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Integrin organization: linking adhesion ligand nanopatterns with altered cell responses.

ABSTRACT: Integrin receptors bind to adhesion ligand (e.g. arginine-glycine-aspartic acid or RGD containing peptides) on extracellular matrix and organize into high-density complexes which mediate many cell behaviors. Biomaterials with RGD nanopatterned into multivalent "islands" (?30-70 nm diameter) have been shown to alter cell responses, although the length scale of pattern features is orders of magnitude smaller than adhesion complexes. In this work, we employ together for the first time an extensive data set on osteoblast responses as a function of ligand nanopatterns, a computational model of integrin binding to ligand nanopatterns, and new measures of integrin organization on the cell surface. We quantify, at multiple length scales, integrin organization generated in silico as a function of RGD nanopattern parameters. We develop a correlative model relating these measures of in silico integrin organization and in vitro MC3T3 preosteoblast cell responses as functions of the same RGD nanopatterns: cell spreading correlates with the number of bound integrins, focal adhesion kinase (FAK) phosphorylation correlates with small, homogeneously distributed clusters of integrins, and osteogenic differentiation correlates with large, heterogeneously distributed integrin clusters. These findings highlight the significance of engineering biomaterials at the nanolevel and suggest new approaches to understanding the mechanisms linking integrin organization to cell responses.

SUBMITTER: Comisar WA

PROVIDER: S-EPMC3056075 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Integrin organization: linking adhesion ligand nanopatterns with altered cell responses.

Comisar W A WA Mooney D J DJ Linderman J J JJ

Journal of theoretical biology 20110119 1

Integrin receptors bind to adhesion ligand (e.g. arginine-glycine-aspartic acid or RGD containing peptides) on extracellular matrix and organize into high-density complexes which mediate many cell behaviors. Biomaterials with RGD nanopatterned into multivalent "islands" (∼30-70 nm diameter) have been shown to alter cell responses, although the length scale of pattern features is orders of magnitude smaller than adhesion complexes. In this work, we employ together for the first time an extensive ...[more]

PMID: 21255586

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Project description:Cell adhesion to extracellular matrices (ECM) is critical to physiological and pathological processes as well as biomedical and biotechnological applications. It has been known that a cell can adhere on an adhesive microisland only over a critical size. But no publication has concerned critical adhesion areas of cells on microislands with nanoarray decoration. Herein, we fabricated a series of micro-nanopatterns with different microisland sizes and arginine-glycine-aspartate (RGD) nanospacings on a nonfouling poly(ethylene glycol) background. Besides reproducing that nanospacing of RGD, a ligand of its receptor integrin (a membrane protein), significantly influences specific cell adhesion on bioactive nanoarrays, we confirmed that the concept of critical adhesion area originally suggested in studies of cells on micropatterns was justified also on the micro-nanopatterns, yet the latter exhibited more characteristic behaviors of cell adhesion. We found increased critical adhesion areas of human mesenchymal stem cells (hMSCs) on nanoarrayed microislands with increased RGD nanospacings. However, the numbers of nanodots with respect to the critical adhesion areas were not a constant. A unified interpretation was then put forward after combining nonspecific background adhesion and specific cell adhesion. We further carried out the asymptotic analysis of a series of micro-nanopatterned surfaces to obtain the effective RGD nanospacing on unpatterned free surfaces with densely grafted RGD, which could be estimated nonzero but has never been revealed previously without the assistance of the micro-nanopatterning techniques and the corresponding analysis.Electronic supplementary materialSupplementary materials and methods (details of fabrication of micro-nanopatterns), and supplementary results (selective adhesion or localization of hMSCs on nanoarrayed microislands with non-fouling background, calculation of critical number of integrin-ligand binding N*, etc.) are available in the online version of this article at 10.1007/s12274-021-3711-6.

Project description:Adhesive and migratory behavior can be cell type, integrin, and substrate dependent. We have compared integrin and substrate differences using three integrin receptors: ?5?1, ?6?1, and ?L?2 expressed in a common cell type, CHO.B2 cells, which lack integrin ? subunits, as well as in different cell types that express one or more of these integrins. We find that CHO.B2 cells expressing either ?6?1 or ?L?2 integrins migrate and protrude faster and are more directionally persistent on laminin or ICAM-1, respectively, than CHO.B2 cells expressing ?5?1 on fibronectin. Despite rapid adhesion maturation and the presence of large adhesions in both the ?6?1- and ?L?2-expressing cells, they display robust tyrosine phosphorylation. In addition, whereas myosin II regulates adhesion maturation and turnover, protrusion rates, and polarity in cells migrating on fibronectin, surprisingly, it does not have comparable effects in cells expressing ?6?1 or ?L?2. This apparent difference in the integration of myosin II activity, adhesion, and migration arises from alterations in the ligand-integrin-actin linkage (molecular clutch). The elongated adhesions in the protrusions of the ?6?1-expressing cells on laminin or the ?L?2-expressing cells on ICAM-1 display a novel, rapid retrograde flux of integrin; this was largely absent in the large adhesions in protrusions of ?5?1-expressing cells on fibronectin. Furthermore, the force these adhesions exert on the substrate in protrusive regions is reduced compared to similar regions in ?5-expressing cells, and the adhesion strength is reduced. This suggests that intracellular forces are not efficiently transferred from actomyosin to the substratum due to altered adhesion strength, that is, avidity, affinity, or the ligand-integrin-actin interaction. Finally, we show that the migration of fast migrating leukocytes on fibronectin or ICAM-1 is also largely independent of myosin II; however, their adhesions are small and do not show retrograde fluxing suggesting other intrinsic factors determine their migration differences.

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Integrin organization: linking adhesion ligand nanopatterns with altered cell responses.

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Integrin organization: linking adhesion ligand nanopatterns with altered cell responses.

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