The myriad ways to engineer cells (2024)

The widening range of strategies to alter the phenotypes and functions of mammalian cells is a boon for their biomedical applications.

‘How to engineer a cell’ could be the title of a thick book that gets substantially heavier with every new edition. Indeed, there is an increasing number of methods to modify mammalian cells to, for instance, express specific receptors, produce certain cytokines, metabolites or hormones, or excrete extracellular vesicles with biased tropism or functionality. When differentiating stem cells, their transformation path can be biased towards certain lineages with increasingly easier or more efficient protocols. And some somatic cell types can be reprogrammed into a more stem-cell-like state, or transdifferentiated into another cell type. In general, many cellular functions can be switched off or potentiated, and new functions introduced. Nearly everything in a cell can be tinkered with — from the genes to the glycocalyx on the cell’s surface (and including the structural organization of the genome, gene-expression profiles, the shuttling of transcription factors through the nucleus, protein production, signalling networks, protein distribution, cytoskeletal organization, organelle functions, and the expression and display of specific cell-surface receptors; this is not an exhaustive list). The biochemical and biophysical microenvironment of cells can also be controlled as a way to alter cellular phenotypes.

The myriad ways to engineer cells (1)

Figure adapted with permission from the Article by Leonard and colleagues, Springer Nature Ltd.

Yet, cell engineering is more than just tinkering with cells; the concept suggests a degree of control for a biological or biomedical purpose. In genome engineering, genes are introduced, knocked out or silenced, or their promoter regions modified, to make cells express specific receptors or produce certain cytokines, for instance. All of these modifications can be done via genome editing (through CRISPR-associated nucleases), transposon systems (such as Sleeping Beauty or piggyBac) or the viral transduction or non-viral transfection of nucleic acid payloads (for example, in optogenetics, these can be light-responsive gene-expression systems). In epigenetic engineering, the epigenetic landscape of cells and thus gene-expression patterns and cellular behaviour can be altered via RNA interference, DNA-methylation editing, or histone or chromatin remodelling. In metabolic engineering, enzymes involved in biosynthetic pathways can be overexpressed or knocked down, or precursors or co-factors can be added, to enhance the production of desired molecules. With synthetic biology, genetic circuits can be reprogrammed (via logic gates or feedback loops, for example) to use cells as sensors or reporters of specific biochemical or physical cues in their microenvironment. With protein engineering, the extracellular domain of receptors can be optimized to enhance their binding affinity or specificity. The composition and targeting specificity of secreted extracellular vesicles can also be engineered (genetically, and via microenvironmental stimuli) for uses in the delivery of biomolecules and in diagnostics. In cell-surface engineering, ligands (typically antibodies) are used to alter cell–cell communication and the interactions of the cells with the extracellular matrix. And bioprinting and culture techniques (culture conditions such as oxygen levels, pH, nutrient availability and shear stress can influence the expression of particular receptors and the secretion of certain cytokines and extracellular vesicles) alongside genetic and epigenetic manipulations can be used to induce specific cell states (such as senescence or pluripotency), and to construct multicellular tissue models to recapitulate the structural and functional aspects of native tissues, or for use in tissue regeneration.

The requirements of the application, the cell type, the cell components to be altered, and the desired levels of control and scalability typically dictate the types of strategy for cell engineering. For example, as shown by Joshua Leonard and colleagues in an Article included in this issue of Nature Biomedical Engineering, to effectively deliver biologics to T cells via extracellular vesicles, the vesicles’ parent cells were genetically modified to secrete vesicles displaying single-chain variable fragments binding to a specific receptor on T cells as well as viral glycoproteins to facilitate vesicle uptake and fusion with the recipient T cells (pictured). The parent cells were also encoded genetically to load specific cargo into the vesicles during their biogenesis (by tagging the cargo with vesicle-localizing domains). And for the delivery of mRNA into neurons, leucocytes can be engineered to produce extracellular vesicles that incorporate retrovirus-like mRNA-packaging capsids (to enhance the loading of the RNA cargo, to recruit enveloping proteins to their surface and to promote uptake by recipient neurons), as described by Shaoyi Jiang, Robert Langer and colleagues in another Article in this issue.

To lower the immunogenicity of transplanted allogeneic cells and tissues, immunomodulatory transgenes can be overexpressed (by inserting the transgenes with expression vectors for piggyBac and Sleeping Beauty transposons), as described by Andras Nagy in this issue, for the ‘cloaking’ of embryonic stem cells and tissues derived from them. And to enhance the antigen-specific immunosuppression of allogeneic mesenchymal stromal cells, which are used to treat immune disorders, Saad Kenderian and co-authors show that the cells can be genetically modified to incorporate chimaeric antigen receptors for the cell-adhesion protein epithelial cadherin, for the treatment of graft-versus-host disease in mice. Moreover, to enhance the antitumour activity of T cells with chimaeric antigen receptors targeting solid tumour antigens, Stephen Gottschalk and colleagues designed a system based on the ‘leucine zipper’ structural motif to replace (via retroviral transduction) the extracellular domains of heterodimeric cytokine receptors in T cells with two leucine zippers (which provided optimal Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling).

Advances in genome engineering, viral and non-viral delivery, high-content screening, computational modelling (for protein design, the processing of omics datasets, and the optimization of nucleic acid sequences, among a plethora of other uses) and in many disparate methods of molecular and cellular biology are widening the range of strategies for cell engineering. Whether the aim is to design or optimize cells as therapeutics or biosensors, or for use in disease modelling or for evaluating the toxicities of biologics, the strategies in the methodological toolbox are myriad.

The myriad ways to engineer cells (2024)


The myriad ways to engineer cells? ›

All of these modifications can be done via genome editing (through CRISPR-associated nucleases), transposon systems (such as Sleeping Beauty or piggyBac) or the viral transduction or non-viral transfection of nucleic acid payloads (for example, in optogenetics, these can be light-responsive gene-expression systems).

How can cells be engineered? ›

One general form of cell engineering involves altering natural cell production to achieve a more desirable yield or shorter production time. A possible method for changing natural cell production includes boosting or repressing genes that are involved in the metabolism of the product.

What is cell bioengineering? ›

Cellular engineering applies the principles and methods of engineering to the problems of cell and molecular biology of both a basic and applied nature. As biomedical engineering has shifted from the organ and tissue level to the cellular and sub-cellular level, cellular engineering has emerged as a new area.

What is an example of cellular engineering? ›

Examples of cellular engineering techniques include genetic engineering, where genes are added, removed, or modified in cells to alter their behavior, and tissue engineering, where cells are combined with biomaterials to create artificial tissues or organs.

Have we created a synthetic cell? ›

In Spiroplasma, scientists had already identified seven genes likely to aid this kind of cell movement. But confirming these genes' precise roles experimentally has proved challenging. The team turned to a synthetic cell, called JCVI-syn3.

Can we engineer a cell? ›

The fast-developing synthetic biology (SB) has provided many genetic tools to reprogram and engineer cells for improved performance, novel functions, and diverse applications. Such cell engineering resources can play a critical role in the research and development of novel therapeutics.

What are three examples of bioengineering? ›

Examples of bioengineering include:
  • artificial hips, knees and other joints.
  • ultrasound, MRI and other medical imaging techniques.
  • using engineered organisms for chemical and pharmaceutical manufacturing.

How are stem cells engineered? ›

Regeneration or reconstruction of damaged or diseased tissues and organs by tissue engineering requires three components: (1) cells harvested from various donor tissues, including adult stem or progenitor cells derived from bone, nerve, liver, cartilage, or embryonic and induced pluripotent stem cells; (2) scaffolds, ...

Is bioengineering a real thing? ›

Bioengineering is the study of applied engineering practices in general biology. Bioengineers' work often focuses on general theory that can be applied to various areas of natural sciences to solve problems.

What is cell tissue engineering? ›

Cell and tissue engineering centers on the application of physical and engineering principles to understand and control cell and tissue behavior. Cellular engineering focuses on cell-level phenomena, while tissue engineering and regenerative medicine seek to generate or stimulate new tissue for disease treatment.

What is an example of stem cell engineering? ›

A simple example is the use of epidermal stem cells for repair of the skin after extensive burns. By culturing cells from undamaged regions of the skin of the burned patient, it is possible to obtain epidermal stem cells quite rapidly in large numbers.

What is cell based tissue engineering? ›

There are four major cell-based tissue-engineering strategies: (1) targeting local connective tissue progenitors where new tissue is desired, (2) transplanting autogenous connective tissue progenitors, (3) transplanting culture-expanded or modified connective tissue progenitors, and (4) transplanting fully formed ...

How can cells be cultured? ›

Most cells require a surface or an artificial substrate to form an adherent culture as a monolayer (one single-cell thick), whereas others can be grown free floating in a medium as a suspension culture. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, such as broth or agar.

How do you invent a cell? ›

Cell was discovered by a British scientist, Robert Hooke in 1665. He observed cells in a cork slice under his self-designed microscope and noticed honeycomb like compartments. He coined them as cells. Term cell was derived from latin word cellula = a hollow space.

Is it possible to create a cell? ›

it is not possible to construct a cell from scratch, for several major reasons: Cell structure and arrangements of cellular components (membranes in particular) are not directly coded in DNA sequence; they represent a sort of “institutional memory” of a cell, and are replicated through a process of cellular division.


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