Selective Cell Attachment to a Biomimetic Polymer Surface Through the Recognition of Cell Surface Tags

Synthetic polymers capable of selectively recognizing proteins or cells play important roles in cell separation, biosensors, and the development of biomedical materials (Ratner 1993, 1996). In general, few synthetic poly mers can recognize a specific biomolecule or cell in vivo because of the complexity of the environment. In a living cell, carbohydrates on the cell surface contribute to most of the communications between the cell and its environment (Dwek 1996). Therefore, it might be possible to control cell functions with polymers, which can affect carbohydrate interactions with a cell surface. Tagging of carbohydrates on the cell membrane, as well as the polymer design, might be effective for the recognition of a specific cell.

The incorporation of unnatural carbohydrates into living cells provides an opportunity to study the specific contributions of sialic acid and its N-acyl side chains to sialic acid-dependent ligand-receptor interactions at a submolecular level. Bertozzi and coworkers have expressed unnatural functional groups (i. e., acetyl, levulinoyl, and azideacetyl groups), on living cell surfaces through the glycosylation of unnatural monosaccharides (Mahal et al. 1997; Saxon and Bertozzi 2000; Yarema and Bertozzi 2001; Yaremaetal. 1998).

Iwasaki et al. (2005) reported a novel strategy for controlling selective cell attachment and detachment even in nonadhesive cells by using biomimetic polymer surface engineering and cell-surface engineering. To this end, they designed reactive biomimetic MPC polymer surfaces with hydrazide groups, which can react selectively with unnatural ketone-containing carbohydrates as a cell surface tag. Figure 18 shows a schematic representation of selective cell attachment through the recognition of a cell-surface tag. The MPC polymer surface prohibits nonspecific interaction with plasma protein, which often interferes with the specificity of the interaction of materials with a cell membrane. Hydrazide groups on the MPC polymer surface react with ketone groups on the cell surface even in cell culture medium. Surface tags on living cells can be introduced in the presence of N-levulinoylmannosamine (ManLev) by surface engineering (Lee et al. 1999; Lemieux et al. 1999). The chemical structures of MPC polymers to control cell attachment are shown in Fig. 19.

Fig. 18. Schematic representation of specific cell attachment to a nonfouling MPC polymer surface through cell-surface tags
Fig. 19. Chemical structures of PMB, poly(MPC-o-BMA-co-MH) (PMBH), and poly(BMA-co-MH) (PBH)

To clarify the possibility of using a polymer surface to recognize specific cells with cell-surface tags, the coculture of ManLev-treated HL-60 cells with native HeLa cells was examined. HeLa cells are typical cancer cells that adhere nonspecifically to conventional polymer surfaces through cell-binding proteins adsorbed on the surface. Figure 20 shows phase-contrast and fluorescence microscopy images of polymer surfaces after the coculture experiment. Cell adhesion on the PMB surface was completely suppressed.

Fig. 20. Phase-contrast and fluorescence micrographs of polymer surfaces after the coculture experiment. White arrows indicate HL-60 cells. Reprinted with permission from Iwasaki et al. (2005), copyright (2005) American Chemical Society

In contrast, both HL-60 and HeLa cells were observed on poly(BMA-co-MH) (PBH). HL-60 cells selectively attached to poly(MPC-o-BMA-co-MH) (PMBH), while HeLa cells did not. The adhesion of HeLa to a polymer surface is closely associated with the adsorption of cell-binding proteins on the surface, such as fibronectin, fibrinogen, and vitronectin, because these proteins have an RGD binding site for the integrin of the cell membrane (Hirano et al. 1993). On PMBH, the adhesion of HeLa cells was reduced due to fibronectin resistance. It has been reported previously that MPC polymer can nonspecifically reduce plasma protein adsorption (Ishihara et al. 1998). The nonfouling property of the MPC polymer surface is quite important for achieving specific interactions with a cell.

These results indicate that cell-surface recognition by a polymer surface is evident in both single- and two-cell systems. Such recognition on an MPC polymer surface is effective in a multiple-cell system because the MPC polymer surface rejects the adhesion of cells without tags. Moreover, the control ofcellattachment canbeappliedtoawiderangeofcellsbecausethe expression of unnatural carbohydrates on cell surfaces has been observed on numerous types of cells.

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