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Direct cell reprogramming: approaches, mechanisms and progress

Abstract

The reprogramming of somatic cells with defined factors, which converts cells from one lineage into cells of another, has greatly reshaped our traditional views on cell identity and cell fate determination. Direct reprogramming (also known as transdifferentiation) refers to cell fate conversion without transitioning through an intermediary pluripotent state. Given that the number of cell types that can be generated by direct reprogramming is rapidly increasing, it has become a promising strategy to produce functional cells for therapeutic purposes. This Review discusses the evolution of direct reprogramming from a transcription factor-based method to a small-molecule-driven approach, the recent progress in enhancing reprogrammed cell maturation, and the challenges associated with in vivo direct reprogramming for translational applications. It also describes our current understanding of the molecular mechanisms underlying direct reprogramming, including the role of transcription factors, epigenetic modifications, non-coding RNAs, and the function of metabolic reprogramming, and highlights novel insights gained from single-cell omics studies.

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Fig. 1: Principles of indirect and direct reprogramming.
Fig. 2: Direct reprogramming across germ layers.
Fig. 3: Functions of reprogramming factors during direct reprogramming.
Fig. 4: Histone modifications that regulate gene expression during direct reprogramming.
Fig. 5: Metabolic switch during direct reprogramming.
Fig. 6: Single-cell omics in direct reprogramming.

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Acknowledgements

We sincerely apologize to those whose work may not have been cited owing to space constraints. J.L. is supported by NIH/NHLBI R01HL139880, R01HL139976; L.Q. is supported by AHA 18TPA34180058, NIH/NHLBI R01HL128331, R01HL144551.

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Supplementary information

Glossary

Myoblasts

The embryonic precursors of myocytes (muscle cells).

Eosinophils

A type of white blood cell containing granules that could be intensively stained with eosin.

Embryonic germ layer

A layer of cells that form at the early stages of embryonic development. The three embryonic germ layers are the endoderm, ectoderm and mesoderm. Cells in each germ layer interact with each other and differentiate to form tissues and embryonic organs.

Autologous cell therapies

A novel therapeutic intervention that utilizes patients’ own cells to obtain therapeutic cells through ex vivo differentiation or reprogramming.

Microenvironment

The surrounding environment of a cell that contains chemical and physical signals that directly or indirectly regulate cellular behaviour.

Macroglial cells

The non-neuronal cells that provide support and protection for neurons.

Sendai virus

A single strand, negative-sense RNA virus that has a large capacity for gene expression and a wide host range.

Single guide RNA

RNA molecule that contains a short sequence complementary to the target DNA sequence and is used to direct Cas9 endonuclease to target loci.

Hydrogel

A network of polymer chains that are hydrophilic and has been extensively studied as a scaffold for in vivo drug delivery.

Poised enhancers

A subclass of enhancers enriched for both the active and the repressive histone marks. In pluripotent cells, these poised enhancers are located near key early developmental genes and are primed to activate target gene expression upon the right environmental cues.

DNA methyltransferase Dnmt3a

Dnmt3a is an enzyme that catalyses the addition of methyl groups to unmethylated DNA at specific CpG sites.

Epithelial−mesenchymal transition

The process where polarized epithelial cells are transformed into mobile and extracellular matrix-secreting mesenchymal cells.

Oxidative phosphorylation

(OxPhos). A process in which ATP is produced because of electron transfer in mitochondria. OxPhos is the main energy source for cells like neurons, cardiomyocytes or muscle-skeletal cells.

Reactive oxygen species

(ROS). A natural by-product of the electron transport chain during the oxidation of glucose. ROS can act as signalling molecules; high levels of ROS can lead to oxidative stress in a cell.

Glycolysis

A metabolic pathway that converts glucose to pyruvate and produces two ATPs. In proliferating cells, glycolysis is a major resource for energy and macromolecules for biosynthesis.

Microfluidics

The precise control and manipulation of fluids at a small scale.

RNA velocity

The time derivative of the gene expression state. It can be used to predict the future state of individual cells on a timescale of hours.

CpG islands

Short interspersed DNA sequences that are 1,000 base pairs on average and show an unusually elevated level of CpG dinucleotides. Most of the CpG islands are found at gene promoters.

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Wang, H., Yang, Y., Liu, J. et al. Direct cell reprogramming: approaches, mechanisms and progress. Nat Rev Mol Cell Biol 22, 410–424 (2021). https://doi.org/10.1038/s41580-021-00335-z

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