scholarly journals Rab35 regulates cadherin-mediated adherens junction formation and myoblast fusion

2013 ◽  
Vol 24 (3) ◽  
pp. 234-245 ◽  
Author(s):  
Sophie Charrasse ◽  
Franck Comunale ◽  
Sylvain De Rossi ◽  
Arnaud Echard ◽  
Cécile Gauthier-Rouvière
Keyword(s):  
Adherens Junction ◽  
Phosphatidyl Inositol ◽  
Myoblast Fusion ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Cell Contact ◽  
Dependent Manner ◽  
Cell Contacts ◽  
Contact Sites ◽  
Cell Cell

Cadherins are homophilic cell–cell adhesion molecules implicated in many fundamental processes, such as morphogenesis, cell growth, and differentiation. They accumulate at cell–cell contact sites and assemble into large macromolecular complexes named adherens junctions (AJs). Cadherin targeting and function are regulated by various cellular processes, many players of which remain to be uncovered. Here we identify the small GTPase Rab35 as a new regulator of cadherin trafficking and stabilization at cell–cell contacts in C2C12 myoblasts and HeLa cells. We find that Rab35 accumulates at cell–cell contacts in a cadherin-dependent manner. Knockdown of Rab35 or expression of a dominant-negative form of Rab35 impaired N- and M-cadherin recruitment to cell–cell contacts, their stabilization at the plasma membrane, and association with p120 catenin and led to their accumulation in transferrin-, clathrin-, and AP-2–positive intracellular vesicles. We also find that Rab35 function is required for PIP5KIγ accumulation at cell–cell contacts and phosphatidyl inositol 4,5-bisphosphate production, which is involved in cadherin stabilization at contact sites. Finally, we show that Rab35 regulates myoblast fusion, a major cellular process under the control of cadherin-dependent signaling. Taken together, these results reveal that Rab35 regulates cadherin-dependent AJ formation and myoblast fusion.

scholarly journals MAGI-1 Is Required for Rap1 Activation upon Cell-Cell Contact and for Enhancement of Vascular Endothelial Cadherin-mediated Cell Adhesion

2006 ◽  
Vol 17 (2) ◽  
pp. 966-976 ◽  
Author(s):  
Atsuko Sakurai ◽  
Shigetomo Fukuhara ◽  
Akiko Yamagishi ◽  
Keisuke Sako ◽  
Yuji Kamioka ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Adherens Junction ◽  
Small Gtpase ◽  
Cell Contact ◽  
Vascular Endothelial ◽  
Nucleotide Exchange ◽  
Cell Contacts ◽  
Vascular Endothelial Cadherin ◽  
Rap1 Activation ◽  
Cell Cell

Rap1 is a small GTPase that regulates adherens junction maturation. It remains elusive how Rap1 is activated upon cell-cell contact. We demonstrate for the first time that Rap1 is activated upon homophilic engagement of vascular endothelial cadherin (VE-cadherin) at the cell-cell contacts in living cells and that MAGI-1 is required for VE-cadherin-dependent Rap1 activation. We found that MAGI-1 localized to cell-cell contacts presumably by associating with β-catenin and that MAGI-1 bound to a guanine nucleotide exchange factor for Rap1, PDZ-GEF1. Depletion of MAGI-1 suppressed the cell-cell contact-induced Rap1 activation and the VE-cadherin-mediated cell-cell adhesion after Ca2+ switch. In addition, relocation of vinculin from cell-extracellular matrix contacts to cell-cell contacts after the Ca2+ switch was inhibited in MAGI-1-depleted cells. Furthermore, inactivation of Rap1 by overexpression of Rap1GAPII impaired the VE-cadherin-dependent cell adhesion. Collectively, MAGI-1 is important for VE-cadherin-dependent Rap1 activation upon cell-cell contact. In addition, once activated, Rap1 upon cell-cell contacts positively regulate the adherens junction formation by relocating vinculin that supports VE-cadherin-based cell adhesion.

scholarly journals Different effects of dominant negative mutants of desmocollin and desmoglein on the cell-cell adhesion of keratinocytes

2000 ◽  
Vol 113 (10) ◽  
pp. 1803-1811
Author(s):  
Y. Hanakawa ◽  
M. Amagai ◽  
Y. Shirakata ◽  
K. Sayama ◽  
K. Hashimoto
Keyword(s):  
Cell Adhesion ◽  
Adherens Junctions ◽  
Dominant Negative ◽  
Cell Contact ◽  
Beta Catenin ◽  
Hacat Cells ◽  
Subsequent Formation ◽  
Contact Sites ◽  
E Cadherin ◽  
Cell Cell

Desmosomes contain two types of cadherin: desmocollin (Dsc) and desmoglein (Dsg). In this study, we examined the different roles that Dsc and Dsg play in the formation of desmosomes, by using dominant-negative mutants. We constructed recombinant adenoviruses (Ad) containing truncated mutants of E-cadherin, desmocollin 3a, and desmoglein 3 lacking a large part of their extracellular domains (EcaddeltaEC, Dsc3adeltaEC, Dsg3deltaEC), using the Cre-loxP Ad system to circumvent the problem of the toxicity of the mutants to virus-producing cells. When Dsc3adeltaEC Ad-infected HaCaT cells were cultured with high levels of calcium, E-cadherin and beta-catenin, which are marker molecules for the adherens junction, disappeared from the cell-cell contact sites, and cell-cell adhesion was disrupted. This also occurred in the cells infected with EcaddeltaEC Ad. With Dsg3deltaEC Ad infection, keratin insertion at the cell-cell contact sites was inhibited and desmoplakin, a marker of desmosomes, was stained in perinuclear dots while the adherens junctions remained intact. Dsc3adeltaEC Ad inhibited the induction of adherens junctions and the subsequent formation of desmosomes with the calcium shift, while Dsg3deltaEC Ad only inhibited the formation of desmosomes. To further determine whether Dsc3adeltaEC directly affected adherens junctions, mouse fibroblast L cells transfected with E-cadherin (LEC5) were infected with these mutant Ads. Both Dsc3adeltaEC and EcaddeltaEC inhibited the cell-cell adhesion of LEC5 cells, as determined by the cell aggregation assay, while Dsg3deltaEC did not. These results indicate that the dominant negative effects of Dsg3deltaEC were restricted to desmosomes, while those of Dsc3adeltaEC were observed in both desmosomes and adherens junctions. Furthermore, the cytoplasmic domain of Dsc3adeltaEC coprecipitated both plakoglobin and beta-catenin in HaCaT cells. In addition, beta-catenin was found to bind the endogenous Dsc in HaCaT cells. These findings lead us to speculate that Dsc interacts with components of the adherens junctions through beta-catenin, and plays a role in nucleating desmosomes after the adherens junctions have been established.

N-cadherin in adult rat cardiomyocytes in culture. I. Functional role of N-cadherin and impairment of cell-cell contact by a truncated N-cadherin mutant

1996 ◽  
Vol 109 (1) ◽  
pp. 1-10 ◽  
Author(s):  
C.M. Hertig ◽  
M. Eppenberger-Eberhardt ◽  
S. Koch ◽  
H.M. Eppenberger
Keyword(s):  
Ectopic Expression ◽  
Extracellular Domain ◽  
Large Deletion ◽  
Binding Domain ◽  
Dominant Negative ◽  
Cell Contact ◽  
Rat Cardiomyocytes ◽  
Cell Contacts ◽  
Adult Rat ◽  
Cell Cell

N-cadherin is a transmembrane Ca(2+)-dependent glycoprotein that is part of adherens junctions. It functions with the cell adhesion N-terminal extracellular domain as a site of homophilic cell-cell contacts. The intracellular C-terminal domain provides via a catenin complex the interaction with the cytoskeleton. Ectopic expression of chicken N-cadherin in adult rat cardiomyocytes (ARC) in culture was obtained after microinjection into non-dividing cardiomyocytes; it was demonstrated that the exogenous protein colocalized with the endogenous N-cadherin at the plasma membrane of the cell and formed contact sites. A dominant negative chicken N-cadherin mutant was constructed by a large deletion of the extracellular domain. This mutant was expressed and inhibited the function of the endogenous rat N-cadherin probably by competing for the catenin complex binding domain, which is essential for the formation of a stable cell-cell contact of ARC. The injected cells lost contact with neighbouring cells and retracted; the connexons of the gap junctions were pulled out as well. This could be avoided by another N-cadherin mutation, which, in addition to the N-terminal truncation, contained a deletion of the catenin binding domain. In the case of the truncated N-cadherin at the N terminus, the sarcomeric structure of the myofibrils of ARC was also affected. Myofibrils were the most vulnerable cytoskeletal structures affected by the overexpressed dominant negative N-cadherin mutation. Similar behaviour was shown when cardiomyocytes separated following Ca2+ depletion and when new cell-cell contacts were formed after Ca2+ replenishment. N-cadherin is thought to be the essential component for establishing new cell-cell contacts which eventually led to a new formation of intercalated disc-like structures in the cardiac cell culture.

scholarly journals The Ras Target AF-6 Interacts with ZO-1 and Serves as a Peripheral Component of Tight Junctions in Epithelial Cells

1997 ◽  
Vol 139 (3) ◽  
pp. 785-795 ◽  
Author(s):  
Takaharu Yamamoto ◽  
Naozumi Harada ◽  
Kyoko Kano ◽  
Shin-ichiro Taya ◽  
Eli Canaani ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tight Junctions ◽  
Adherens Junctions ◽  
Pdz Domain ◽  
Cell Junctions ◽  
Cell Contact ◽  
Fusion Partner ◽  
Cell Contacts ◽  
Contact Sites ◽  
Cell Cell

The dynamic rearrangement of cell–cell junctions such as tight junctions and adherens junctions is a critical step in various cellular processes, including establishment of epithelial cell polarity and developmental patterning. Tight junctions are mediated by molecules such as occludin and its associated ZO-1 and ZO-2, and adherens junctions are mediated by adhesion molecules such as cadherin and its associated catenins. The transformation of epithelial cells by activated Ras results in the perturbation of cell–cell contacts. We previously identified the ALL-1 fusion partner from chromosome 6 (AF-6) as a Ras target. AF-6 has the PDZ domain, which is thought to localize AF-6 at the specialized sites of plasma membranes such as cell–cell contact sites. We investigated roles of Ras and AF-6 in the regulation of cell–cell contacts and found that AF-6 accumulated at the cell–cell contact sites of polarized MDCKII epithelial cells and had a distribution similar to that of ZO-1 but somewhat different from those of catenins. Immunoelectron microscopy revealed a close association between AF-6 and ZO-1 at the tight junctions of MDCKII cells. Native and recombinant AF-6 interacted with ZO-1 in vitro. ZO-1 interacted with the Ras-binding domain of AF-6, and this interaction was inhibited by activated Ras. AF-6 accumulated with ZO-1 at the cell–cell contact sites in cells lacking tight junctions such as Rat1 fibroblasts and PC12 rat pheochromocytoma cells. The overexpression of activated Ras in Rat1 cells resulted in the perturbation of cell–cell contacts, followed by a decrease of the accumulation of AF-6 and ZO-1 at the cell surface. These results indicate that AF-6 serves as one of the peripheral components of tight junctions in epithelial cells and cell–cell adhesions in nonepithelial cells, and that AF-6 may participate in the regulation of cell–cell contacts, including tight junctions, via direct interaction with ZO-1 downstream of Ras.

scholarly journals Distribution and lateral mobility of the urokinase-receptor complex at the cell surface.

1993 ◽  
Vol 41 (9) ◽  
pp. 1291-1301 ◽  
Author(s):  
H T Myöhänen ◽  
R W Stephens ◽  
K Hedman ◽  
H Tapiovaara ◽  
E Rønne ◽  
...  
Keyword(s):  
Human Fibroblasts ◽  
Focal Adhesions ◽  
Cell Contact ◽  
Lateral Mobility ◽  
Cell Contacts ◽  
Contact Sites ◽  
The Matrix ◽  
Rd Cells ◽  
Alpha V Beta 3 ◽  
Cell Cell

Pro-urokinase (pro-uPA) and activated uPA are confined to focal adhesions and cell-cell contacts. We studied the distribution of the uPA receptor (uPAR) on human fibroblasts (HES) and rhabdomyosarcoma (RD) cells by immunofluorescence and immunoelectron microscopy. Two monoclonal antibodies (MAb) utilized were against uPAR: MAb R4, which reacts with occupied and unoccupied uPAR, was concentrated at focal adhesions; MAb R3 reacting with unoccupied receptor stained cell surfaces diffusely. MAb R4 stained cell-cell contacts, tips of microspikes, and co-localized with vinculin. Of the matrix and integrin components tested, alpha v beta 3 integrin was found at focal adhesions but more centrally than uPAR. Since uPAR is anchored to the plasma membrane through a GPI lipid, we studied its mobility by antibody-induced clustering. This revealed that unoccupied uPAR was relatively mobile; MAb R3 redistributed it to clusters. In contrast, uPAR R4 and uPA antibodies at the focal contact sites remained mostly within focal contacts. Addition of exogenous uPA resulted in loss of R3 staining and increase of uPA in focal adhesions. These results suggest that occupancy of the receptor with uPA is associated with localization to cell contact sites and restricted lateral mobility.

scholarly journals The costs of close contacts: Visualizing the energy landscape of cell contacts at the nanoscale

2019 ◽  
Author(s):  
K. Kulenkampff ◽  
A. H. Lippert ◽  
J. McColl ◽  
A. M. Santos ◽  
A. Ponjavic ◽  
...  
Keyword(s):  
T Cell ◽  
Energy Landscape ◽  
Small Scale ◽  
Cell Contact ◽  
Dependent Manner ◽  
Adhesion Protein ◽  
Cell Contacts ◽  
Size Dependent ◽  
Protein Density ◽  
Cell Cell

AbstractCell-cell contact often underpins signalling between cells. Contact is mediated by proteins on both cells creating interfaces with gap sizes typically around 14 nm. Protein binding and accumulation leads to the contact becoming crowded, reducing the rate of protein diffusion, even for unbound proteins. Here we show that, by tracking quantum dots of different dimensions for extended periods of time, it is possible to obtain the probability of a molecule entering the contact, the change in its diffusion upon entry and the impact of spatial heterogeneity of adhesion protein density in the contact. By analysing the contacts formed by a T cell interacting with adhesion proteins anchored to a supported lipid bilayer, we find that probes are excluded from contact entry in a size-dependent manner for gap-to-probe differences of 4.1 nm. We also observe probes being trapped inside the contact and a decrease in diffusion of up to 85% in dense adhesion protein contacts. This approach provides new insights into the nature of cell-cell contacts, revealing that cell contacts are highly heterogeneous, due to topography- and protein density-related processes. These effects are likely to profoundly influence signalling between cells.Statement of SignificanceThe spatial distribution and diffusion of proteins has been shown to be important for various signalling machineries. As such size-dependent reorganisation of proteins in the immune cell-contact has been shown to affect activation of immune cells. While these studies relied on bulk measurements to investigate protein exclusion, small scale topographical changes and protein dynamics could not be evaluated. However, recent studies show that T cell activation is mediated by nanoscale structures. In our study the use molecular probes of various sizes to investigate the energy landscape of single molecules in a cell contact. This provides additional information and insights which cannot be determined by performing bulk experiments alone indicates.

Phosphatidylinositol 3-kinase mediates integrin-dependent NF-(κ)B and MAPK activation through separate signaling pathways

2001 ◽  
Vol 114 (8) ◽  
pp. 1579-1589 ◽  
Author(s):  
M. Reyes-Reyes ◽  
N. Mora ◽  
A. Zentella ◽  
C. Rosales
Keyword(s):  
Signaling Pathways ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Small Gtpase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Dependent Manner ◽  
Monocytic Leukemia ◽  
Monocytic Cells ◽  
Mapk Activation

Integrin-mediated signals play an important but poorly understood role in regulating many leukocyte functions. In monocytes and monocytic leukemia cells, (β)1 integrin-mediated adhesion results in a strong induction of immediate-early genes that are important in inflammation. To investigate the signaling pathways from integrins in monocytic cells, THP-1 cells were stimulated via (β)1 integrins by binding to fibronectin and by crosslinking the integrins with specific monoclonal antibodies. The involvement of MAPK and PI 3-K on nuclear factor (κ)B (NF-(κ)B) activation was then analyzed. We found that integrins activated both NF-(κ)B and MAPK in a PI 3-K-dependent manner, as wortmannin and LY294002 blocked these responses. However, the specific MEK inhibitor PD98059 did not prevent integrin-mediated NF-(κ)B activation. In contrast, a dominant negative mutant of Rac completely prevented NF-(κ)B activation, but it did not affect MAPK activation. These results indicate that integrin signaling to NF-(κ)B is not mediated by the MAPK pathway, but rather by the small GTPase Rac. In addition, a dominant negative form of Ρ augmented NF-(κ)B activation and blocked MAPK activation, implying that these two pathways are in competition with each other. These data suggest that integrins activate different signaling pathways in monocytic cells. One uses PI 3-K and Rac to activate NF-(κ)B, while the other uses PI 3-K, MEK, and MAPK to activate other nuclear factors, such as Elk-1.

scholarly journals The proportion of periportal mesenchyme to ductal epithelial cells acts as a proliferative rheostat in liver regeneration

2020 ◽  
Author(s):  
Lucía Cordero-Espinoza ◽  
Timo N. Kohler ◽  
Anna M. Dowbaj ◽  
Bernhard Strauss ◽  
Olga Sarlidou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tissue Injury ◽  
Portal Tract ◽  
Mesenchymal Cells ◽  
Dependent Manner ◽  
Cell Contacts ◽  
Ductal Cells ◽  
Ductal Cell ◽  
Cell Cell

AbstractIn the homeostatic liver, ductal cells intermingle with a microenvironment of endothelial and mesenchymal cells to form the functional unit of the portal tract. Ductal cells proliferate rarely in homeostasis but do so transiently after tissue injury to replenish any lost epithelium. We have shown that liver ductal cells can be expanded as liver organoids that recapitulate several of the cell-autonomous mechanisms of regeneration, but lack the stromal cell milieu of the biliary tract in vivo. Here, we describe a subpopulation of SCA1+ periportal mesenchymal cells that closely surrounds ductal cells in vivo and exerts a dual control on their proliferative capacity. Mesenchymal-secreted mitogens support liver organoid formation and expansion from differentiated ductal cells. However, direct mesenchymal-to-ductal cell-cell contact, established following a microfluidic co-encapsulation that enables the cells to self-organize into chimeric organoid structures, abolishes ductal cell proliferation in a mesenchyme-dose dependent manner. We found that it is the ratio between mesenchymal and epithelial cell contacts that determines the net outcome of ductal cell proliferation both in vitro, and in vivo, during damage-regeneration. SCA1+ mesenchymal cells control ductal cell proliferation dynamics by a mechanism involving, at least in part, Notch signalling activation. Our findings underscore how the relative abundance of cell-cell contacts between the epithelium and its mesenchymal microenvironment are key regulatory cues involved in the control of tissue regeneration.SummaryIn the homeostatic liver, the ductal epithelium intermingles with a microenvironment of stromal cells to form the functional unit of the portal tract. Ductal cells proliferate rarely in homeostasis but do so transiently after tissue injury. We have shown that these cells can be expanded as liver organoids that recapitulate several of the cell-autonomous mechanisms of regeneration, but lack the stromal cell milieu of the portal tract in vivo. Here, we describe a subpopulation of SCA1+ periportal mesenchymal niche cells that closely surrounds ductal cells in vivo and exerts a dual control on their proliferative capacity. Mesenchymal-secreted mitogens support liver organoid formation and expansion from differentiated ductal cells. However, direct mesenchymal-to-ductal cell-cell contact, established through a microfluidic co-encapsulation method that enables the cells to self-organize into chimeric organoid structures, abolishes ductal cell proliferation in a mesenchyme-dose dependent manner. We found that it is the ratio between mesenchymal and epithelial cell contacts that determines the net outcome of ductal cell proliferation both in vitro, and in vivo, during damage-regeneration. SCA1+ mesenchymal cells control ductal cell proliferation dynamics by a mechanism involving, at least in part, Notch signalling activation. Our findings re-evaluate the concept of the cellular niche, whereby the proportions of cell-cell contacts between the epithelium and its mesenchymal niche, and not the absolute cell numbers, are the key regulatory cues involved in the control of tissue regeneration.

N-cadherin in adult rat cardiomyocytes in culture. II. Spatio-temporal appearance of proteins involved in cell-cell contact and communication. Formation of two distinct N-cadherin/catenin complexes

1996 ◽  
Vol 109 (1) ◽  
pp. 11-20 ◽  
Author(s):  
C.M. Hertig ◽  
S. Butz ◽  
S. Koch ◽  
M. Eppenberger-Eberhardt ◽  
R. Kemler ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Gap Junctions ◽  
Connexin 43 ◽  
Cell Contact ◽  
Beta Catenin ◽  
Rat Cardiomyocytes ◽  
Cell Contacts ◽  
Adult Rat ◽  
Spatio Temporal ◽  
Cell Cell

The spatio-temporal appearance and distribution of proteins forming the intercalated disc were investigated in adult rat cardiomyocytes (ARC). The ‘redifferentiation model’ of ARC involves extensive remodelling of the plasma membrane and of the myofibrillar apparatus. It represents a valuable system to elucidate the formation of cell-cell contact between cardiomyocytes and to assess the mechanisms by which different proteins involved in the cell-cell adhesion process are sorted in a precise manner to the sites of function. Appearance of N-cadherin, the catenins and connexin43 within newly formed adherens and gap junctions was studied. Here first evidence is provided for a formation of two distinct and separable N-cadherin/catenin complexes in cardiomyocytes. Both complexes are composed of N-cadherin and alpha-catenin which bind to either beta-catenin or plakoglobin in a mutually exclusive manner. The two N-cadherin/catenin complexes are assumed to be functionally involved in the formation of cell-cell contacts in ARC; however, the differential appearance and localization of the two types of complexes may also point to a specific role during ARC differentiation. The newly synthesized beta-catenin containing complex is more abundant during the first stages in culture after ARC isolation, while the newly synthesized plakoglobin containing complex progressively accumulates during the morphological changes of ARC. ARC formed a tissue-like pattern in culture whereby the new cell-cell contacts could be dissolved through Ca2+ depletion. Presence of cAMP and replenishment of Ca2+ content in the culture medium not only allowed reformation of cell-cell contacts but also affected the relative protein ratio between the two N-cadherin/catenin complexes, increasing the relative amount of newly synthesized beta-catenin over plakoglobin at a particular stage of ARC differentiation. The clustered N-cadherin/catenin complexes at the plasma membrane appear to be a prerequisite for the following gap junction formation; a temporal sequence of the appearance of adherens junction proteins and of gap junctions forming connexin-43 is suggested.

The localized assembly of extracellular matrix integrin ligands requires cell-cell contact

2000 ◽  
Vol 113 (21) ◽  
pp. 3715-3723 ◽  
Author(s):  
M.D. Martin-Bermudo ◽  
N.H. Brown
Keyword(s):  
Extracellular Matrix ◽  
Drosophila Embryo ◽  
Cell Contact ◽  
Primary Role ◽  
Dependent Manner ◽  
Muscle Attachment ◽  
Matrix Assembly ◽  
Attachment Sites ◽  
Genetically Manipulated ◽  
Cell Cell

The assembly of an organism requires the interaction between different layers of cells, in many cases via an extracellular matrix. In the developing Drosophila larva, muscles attach in an integrin-dependent manner to the epidermis, via a specialized extracellular matrix called tendon matrix. Tiggrin, a tendon matrix integrin ligand, is primarily synthesized by cells distant to the muscle attachment sites, yet it accumulates specifically at these sites. Previous work has shown that the PS integrins are not required for tiggrin localization, suggesting that there is redundancy among tiggrin receptors. We have examined this by testing whether the PS2 integrin can recruit tiggrin to ectopic locations within the Drosophila embryo. We found that neither the wild type nor modified forms of the PS2 integrin, which have higher affinity for tiggrin, can recruit tiggrin to new cellular contexts. Next, we genetically manipulated the fate of the muscles and the epidermal muscle attachment cells, which demonstrated that muscles have the primary role in recruiting tiggrin to the tendon matrix and that cell-cell contact is necessary for this recruitment. Thus we propose that the inherent polarity of the muscle cells leads to a molecular specialization of their ends, and interactions between the ends produces an integrin-independent tiggrin receptor. Thus, interaction between cells generates an extracellular environment capable of nucleating extracellular matrix assembly.

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