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First published online January 23, 2008
doi: 10.1242/10.1242/jcs.006064

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Extracellular matrix dynamics in development and regenerative medicine

¹ Department of Biological Sciences, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA
² Graduate Program in Molecular, Cellular, Developmental, and Neural Biology, University at Albany, State University of New York, 1400 Washington Avenue, Albany, NY 12222, USA

View larger version (54K): [in this window] [in a new window]   Fig. 1. ECM-mediated effects on matrix remodeling. The 3D matrix environment stimulates integrin-mediated FN assembly through inhibiting a Raf1-mediated signaling pathway. Activation of integrin 5β1 by uPAR and its P25 ligand also stimulates FN assembly in combination with EGFR via a Src-kinase-mediated pathway. Activation of PTEN by 3D collagen contraction converts a FAK/PI3K-mediated survival signal into a pro-apoptotic signal. Activation of RhoA, presumably ECM-mediated, leads to assembly of a myosin II ring that facilitates FN unfolding during FN fibrillogenesis. SPARC stimulates FN unfolding and assembly using an ILK-dependent pathway.

View larger version (59K): [in this window] [in a new window]   Fig. 2. ECM remodeling by proteolytic degradation. Cathepsins associated with membrane microdomains can degrade ECM proteins such as collagen, FN and laminin. Pro-uPA and uPAR, in complex with uPARAP, mediate the endocytosis of extracellular collagen. Such collagen is then degraded by cathepsins in intracellular vesicles. TGFβ1 signaling triggers transcriptional changes, including the upregulation of procathepsin B, which then participates in further ECM remodeling. Cathepsins also activate pro-uPA, setting off a uPA-mediated cascade of proteolytic cleavage that results in the activation of plasmin, fibrin and pro-MMPs.

View larger version (106K): [in this window] [in a new window]   Fig. 3. Live imaging of FN remodeling during salivary gland branching morphogenesis. A live embryonic mouse salivary gland epithelial rudiment was incubated with media containing labeled soluble FN (green), washed and subsequently labeled via incubation with media containing red-labeled FN. Assembled (green) FN accumulates in clefts, whereas newer (red) FN is incorporated distal to the cleft. Scale bar: 100 µm. Adapted from Larsen et al. (Larsen et al., 2006).

View larger version (56K): [in this window] [in a new window]   Fig. 4. ECM-mediated effects on stem cells within the bone marrow stem cell niche. The ECM regulates stem cell attachment and quiescence via integrins and HSPs. Osteopontin participates in regulating quiescence by interacting with integrins and CD44. Notch-jagged and KitL-Kit signaling also maintain quiescence. MMP cleaves the transmembrane form of KitL to create sKitL, which interacts with Kit as a dimer to activate HSCs. Integrins participate in the mobilization of progenitor cells.

View larger version (63K): [in this window] [in a new window]   Fig. 5. Cells growing on engineered scaffolds. (a,b) Scanning electron microscopy (SEM) images of mouse fibroblasts grown on PLGA nanofibers for 7 days, as described previously (Li et al., 2002). Images are displayed at: (a) original magnification x1500 and (b) original magnification x2500. Scale bar: 10 µm. Images printed with permission from Li et al. (Li et al., 2002). (c) Side view of rabbit corneal epithelial cells immunostained with an anti-cornea-specific cytokeratin K3/12 (clone AE5, green) grown on a vitrified collagen `vitrigel' sheet (light green). Scale bar: 50 µm. Image courtesy of Winnette McIntosh Ambrose, Toshiaki Takezawa and Jennifer H. Elisseeff.