nature reviews drug discovery
Naturally occurring stem cells isolated from humans have been used therapeutically for decades. This has primarily involved the transplantation of primary cells such as haematopoietic and mesenchymal stem cells and, more recently, derivatives of pluripotent stem cells. However, the advent of cell-engineering approaches is ushering in a new generation of stem cell-based therapies, greatly expanding their therapeutic utility. These next-generation stem cells are being used as ‘Trojan horses’ to improve the delivery of drugs and oncolytic viruses to intractable tumours and are also being engineered with angiogenic, neurotrophic and anti-inflammatory molecules to accelerate the repair of injured or diseased tissues. Moreover, gene therapy and gene editing technologies are being used to create stem cell derivatives with improved functionality, specificity and responsiveness compared with their natural counterparts. Here, we review these engineering approaches and areas in which they will help broaden the utility and clinical applicability of stem cells.
E.A.K. and R.L. are employees of Astellas Institute for Regenerative Medicine.
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The ability to give rise to all cell types in the body.
The tendency (for a stem cell) to migrate towards a tumour, usually induced by chemoattraction of that cell to chemoattractants, angiogenic factors or inflammatory signals produced by a tumour.
Chimeric antigen receptor
(CAR). A class of genetically engineered, modular receptors that can be used to elicit highly potent, antigen-specific immune responses. The basic CAR structure consists of an extracellular antigen-specific binding domain, a hinge domain, a transmembrane domain and an intracellular signalling domain, although many versions of CARs also contain co-stimulatory domains and other modular features.
An engineering approach to introduce genes that encode light-responsive proteins into cells in order to be able to control cellular signalling pathways upon exposure to specific wavelengths of light.
X-linked severe combined immunodeficiency
(SCID). A rare inherited immune system disorder caused by mutations in the IL2RG gene, which is typically fatal early in life unless reconstitution of the immune system is achieved through bone marrow transplantation or gene therapy.
An X-linked primary immunodeficiency disorder caused by mutations in the WAS gene, which encodes a cytoskeletal protein essential for normal immune cell function. Insertion of a normal, wild-type WAS gene into a patient’s haematopoietic stem and progenitor cells may thus be able to functionally compensate for their mutated gene upon their differentiation into the afflicted immune cells.
An engineering approach to express genes encoding designer receptors in cells in order to be able to control the cells’ activity through administration of chemicals/drugs specifically designed to bind to the designer receptors.
The use of bio-orthogonal functional groups that enables linking two molecules of interest (biological and/or purely synthetic) together, such as the attachment of azide-coated cells with cyclooctyene-coated nanoparticles.
γδ T cells
A rare subset of T cells that can be found in the gut mucosa, skin and lungs, thought to help bridge the innate and adaptive immune systems. Their name originates from the unique composition of their T cell receptor, which consists of a γ-chain and a δ-chain, as opposed to the more abundant αβ T cell subset whose T cell receptor consists of an α-chain and a β-chain.
Duchenne muscular dystrophy
A neuromuscular disorder caused by mutations in the gene encoding dystrophin, which result in severe muscle wasting.
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Kimbrel, E.A., Lanza, R. Next-generation stem cells — ushering in a new era of cell-based therapies. Nat Rev Drug Discov (2020). https://doi.org/10.1038/s41573-020-0064-x