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Transcriptional networks controlling stromal cell differentiation

Abstract

Stromal progenitors are found in many different tissues, where they play an important role in the maintenance of tissue homeostasis owing to their ability to differentiate into parenchymal cells. These progenitor cells are differentially pre-programmed by their tissue microenvironment but, when cultured and stimulated in vitro, these cells — commonly referred to as mesenchymal stromal cells (MSCs) — exhibit a marked plasticity to differentiate into many different cell lineages. Loss-of-function studies in vitro and in vivo have uncovered the involvement of specific signalling pathways and key transcriptional regulators that work in a sequential and coordinated fashion to activate lineage-selective gene programmes. Recent advances in omics and single-cell technologies have made it possible to obtain system-wide insights into the gene regulatory networks that drive lineage determination and cell differentiation. These insights have important implications for the understanding of cell differentiation, the contribution of stromal cells to human disease and for the development of cell-based therapeutic applications.

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Fig. 1: Culture conditions and plasticity of stromal progenitor cells in vitro.
Fig. 2: Adipocyte lineage determination and differentiation.
Fig. 3: The osteochondral lineage.
Fig. 4: The muscle cell lineage.
Fig. 5: The ability of master regulators to drive lineage determination.
Fig. 6: Chromatin-looping, lineage-selective and stem cell transcription factors in the control of lineage fate.

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Acknowledgements

The authors would like to thank members from the Mandrup group and the Kassem group for valuable discussions on the topic of this review as well as Rasmus Siersbæk for constructive feedback on the manuscript. The work was supported by grants to A.R. from the Novo Nordisk Foundation (NNF17OC0029290), the Independent Research Fund Denmark (0134-00292B), and the Lundbeck Foundation (R335-2019-2195) and to S.M. from The Danish National Research Foundation to the Center for Functional Genomics and Tissue Plasticity (ATLAS) (Project grant: 141), and the Independent Research Fund Denmark, the Lundbeck Foundation and the Novo Nordisk Foundation.

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Correspondence to Alexander Rauch or Susanne Mandrup.

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Nature Reviews Molecular Cell Biology thanks Jacques Galipeau, Armand Keating and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Immortalized stromal progenitors

Manipulation of cells to overcome proliferative senescence but does not have to result in transformation.

Genetic driver

Regulatory element of a gene used to control the expression of a transgene in order to recapitulate the expression of the endogenous target.

Neural crest cells

Temporary group of cells that leave from the dorsal part of the neurol tube after its formation.

Hypertrophy

Increase in tissue mass due to the enlargement of cells.

Hyperplasia

Increase in tissue mass due to the proliferation of cells.

Reticular interstitium

A fluid-filled small space in tissues with a specialized extracellular matrix and that is drained by lymph nodes.

Droplet-based single-cell sequencing

Microfluidic device-based compartmentalization of single cells into lysis buffer and barcoded microbeads containing droplets that allows the parallel analysis of thousands of cells.

Single-nucleus RNA-seq

(snRNA-seq). Adaptation of single-cell RNA-seq procedure with isolated nuclei, which offers the recovery of cell types that evade droplet-based sequencing techniques.

Super-enhancers

Groups of enhancers that are in close linear genomic proximity with high levels of enhancer activity. These enhancers control many genes important for lineage determination and cell-type specification.

IMAGE machine learning tool

Modelling approach to predict the contribution of transcription factors to the overall enhancer and gene activity based on the occurrence of all known motifs.

Cartilage anlagen

The initial clustering of cells during embryonic development from which the bones develop.

Growth plate

A disc-like structure of cartilage located near the ends of the bones that permit growth in length.

Articular cartilage

Smooth tissue layer that covers the ends of the bones where they form the joints.

Periosteum

A dense, fibrous cell-containing membrane covering the surface of bones, which is not covered by articular cartilage and which serves as attachment for tendons and muscles.

Epithelial-to-mesenchymal transition

A process by which epithelial cells lose their cell polarity and cell–cell adhesion in order to gain migratory and invasive properties characteristic of the mesenchymal lineage.

Closed chromatin

State of chromatin in which nucleosome density reduces DNA accessibility for interacting proteins, for example, transcription factors.

Lipid droplet

Lipid-rich cellular organelles, also called oil bodies, for the storage and hydrolysis of neutral lipids.

Enhancer capture Hi-C

A method to specifically enrich highly complex Hi-C libraries of DNA fragments containing sequences of the enhancer of interest using biotinylated RNA baits with complementary sequence. Hi-C is a high throughput method to measure pairwise contacts between virtually any genomic region.

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Rauch, A., Mandrup, S. Transcriptional networks controlling stromal cell differentiation. Nat Rev Mol Cell Biol (2021). https://doi.org/10.1038/s41580-021-00357-7

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