Chemical–biological approaches for the direct regulation of cell–cell aggregation

Abstract

Cell-cell aggregation is one of the most well-known modes of intercellular communication. The aggregation also plays a vital role in the formation of multicellularity, thus manipulating the growth and development of organisms. In the past decades, cell-cell aggregation-related bioprocesses and molecular mechanisms have attracted enormous interest from scientists in biology, and bioengineering. People have developed a series of strategies to artificially regulate cell-cell aggregation through chemical-biological approaches. To date, not only the chemical reagents such as coordination compounds and polymers but also the biomacromolecules such as proteins and nucleic acids, are employed as the "cell glue" to achieve the control of the cell aggregation. So it is meaningful to review the recent advances of the chemical-biological approaches in cell-cell aggregation manipulation. In this review, we discuss the mechanisms and features of recently developed strategies to control cell-cell aggregation. We introduce molecules and designs relying on chemical reactions and biological conjugations respectively, and talk about their advantages and suitable applications. A perspective on the challenges in future applications in cell manipulation and cell-based therapy is also proposed. We expect this review could inspire innovative work on manipulating cell-cell aggregation and further modulate cell-cell interactions in the research of bio/chemical fields.

Cell Surface Engineering Tools for Programming Living Assemblies

“…This could be useful in scenarios where the multivalent electrostatic interactions alone are not strong enough to promote cell aggregation. [68,69] Alongside, silicification processes involving the adsorption of silicates into a cationic polymer, previously installed electrostatically on the cell surface, have also been used to promote the functionalization of single cells and generate multicellular assemblies, as will be further highlighted. [59,61,70] The widespread applicability of these methodologies is however limited by a lack of cell-type selectivity, which could be a challenge for applications that aim to explore one-step, cell-specific modification in the context of heterotypic living constructs assembly.…”

“…As above discussed, so far, different functional moieties have been introduced in the cell surface to directly promote interactions or to act as an anchoring point for conjugating intermediary elements capable of recognizing and connecting multiple cells, thus enabling a precise control over cell-cell and cell-biomaterial interactions. [69] Through rationally designing the cell surface, such functionalized cellular building blocks can be spatiotemporally molded and processed for the establishment of robust and complex 3D bioarchitectures with living features. The following section provides an outlook of <30 min (synthetic polycation-PLL) [80] Relatively prolonged exposure (>7 days, natural biopolymer) [61] [ [ 76,77] Up to 7 days (liposome fusion) [10] [ Up to 7 days [178] [71, 155, 179]…”

Controlled E. coli Aggregation Mediated by DNA and XNA Hybridization

“…In addition, chemical handles should not induce any undesired toxicity, and their production needs to be high yielding under in vivo conditions. [15,16] In this context, Bertozzi et al introduced in 2000 the Staudinger ligation reaction as biorthogonal reaction for reliable and controlled cell-cell aggregation. [17] Since this pioneering work, other approaches based on covalent or non-covalent fixation have been developed for the induction of bio-orthogonal interactions between bacteria including the grafting of antigennanobody, [18,19] antiparallel coiled-coil peptides, [20][21][22] photoswitchable proteins.…”

“…The criteria are rather strict since an ideal conjugation chemistry for inducing controlled, artificial cell‐cell aggregations should be fully orthogonal to the biological systems so as to avoid off‐target aggregations or loss of biological activity. In addition, chemical handles should not induce any undesired toxicity, and their production needs to be high yielding under in vivo conditions [15,16] . In this context, Bertozzi et al .…”

Reassembly of Peptide Nanofibrils on Live Cell Surfaces Promotes Cell–Cell Interactions

“…Engineering live cell surfaces with synthetic materials offers significant promise for expanding the properties of cells and regulating cellular interactions beyond nature’s capability. − Compared with direct cell-membrane modifications with ligands and reactive groups, constructing high-aspect ratio nanostructures on cells has emerged as a method for expanding the surface area of cells for the display of functionalities with increased amounts and varieties. It has recently attracted considerable research interest for the assembly of biomacromolecules into nanofibers and filaments on live cell surfaces, − which have promoted immune cancer cell recognition, , afforded stimulus-responsive cellular interactions, , and induced the formation of cell spheroids. , Despite the progress propelled by diverse functionalization of these nanostructures, it remains challenging to modulate cellular interactions by tuning the structures of these ligand scaffolds.…”