct vertebrate gastrulation modes via ...
Jan 4, 2023 · The morphology of gastrulation driving the internalization of the mesoderm and endoderm differs markedly among vertebrate species.
[37]
Mesoderm specification and diversification: from single cells to ... - NIH
Aug 30, 2019 · Although mesoderm-derived cells are the highly represented within the vertebrate body, the mesoderm is the youngest germ layer in evolutionary ...
[38]
Signaling Gradients during Paraxial Mesoderm Development - PMC
In the posterior part of the embryo, the paraxial mesoderm is arranged as mesenchymal, still unsegmented tissue called the presomitic mesoderm (PSM).
[39]
Evidence for Intermediate Mesoderm and Kidney Progenitor Cell ...
Activation of the Pax2 gene marks the intermediate mesoderm shortly after gastrulation, as the mesoderm becomes compartmentalized into paraxial, intermediate, ...
[40]
Lateral Plate Mesoderm - an overview | ScienceDirect Topics
Lateral to the paraxial mesoderm is a compact region of intermediate mesoderm, which ultimately gives rise to the urogenital system. Beyond that, the lateral ...
[41]
Single cell transcriptomics identifies a signaling network ... - Nature
Aug 27, 2020 · The lateral plate mesoderm emerges from the streak after the extra-embryonic mesoderm, and is followed by the intermediate, paraxial, and axial ...
[42]
Back and Forth between Cell Fate Specification and Movement ...
At the onset of gastrulation, a ventral to dorsal gradient of BMP signaling is established, playing a key role in mesoderm induction and dorsoventral patterning ...
[43]
Nodal signaling establishes a competency window for stochastic cell ...
Specification of the germ layers by Nodal signaling has long been regarded as an archetype of how graded morphogens induce different cell fates.
[44]
Functional Roles of FGF Signaling in Early Development of ... - NIH
Aug 20, 2021 · FGF signal is inhibitory to BMP/Smad1 in ectoderm specification. However, FGF/Xbra functions synergistically to BMP/Smad1 in ventral mesoderm ...
[45]
Population-level antagonism between FGF and BMP signaling ... - NIH
Aug 17, 2023 · The BMP, Wnt and Nodal signaling ... FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak.
[46]
Evolutionary conservation of early mesoderm specification by ...
Nov 27, 2013 · Here we show that a common mechanosensitive pathway involving β-catenin specifies early mesodermal identity at gastrulation in zebrafish and Drosophila.
[47]
New insights into mesoderm and endoderm development, and the ...
Jan 25, 2024 · Our data suggest that the gene regulatory networks that underly mesoderm and endoderm development in bilaterian animals are widely conserved ...
[48]
Conservation of Brachyury, Mef2, and Snail in the Myogenic ...
One major difference between simple metazoans such as cnidarians and all the bilaterian animals is thought to involve the invention of mesoderm.
[49]
The notochord: structure and functions - PMC - PubMed Central
The notochord is an embryonic midline structure common to all members of the phylum Chordata, providing both mechanical and signaling cues to the developing ...
[50]
Notochord morphogenesis in mice: Current understanding & open ...
Feb 4, 2016 · Prechordal plate, Anterior-most mesoderm in the vertebrate embryo, located anterior to the notochord, that gives rise to various ventral ...
[51]
Embryology, Week 2-3 - StatPearls - NCBI Bookshelf
The second and third weeks of embryological development are crucial, involving the implantation of the blastocyst into the uterine wall.
[52]
Intermediate Mesoderm - Developmental Biology - NCBI Bookshelf
The metanephrogenic mesenchyme causes the ureteric bud to elongate and branch. The tips of these branches induce the loose mesenchyme cells to form epithelial ...
[53]
Paraxial Mesoderm: The Somites and Their Derivatives - NCBI - NIH
Somite formation begins as paraxial mesoderm cells become organized into whorls of cells called somitomeres. The somitomeres become compacted and bound together ...Missing: secondary | Show results with:secondary
[54]
Embryology: 3rd week of development - Kenhub
This primitive (Spemann's) streak develops as epiblast cells replicate and migrate to the midline of the bilaminar disc under the influence of nodal. Nodal is a ...
[55]
Evolution and Development of the Neural Crest: An Overview - NIH
The neural crest is an embryonic cell type that is unique to vertebrates and forms numerous, diverse derivatives.
[56]
The origin and evolution of vertebrate neural crest cells | Open Biology
Jan 29, 2020 · The neural crest is a vertebrate-specific migratory stem cell population that generates a remarkably diverse set of cell types and structures.
[57]
The Contribution of the Neural Crest to the Vertebrate Body - NCBI
The crest-derived mesenchyme, which arises from the posterior diencephalic level, is destined to populate the upper facial primordia corresponding to the naso- ...
[58]
The Neural Crest - Developmental Biology - NCBI Bookshelf
The cranial neural crest migrates into the branchial arches and the face to form the bones and cartilage of the face and neck. It also produces pigment and ...Missing: organogenesis | Show results with:organogenesis
[59]
Mechanisms of thymus organogenesis and morphogenesis - PMC
The thymus consists of cells of stromal and hematopoietic origin, and includes thymic epithelial cells (TECs), neural crest-derived mesenchymal cells, ...
[60]
Formation of the Limb Bud - Developmental Biology - NCBI Bookshelf
Limb development begins when mesenchyme cells proliferate from the somatic layer of the limb field lateral plate mesoderm (limb skeletal precursors) and from ...
[61]
The roles of FGFs in the early development of vertebrate limbs
Fgf10 is one of the genes expressed in the distal limb bud mesenchyme that may be a direct target of FGF signaling from the AER (Ohuchi et al. 1997). As ...
[62]
Human placental trophoblast invasion and differentiation - Frontiers
Throughout pregnancy, these primary villi transform into secondary and tertiary villi characterized by invasion of extraembryonic mesenchymal cells, villous ...
[63]
Human placental trophoblast invasion and differentiation - NIH
Sep 26, 2013 · Throughout pregnancy, these primary villi transform into secondary and tertiary villi characterized by invasion of extraembryonic mesenchymal ...
[64]
Kidney development: from ureteric bud formation to branching ...
Kidney development involves ureteric bud formation, invasion of metanephric mesenchyme, and branching to form the renal collecting system and nephrons.
[65]
https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2013.00190/full
[66]
Gonadal Sex Differentiation: Supporting Versus Steroidogenic Cell ...
Dec 18, 2020 · The gonad develops in close association with the mesonephric kidney and at the undifferentiated stage (sometimes called the “genital ridge”) it ...
[67]
PAX2+ Mesenchymal Origin of Gonadal Supporting Cells Is ...
Aug 27, 2021 · Recent research has shown that, in contrast to mouse, chicken gonadal supporting cells derive from a PAX2/OSR1/DMRT1/WNT4 positive mesenchymal cell population.
[68]
The Early Development of Sea Urchins - NCBI
The primary mesenchyme cells arrange themselves in a ring at a specific position along the animal-vegetal axis. At two sites near the future ventral side of the ...
[69]
Mechanisms of the epithelial-to-mesenchymal transition in sea ...
HpEts, an ets-related transcription factor implicated in primary mesenchyme cell differentiation in the sea urchin embryo. ... secondary mesenchyme cells in ...
[70]
Regulatory feedback between VEGF and ERK pathways controls tip ...
Sea urchin VEGF and ERK pathways drive skeletal elongation, but the regulatory interactions between them remain unclear. Here, we reveal positive-feedback ...
[71]
HpEts, an Ets-Related Transcription Factor Implicated in ... - PubMed
In this study we have identified a sea urchin homologue of ets 1 + 2. HpEts, which is maternally expressed ubiquitously during the cleavage stage.
[72]
Specification and differentiation processes of secondary ... - PubMed
Four types of mesoderm cells (pigment cells, blastocoelar cells, coelomic pouch cells ... cells) are derived from secondary mesenchyme cells (SMC) in sea urchinMissing: mesendoderm | Show results with:mesendoderm
[73]
The Use of Larval Sea Stars and Sea Urchins in the Discovery of ...
Jul 13, 2021 · Additionally, sea urchin and star larvae mesenchymal cells perform a variety of functions, including immune function [38,39]. While the ...
[74]
The Architecture and Evolution of the Skeletogenic Gene Regulatory ...
Unequal divisions at the third cleavage increase the number of primary mesenchyme cells in sea urchin embryos. Dev Growth Differ 40:545–53. [DOI] [PubMed] ...B). Alx1 And Ets1: Key Early... · A). Echinoderm Phylogeny · Fig. 7-. Echinoderm...
[75]
Insights from diploblasts; the evolution of mesoderm and muscle
Dec 10, 2007 · The origin of both mesoderm and muscle are central questions in metazoan evolution. The majority of metazoan phyla are triploblasts, ...
[76]
Stem cell systems and regeneration in planaria
Nov 9, 2012 · Neoblasts are abundantly present throughout the mesenchyme and divide continuously. The resulting stream of progenitors and turnover of ...
[77]
The exceptional stem cell system of Macrostomum lignano
Mar 9, 2007 · Flatworms are characterized by an outstanding stem cell system. These stem cells (neoblasts) can give rise to all cell types including germ ...
[78]
Hematopoiesis and Hematopoietic Organs in Arthropods - PMC
Mar 1, 2014 · Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and body cavity (mesothelia). In ...
[79]
Common Origin of Insect Trachea and Endocrine Organs from a ...
Jan 6, 2014 · (C) Tracheal primordia from T2 to A8 start branching at the time when the sna-rg-EGFP cells experience the epithelial-mesenchymal transition.
[80]
(PDF) Mollusca: Mesenchymata with a "coelom" - ResearchGate
The contradictory understanding of the molluscan organization, i.e., its having evolved from a mesenchymate configuration or from organisms with a ...
[81]
The coelom and the origin of the annelid body plan | Hydrobiologia
The structure of the coelomic lining ranges between a simple myoepithelium composed of epithelio-muscle cells and a non-muscular peritoneum that covers the body ...Missing: mollusks | Show results with:mollusks
[82]
Key Transcription Factors in the Differentiation of Mesenchymal ...
Recent studies have explored the integration of transcription factors, including Runx2, Sox9, PPARγ, MyoD, GATA4, and GATA6 in the differentiation of MSCs.
[83]
Neural crest stem cells: discovery, properties and potential for therapy
Jan 10, 2012 · The isolated postmigratory NCSC population differentiated into neurons, Schwann cells, and smooth muscle-like myofibroblasts in vitro; when ...
[84]
Osteogenic Programming of Human Mesenchymal Stem Cells with ...
Oct 31, 2017 · Therefore, RUNX2 activity is explicitly required to trigger the initial osteogenic gene regulatory network and direct the bone developmental ...
[85]
Sox9 Directs Hypertrophic Maturation and Blocks Osteoblast ...
Mar 13, 2012 · We show that Sox9 is required to maintain chondrocyte columnar proliferation and generate cell hypertrophy, two key features of functional growth plates.<|separator|>
[86]
The neural crest is a source of mesenchymal stem cells with ...
In this study, we investigated the developmental origin and functions of MSCs in the primordial marrow of long bones. We show that, like peripheral neural and ...
[87]
Cell signaling and transcriptional regulation of osteoblast lineage ...
Jul 2, 2024 · The initiation of osteogenesis primarily occurs as mesenchymal stem cells undergo differentiation into osteoblasts. This differentiation ...
[88]
Sonic hedgehog promotes somitic chondrogenesis by altering the ...
This work has led to an appreciation of the critical role played by the bone morphogenetic proteins (BMPs) in the formation and differentiation of cartilage.
[89]
Multilineage stem cells in the adult: A perivascular legacy? - NIH
Mesenchymal stem cells proliferate extensively in cultures of unselected, total cell isolates from multiple fetal and adult organs.
[90]
Unveiling the Differences of Secretome of Human Bone Marrow ...
Unveiling the Differences of Secretome of Human Bone Marrow Mesenchymal Stem Cells, Adipose Tissue-Derived Stem Cells, and Human Umbilical Cord Perivascular ...
[91]
Adipose-derived stem cells: Sources, potency, and implications for ...
Mesenchymal stem cells (MSCs), originally identified in bone marrow, are adult stem cells [10,11]. It has been demonstrated that MSCs can be isolated from ...
[92]
Effects of dexamethasone, ascorbic acid and β-glycerophosphate on ...
The standard procedure for the osteogenic differentiation of multipotent stem cells is treatment of a confluent monolayer with a cocktail of dexamethasone (Dex) ...Dexamethasone · Runx2-Bone Morphogenetic... · Ascorbic Acid
[93]
Dexamethasone Induces Changes in Osteogenic Differentiation of ...
The synthetic glucocorticoid dexamethasone (dex) is commonly used in vitro in trilineage differentiation protocols for mesenchymal stromal cells (MSCs).
[94]
Reciprocal epithelial-mesenchymal FGF signaling is required ... - NIH
In the developing lung, FGF9 and FGF10 form a reciprocal pair of ligands that regulate branching and budding morphogenesis. FGF10 is expressed at high levels in ...
[95]
Epithelial heparan sulfate regulates Sonic Hedgehog signaling in ...
During normal lung branching, SHH produced by epithelium signals to mesenchyme to ensure a focal Fgf10 expression pattern, epithelial HS is required for the ...
[96]
(PDF) BMP4 and FGF10 play opposing roles during lung bud ...
Aug 6, 2025 · Morphogenesis of the mouse lung involves reciprocal interactions between the epithelial endoderm and the surrounding mesenchyme, ...
[97]
Molecular Mechanisms of Early Lung Specification and Branching ...
Early lung branching morphogenesis is mediated by finely regulated, interactive growth factor signaling mechanisms that determine the automaticity of branching.<|control11|><|separator|>
[98]
Wnt signaling in lung development, regeneration, and disease ...
May 20, 2021 · More recently, epithelial Wnt ligands were shown to activate mesenchymal β-catenin, which alongside Fgf10/Fgfr2, regulate both cartilage ...Development · Submucosal Gland Biology · Disease Pathogenesis
[99]
Sonic Hedgehog Signaling in Limb Development - PMC - NIH
Feb 28, 2017 · It has been shown that Shh signaling can specify antero-posterior positional values in limb buds in both a concentration- (paracrine) and time-dependent ( ...
[100]
Notch Signaling in Vascular Development
The Notch pathway is involved in multiple aspects of vascular development, including proliferation, migration, smooth muscle differentiation, angiogenic ...Missing: vascularization | Show results with:vascularization
[101]
Canonical Notch signaling in the developing lung is required for ...
Mesenchymal cells experiencing Notch1 activation contribute predominantly to the lung vasculature. X-gal staining of N1IP::CREHI, R26R lung sections at E13.5 (A ...Missing: vascularization | Show results with:vascularization<|control11|><|separator|>
[102]
Intertwined Signaling Pathways Governing Tooth Development
Oct 29, 2021 · This review provides an integrated overview of the interplay between canonical Wnt and Shh throughout mouse tooth formation stages.
[103]
Enamel Knots as Signaling Centers Linking Tooth Morphogenesis ...
We suggest that the enamel knots are central regulators of tooth development, since they link cell differentiation to morphogenesis.Missing: disruptions agenesis
[104]
Tooth number abnormality: from bench to bedside - Nature
Jan 6, 2023 · Tooth number abnormality is one of the most common dental developmental diseases, which includes both tooth agenesis and supernumerary teeth.
[105]
The transcription factor NKX2-3 mediates p21 expression and ...
Together, our results indicate that EDA/NKX2-3 signaling is essential for enamel knot formation during tooth morphogenesis in mice. Keywords. tooth ...Reduction Of Nkx2-3... · Nkx2-3 Inhibits Cell... · Nkx2-3 Regulates Cell Cycle...
[106]
Induction and Competence - Developmental Biology - NCBI Bookshelf
Here, the mesenchyme plays an instructive ... It is easy to distinguish permissive and instructive interactions by an analogy with a more familiar situation.
[107]
Mesenchyme instructs growth while epithelium directs branching in ...
Mar 5, 2024 · ... instructive role of the mesenchyme in mammary gland branching morphogenesis. ... permissive cues that allow the mammary bud to exit ...
[108]
The Mesenchymal Factors Regulating Epithelial Morphogenesis ...
These studies have revealed that we can distinguish two types of interactions: instructive induction and permissive induction. The former is characterized by ...
[109]
Mesenchymal stem cells in treating human diseases - Nature
Aug 22, 2025 · MSCs are nonhematopoietic, multipotent stem cells that can differentiate into various mesodermal lineages and modulate the immune system. The ...
[110]
Minimal criteria for defining multipotent mesenchymal stromal cells ...
First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, ...Missing: DMEM FBS 2017
[111]
Minimal criteria for defining multipotent mesenchymal stromal cells ...
First, MSC must be plastic-adherent when maintained in standard culture conditions. Second, MSC must express CD105, CD73 and CD90, and lack expression of CD45, ...
[112]
Validated methods for isolation and qualification of mesenchymal ...
Sep 2, 2025 · Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24(5):1294–301 ...
[113]
Culturing Human Mesenchymal Stem Cells (MSCs) under Serum ...
Mar 17, 2014 · Human bone marrow–derived MSCs expanded in (A) DMEM (low glucose) + 10% MSC-Qualified FBS, or (B) StemPro MSC SFM XenoFree + CTS™ CELLstart™ ...Introduction · Preparing Media and Materials · Subculturing MSCs
[114]
Therapeutic Use of Mesenchymal Stromal Cells: The Need for ...
In 2019, ISCT updated their MSC definition to suggest (1) including the tissue origin of cells, (2) use of stromal cell nomenclature unless rigorous evidence ...
[115]
Immunomodulatory Properties of Mesenchymal Stromal Cells - NIH
Mesenchymal stromal cells (MSCs) are characterized by an extraordinary capacity to modulate the phenotype and functional properties of various immune cells.
[116]
Immunomodulatory potential of mesenchymal stem cell role in ...
However, MSCs also directly inhibit DC maturation and the proliferation of T and B cells through the secretion of PGE2 and IDO. ... suppress antigen-specific T ...
[117]
Immunomodulatory properties of mesenchymal stromal cells | Blood
Mesenchymal stem cells (MSCs) are multipotential nonhematopoietic progenitor cells capable of differentiating into multiple lineages of the mesenchyme.
[118]
SDF-1 mediates mesenchymal stem cell recruitment and migration ...
Aug 10, 2025 · Notably, stromal-derived factor 1 (SDF-1), exclusively detected in EnSC-derived exosomes, mediates MSC recruitment and tissue repair via the SDF ...
[119]
Temporal and spatial cooperation of Snail1 and Twist1 ... - PubMed
Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence · Abstract.
[120]
Shared and Context-Specific Mechanisms of EMT and Cellular ...
Sep 27, 2025 · Originally described in embryogenesis, EMT is now recognized as a key driver in both tumor progression and fibrotic remodeling. In cancer, EMT ...
[121]
Calpain 9 as a therapeutic target in TGFβ-induced mesenchymal ...
Jul 17, 2019 · Although the progenitor cell types and cellular programs giving rise to myofibroblasts through mesenchymal transition can vary between tissues ...
[122]
Targeting fibrosis: mechanisms and clinical trials - Nature
Jun 30, 2022 · Paracrine signalling during ZEB1-mediated epithelial-mesenchymal transition augments local myofibroblast differentiation in lung fibrosis.
[123]
Osteosarcomas and Ewing's sarcomas. Comparative ... - PubMed
Osteosarcomas were positive for vimentin and, in part, for HLA-DR. Other types of intermediate-sized filaments were not detected in tumour cells. In a small ...
[124]
Inactivation of TGFβ signaling in neural crest stem cells leads ... - NIH
DiGeorge syndrome is the most common microdeletion syndrome in humans, characterized by cardiovascular defects plus thymic, parathyroid, and craniofacial ...
[125]
Tcof1/Treacle is required for neural crest cell formation and ... - PNAS
Sep 5, 2006 · Treacher Collins syndrome (TCS) is characterized by hypoplasia of the facial bones, cleft palate, and middle and external ear defects.