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Key Points Mature, terminally differentiated cells have the capacity to de-differentiate or transdifferentiate in vivo . De-differentiation and transdifferentiation can be forced experimentally, but these processes also occur physiologically in response to tissue injury and/or cell loss. Cellular plasticity involves the repression of genes associated with the previous cell type, as well as activation of genes associated with the new cell type. Cells may occupy 'intermediate' identity states while undergoing de-differentiation or transdifferentiation. Such changes can be reversible. Cellular plasticity can be driven by factors that induce a new identity or by the loss of inhibitory factors that maintain the old identity. Some terminally differentiated cells have the capacity to de-differentiate or transdifferentiate under physiological conditions as part of a normal response to injury. Recent insights have been gained into the role of this cell plasticity in maintaining tissue and organ homeostasis, and this has important implications for cell-based therapies. Biologists have long been intrigued by the possibility that cells can change their identity, a phenomenon known as cellular plasticity. The discovery that terminally differentiated cells can be experimentally coaxed to become pluripotent has invigorated the field, and recent studies have demonstrated that changes in cell identity are not limited to the laboratory. Specifically, certain adult cells retain the capacity to de-differentiate or transdifferentiate under physiological conditions, as part of an organ's normal injury response. Recent studies have highlighted the extent to which cell plasticity contributes to tissue homeostasis, findings that have implications for cell-based therapy.

Key Points The epithelial–mesenchymal transition (EMT) process results in the downregulation of epithelial, and activation of mesenchymal, cell characteristics and behaviour. This transdifferentiation process is initially reversible, with mesenchymal–epithelial transition (MET) enabling reversion to an epithelial phenotype. Both epithelial and endothelial cells can transition into a mesenchymal phenotype. EMT is integral in development, starting with the generation of mesoderm, and consecutive waves of EMT and MET occur in the generation of diverse cell types and tissues. EMT is pathologically reactivated in, and contributes to, the progression of fibrosis and cancer. In carcinomas, EMT has been associated with the generation of invasive cells and acquisition of cancer stem cell properties. EMT is initiated by the deconstruction of epithelial cell–cell junctions and apical–basal polarity, subsequently enabling the cells to establish a front–rear polarity, which is required for directional migration. Further changes in cell adhesion and membrane extrusions contribute to the increased cell motility following EMT. Integral in the EMT process is the reprogramming of gene expression, that is, the repression of an epithelial gene expression pattern and the activation of genes that contribute to EMT and the mesenchymal phenotype. EMT-associated gene reprogramming involves key transcription factors with central roles in driving this transdifferentiation process. Superimposed on the changes in gene expression are extensive and selective alterations in the splicing patterns of nascent transcripts, which are mediated by changes in splicing factor expression. In addition, an extensive network of microRNAs (miRNAs) represses the expression of EMT transcription factors and other targets; in some cases, miRNAs regulate EMT and MET through functional feedback mechanisms. Transforming growth factor-β (TGFβ) family proteins are potent inducers of EMT, partly through the SMAD-mediated activation of EMT transcription factor expression and the subsequent SMAD-mediated control of their transcription activities. TGFβ family proteins also activate complementary non-SMAD signalling pathways that contribute to the induction and progression of EMT. EMT is elaborated through the functional cooperation of signalling pathways that can be activated by diverse extracellular signals. These pathways converge at multiple levels, including at the level of gene reprogramming. Epithelial–mesenchymal transition (EMT) is integral to development and pathology. This switch in cell differentiation and behaviour requires key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix–loop–helix transcription factors, and is regulated by several signalling pathways, including those mediated by the transforming growth factor-β (TGFβ) family. The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial–mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix–loop–helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Epithelial–mesenchymal transitions (EMTs) are the epitome of cell plasticity in embryonic development and cancer; during EMT, epithelial cells undergo dramatic phenotypic changes and become able to migrate to form different tissues or give rise to metastases, respectively. The importance of EMTs in other contexts, such as tissue repair and fibrosis in the adult, has become increasingly recognized and studied. In this Review, we discuss the function of EMT in the adult after tissue damage and compare features of embryonic and adult EMT. Whereas sustained EMT leads to adult tissue degeneration, fibrosis and organ failure, its transient activation, which confers phenotypic and functional plasticity on somatic cells, promotes tissue repair after damage. Understanding the mechanisms and temporal regulation of different EMTs provides insight into how some tissues heal and has the potential to open new therapeutic avenues to promote repair or regeneration of tissue damage that is currently irreversible. We also discuss therapeutic strategies that modulate EMT that hold clinical promise in ameliorating fibrosis, and how precise EMT activation could be harnessed to enhance tissue repair.During embryonic epithelial–mesenchymal transition, epithelial cells undergo substantial phenotypic changes and acquire migration capacity. This Review compares embryonic and adult non-cancer EMTs and discusses the role of EMTs in adult tissue repair and fibrosis, highlighting therapeutic opportunities to modulate EMT to reduce fibrosis and promote repair.

Bone marrow stromal cells (BMSCs) are versatile mesenchymal cell populations underpinning the major functions of the skeleton, a majority of which adjoin sinusoidal blood vessels and express C-X-C motif chemokine ligand 12 (CXCL12). However, how these cells are activated during regeneration and facilitate osteogenesis remains largely unknown. Cell-lineage analysis using Cxcl12-creER mice reveals that quiescent Cxcl12-creER + perisinusoidal BMSCs differentiate into cortical bone osteoblasts solely during regeneration. A combined single cell RNA-seq analysis demonstrate that these cells convert their identity into a skeletal stem cell-like state in response to injury, associated with upregulation of osteoblast-signature genes and activation of canonical Wnt signaling components along the single-cell trajectory. β-catenin deficiency in these cells indeed causes insufficiency in cortical bone regeneration. Therefore, quiescent Cxcl12-creER + BMSCs transform into osteoblast precursor cells in a manner mediated by canonical Wnt signaling, highlighting a unique mechanism by which dormant stromal cells are enlisted for skeletal regeneration. Bone marrow stromal cells (BMSCs) lining sinusoidal blood vessels are mesenchymal cells whose function is critical for the skeleton. Here the authors show that quiescent CXCL12-expressing BMSCs can convert into a skeletal stem cell-like state, and differentiate into cortical bone osteoblasts only in response to injury.

The cochlea uses two types of mechanosensory cell to detect sounds. A single row of inner hair cells (IHCs) synapse onto neurons to transmit sensory information to the brain, and three rows of outer hair cells (OHCs) selectively amplify auditory inputs 1 . So far, two transcription factors have been implicated in the specific differentiation of OHCs, whereas, to our knowledge, none has been identified in the differentiation of IHCs 2 – 4 . One such transcription factor for OHCs, INSM1, acts during a crucial embryonic period to consolidate the OHC fate, preventing OHCs from transdifferentiating into IHCs 2 . In the absence of INSM1, embryonic OHCs misexpress a core set of IHC-specific genes, which we predict are involved in IHC differentiation. Here we find that one of these genes, Tbx2 , is a master regulator of IHC versus OHC differentiation in mice. Ablation of Tbx2 in embryonic IHCs results in their development as OHCs, expressing early OHC markers such as Insm1 and eventually becoming completely mature OHCs in the position of IHCs. Furthermore, Tbx2 is epistatic to Insm1 : in the absence of both genes, cochleae generate only OHCs, which suggests that TBX2 is necessary for the abnormal transdifferentiation of INSM1-deficient OHCs into IHCs, as well as for normal IHC differentiation. Ablation of Tbx2 in postnatal, largely differentiated IHCs makes them transdifferentiate directly into OHCs, replacing IHC features with those of mature and not embryonic OHCs. Finally, ectopic expression of Tbx2 in OHCs results in their transdifferentiation into IHCs. Hence, Tbx2 is both necessary and sufficient to make IHCs distinct from OHCs and maintain this difference throughout development. Tbx2 is a master regulator of cochlear inner hair cells.

Barrett’s oesophagus—a metaplasia that can be induced by persistent acid reflux, and predisposes patients to oesophageal cancer—arises from a population of basal cells at the gastro-oesophageal junction. Cells cross the junction of throat cancer Barrett's metaplasia occurs at the gastro-oesophageal junction, sometimes as a result of persistent acid reflux, and predisposes patients to oesophageal cancer. There has been some debate over which cells generate Barrett's oesophagus. Jianwen Que and colleagues now identify a population of basal cells at the gastro-oesophageal junction that give rise to Barrett's metaplasia in mice. Data from human samples suggest the same population of cells gives rise to Barrett's metaplasia in humans. In several organ systems, the transitional zone between different types of epithelium is a hotspot for pre-neoplastic metaplasia and malignancy 1 , 2 , 3 , but the cells of origin for these metaplastic epithelia and subsequent malignancies remain unknown 1 , 2 , 3 . In the case of Barrett’s oesophagus, intestinal metaplasia occurs at the gastro-oesophageal junction, where stratified squamous epithelium transitions into simple columnar cells 4 . On the basis of a number of experimental models, several alternative cell types have been proposed as the source of this metaplasia but in all cases the evidence is inconclusive: no model completely mimics Barrett’s oesophagus in terms of the presence of intestinal goblet cells 5 , 6 , 7 , 8 . Here we describe a transitional columnar epithelium with distinct basal progenitor cells (p63 + KRT5 + KRT7 + ) at the squamous–columnar junction of the upper gastrointestinal tract in a mouse model. We use multiple models and lineage tracing strategies to show that this squamous–columnar junction basal cell population serves as a source of progenitors for the transitional epithelium. On ectopic expression of CDX2, these transitional basal progenitors differentiate into intestinal-like epithelium (including goblet cells) and thereby reproduce Barrett’s metaplasia. A similar transitional columnar epithelium is present at the transitional zones of other mouse tissues (including the anorectal junction) as well as in the gastro-oesophageal junction in the human gut. Acid reflux-induced oesophagitis and the multilayered epithelium (believed to be a precursor of Barrett’s oesophagus) are both characterized by the expansion of the transitional basal progenitor cells. Our findings reveal a previously unidentified transitional zone in the epithelium of the upper gastrointestinal tract and provide evidence that the p63 + KRT5 + KRT7 + basal cells in this zone are the cells of origin for multi-layered epithelium and Barrett’s oesophagus.

Single-cell transcriptomics analyses of cell intermediates during the reprogramming from fibroblast to cardiomyocyte were used to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in this process. Fibroblast splicing factor To elucidate the mechanistic underpinnings of fibroblasts reprogramming to cardiomyocytes, Li Qian and colleagues have used a single-cell RNA sequencing approach. They find that the initial steps that drive the global expression changes that are critical for reprogramming encompass the downregulation of factors involved in mRNA processing and splicing, and in particular the splicing factor Ptbp1. Downregulation of Ptbp1 is essential for cells to adopt a cardiac-specific splicing pattern. The approach also led to the identification of surface markers that allow enrichment of induced cardiomyocytes during reprogramming. Direct lineage conversion offers a new strategy for tissue regeneration and disease modelling. Despite recent success in directly reprogramming fibroblasts into various cell types, the precise changes that occur as fibroblasts progressively convert to the target cell fates remain unclear. The inherent heterogeneity and asynchronous nature of the reprogramming process renders it difficult to study this process using bulk genomic techniques. Here we used single-cell RNA sequencing to overcome this limitation and analysed global transcriptome changes at early stages during the reprogramming of mouse fibroblasts into induced cardiomyocytes (iCMs) 1 , 2 , 3 , 4 . Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells during reprogramming. We also constructed routes of iCM formation, and delineated the relationship between cell proliferation and iCM induction. Further analysis of global gene expression changes during reprogramming revealed unexpected downregulation of factors involved in mRNA processing and splicing. Detailed functional analysis of the top candidate splicing factor, Ptbp1, revealed that it is a critical barrier for the acquisition of cardiomyocyte-specific splicing patterns in fibroblasts. Concomitantly, Ptbp1 depletion promoted cardiac transcriptome acquisition and increased iCM reprogramming efficiency. Additional quantitative analysis of our dataset revealed a strong correlation between the expression of each reprogramming factor and the progress of individual cells through the reprogramming process, and led to the discovery of new surface markers for the enrichment of iCMs. In summary, our single-cell transcriptomics approaches enabled us to reconstruct the reprogramming trajectory and to uncover intermediate cell populations, gene pathways and regulators involved in iCM induction.

Rodent cardiomyocytes are converted to sinoatrial-node pacemaker cells by expression of the transcription factor Tbx18. The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the ∼5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18 , a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo , focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.

Hematopoietic stem and progenitor cells (HSPCs) originate from an endothelial-to-hematopoietic transition (EHT) during embryogenesis. Characterization of early hemogenic endothelial (HE) cells is required to understand what drives hemogenic specification and to accurately define cells capable of undergoing EHT. Using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq), we define the early subpopulation of pre-HE cells based on both surface markers and transcriptomes. We identify the transcription factor Meis1 as an essential regulator of hemogenic cell specification in the embryo prior to Runx1 expression. Meis1 is expressed at the earliest stages of EHT and distinguishes pre-HE cells primed towards the hemogenic trajectory from the arterial endothelial cells that continue towards a vascular fate. Endothelial-specific deletion of Meis1 impairs the formation of functional Runx1 -expressing HE which significantly impedes the emergence of pre-HSPC via EHT. Our findings implicate Meis1 in a critical fate-determining step for establishing EHT potential in endothelial cells. Hematopoietic stem cell formation via the endothelial-to-hematopoietic transition is initiated by a complex rewiring of the aortic endothelium. Here the authors identify Meis1 as an early driver of hemogenic specification of this arterial endothelium.