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Billions of cells are eliminated daily from our bodies1-4. Although macrophages and dendritic cells are dedicated to migrating and engulfing dying cells and debris, many epithelial and mesenchymal tissue cells can digest nearby apoptotic corpses1-4. How these non-motile, non-professional phagocytes sense and eliminate dying cells while maintaining their normal tissue functions is unclear. Here we explore the mechanisms that underlie their multifunctionality by exploiting the cyclical bouts of tissue regeneration and degeneration during hair cycling. We show that hair follicle stem cells transiently unleash phagocytosis at the correct time and place through local molecular triggers that depend on both lipids released by neighbouring apoptotic corpses and retinoids released by healthy counterparts. We trace the heart of this dual ligand requirement to RARγ-RXRα, whose activation enables tight regulation of apoptotic cell clearance genes and provides an effective, tunable mechanism to offset phagocytic duties against the primary stem cell function of preserving tissue integrity during homeostasis. Finally, we provide functional evidence that hair follicle stem cell-mediated phagocytosis is not simply redundant with professional phagocytes but rather has clear benefits to tissue fitness. Our findings have broad implications for other non-motile tissue stem or progenitor cells that encounter cell death in an immune-privileged niche.
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Technological advancements in biology and microscopy have empowered a transition from bioimaging as an observational method to a quantitative one. However, as biologists are adopting quantitative bioimaging and these experiments become more complex, researchers need additional expertise to carry out this work in a rigorous and reproducible manner. This Essay provides a navigational guide for experimental biologists to aid understanding of quantitative bioimaging from sample preparation through to image acquisition, image analysis, and data interpretation. We discuss the interconnectedness of these steps, and for each, we provide general recommendations, key questions to consider, and links to high-quality open-access resources for further learning. This synthesis of information will empower biologists to plan and execute rigorous quantitative bioimaging experiments efficiently.
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Procesamiento de Imagen Asistido por Computador , MicroscopíaRESUMEN
Macrophages and dendritic cells have long been appreciated for their ability to migrate to and engulf dying cells and debris, including some of the billions of cells that are naturally eliminated from our body daily. However, a substantial number of these dying cells are cleared by 'non-professional phagocytes', local epithelial cells that are critical to organismal fitness. How non-professional phagocytes sense and digest nearby apoptotic corpses while still performing their normal tissue functions is unclear. Here, we explore the molecular mechanisms underlying their multifunctionality. Exploiting the cyclical bouts of tissue regeneration and degeneration during the hair cycle, we show that stem cells can transiently become non-professional phagocytes when confronted with dying cells. Adoption of this phagocytic state requires both local lipids produced by apoptotic corpses to activate RXRα, and tissue-specific retinoids for RARγ activation. This dual factor dependency enables tight regulation of the genes requisite to activate phagocytic apoptotic clearance. The tunable phagocytic program we describe here offers an effective mechanism to offset phagocytic duties against the primary stem cell function of replenishing differentiated cells to preserve tissue integrity during homeostasis. Our findings have broad implications for other non-motile stem or progenitor cells which experience cell death in an immune-privileged niche.
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Pathogen infection and tissue injury are universal insults that disrupt homeostasis. Innate immunity senses microbial infections and induces cytokines/chemokines to activate resistance mechanisms. Here, we show that, in contrast to most pathogen-induced cytokines, interleukin-24 (IL-24) is predominately induced by barrier epithelial progenitors after tissue injury and is independent of microbiome or adaptive immunity. Moreover, Il24 ablation in mice impedes not only epidermal proliferation and re-epithelialization but also capillary and fibroblast regeneration within the dermal wound bed. Conversely, ectopic IL-24 induction in the homeostatic epidermis triggers global epithelial-mesenchymal tissue repair responses. Mechanistically, Il24 expression depends upon both epithelial IL24-receptor/STAT3 signaling and hypoxia-stabilized HIF1α, which converge following injury to trigger autocrine and paracrine signaling involving IL-24-mediated receptor signaling and metabolic regulation. Thus, parallel to innate immune sensing of pathogens to resolve infections, epithelial stem cells sense injury signals to orchestrate IL-24-mediated tissue repair.
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Citocinas , Heridas y Lesiones , Animales , Ratones , Inmunidad Adaptativa , Quimiocinas , Epidermis , Inmunidad Innata , Heridas y Lesiones/inmunologíaRESUMEN
The COVID-19 pandemic has increased use of rapid diagnostic tests (RDTs). In winter 2021 to 2022, the Omicron variant surge made it apparent that although RDTs are less sensitive than quantitative reverse transcription-PCR (qRT-PCR), the accessibility, ease of use, and rapid readouts made them a sought after and often sold-out item at local suppliers. Here, we sought to qualify the Abbott BinaxNOW RDT for use in our university testing program as a method to rule in positive or rule out negative individuals quickly at our priority qRT-PCR testing site. To perform this qualification study, we collected additional swabs from individuals attending this site. All swabs were tested using BinaxNOW. Initially as part of a feasibility study, test period 1 (n = 110) samples were stored cold before testing. In test period 2 (n = 209), samples were tested immediately. Combined, 102/319 samples tested severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive via qRT-PCR. All sequenced samples were Omicron (n = 92). We calculated 53.9% sensitivity, 100% specificity, a 100% positive predictive value, and an 82.2% negative predictive value for BinaxNOW (n = 319). Sensitivity would be improved (75.3%) by changing the qRT-PCR positivity threshold from a threshold cycle (CT) value of 40 to a CT value of 30. The receiver operating characteristic (ROC) curve shows that for qRT-PCR-positive CT values of between 24 and 40, the BinaxNOW test is of limited value diagnostically. Results suggest BinaxNOW could be used in our setting to confirm SARS-CoV-2 infection in individuals with substantial viral load, but a significant fraction of infected individuals would be missed if we used RDTs exclusively to rule out infection. IMPORTANCE Our results suggest BinaxNOW can rule in SARS-CoV-2 infection but would miss infections if RDTs were exclusively used.
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COVID-19 , SARS-CoV-2 , Humanos , SARS-CoV-2/genética , Pandemias , Transcripción Reversa , COVID-19/diagnóstico , Reacción en Cadena de la PolimerasaRESUMEN
In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the first cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for COVID-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University (BU), created an on-campus COVID-19 screening protocol as part of a plan for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we put together an automated high-throughput clinical testing laboratory with the capacity to run 45,000 individual tests weekly by Fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed reverse transcription PCR (RT-qPCR) test, robotic instrumentation, and trained staff. There were many challenges including supply chain issues for personal protective equipment and testing materials in addition to equipment that were in high demand. The BU Clinical Testing Laboratory (CTL) was operational at the start of Fall 2020 and performed over 1 million SARS-CoV-2 PCR tests during the 2020-2021 academic year.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Prueba de COVID-19 , Humanos , Pandemias/prevención & control , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Estados UnidosRESUMEN
Immune and tissue stem cells retain an epigenetic memory of inflammation that intensifies sensitivity to future encounters. We investigated whether and to what consequence stem cells possess and accumulate memories of diverse experiences. Monitoring a choreographed response to wounds, we found that as hair follicle stem cells leave their niche, migrate to repair damaged epidermis, and take up long-term foreign residence there, they accumulate long-lasting epigenetic memories of each experience, culminating in post-repair epigenetic adaptations that sustain the epidermal transcriptional program and surface barrier. Each memory is distinct, separable, and has its own physiological impact, collectively endowing these stem cells with heightened regenerative ability to heal wounds and broadening their tissue-regenerating tasks relative to their naïve counterparts.
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Células Epidérmicas/citología , Epigénesis Genética , Folículo Piloso/citología , Células Madre/fisiología , Adaptación Fisiológica , Animales , Movimiento Celular , Cromatina/metabolismo , Células Epidérmicas/fisiología , Homeostasis , Inflamación , Ratones , Regeneración , Nicho de Células Madre , Transcriptoma , Cicatrización de HeridasRESUMEN
BACKGROUND & AIMS: There are few in vitro models for studying the 3-dimensional interactions among different liver cell types during organogenesis or disease development. We aimed to generate hepatic organoids that comprise different parenchymal liver cell types and have structural features of the liver, using human pluripotent stem cells. METHODS: We cultured H1 human embryonic stem cells (WA-01, passage 27-40) and induced pluripotent stem cells (GM23338) with a series of chemically defined and serum-free media to induce formation of posterior foregut cells, which were differentiated in 3 dimensions into hepatic endoderm spheroids and stepwise into hepatoblast spheroids. Hepatoblast spheroids were reseeded in a high-throughput format and induced to form hepatic organoids; development of functional bile canaliculi was imaged live. Levels of albumin and apolipoprotein B were measured in cell culture supernatants using an enzyme-linked immunosorbent assay. Levels of gamma glutamyl transferase and alkaline phosphatase were measured in cholangiocytes. Organoids were incubated with troglitazone for varying periods and bile transport and accumulation were visualized by live-imaging microscopy. Organoids were incubated with oleic and palmitic acid, and formation of lipid droplets was visualized by staining. We compared gene expression profiles of organoids incubated with free fatty acids or without. We also compared gene expression profiles between liver tissue samples from patients with nonalcoholic steatohepatitis (NASH) versus without. We quantified hepatocyte and cholangiocyte populations in organoids using immunostaining and flow cytometry; cholangiocyte proliferation of cholangiocytes was measured. We compared the bile canaliculi network in the organoids incubated with versus without free fatty acids by live imaging. RESULTS: Cells in organoids differentiated into hepatocytes and cholangiocytes, based on the expression of albumin and cytokeratin 7. Hepatocytes were functional, based on secretion of albumin and apolipoprotein B and cytochrome P450 activity; cholangiocytes were functional, based on gamma glutamyl transferase and alkaline phosphatase activity and proliferative responses to secretin. The organoids organized a functional bile canaliculi system, which was disrupted by cholestasis-inducing drugs such as troglitazone. Organoids incubated with free fatty acids had gene expression signatures similar to those of liver tissues from patients with NASH. Incubation of organoids with free fatty acid-enriched media resulted in structural changes associated with nonalcoholic fatty liver disease, such as decay of bile canaliculi network and ductular reactions. CONCLUSIONS: We developed a hepatic organoid platform with human cells that can be used to model complex liver diseases, including NASH.
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Hepatocitos/citología , Hepatopatías/etiología , Hepatopatías/patología , Organoides/crecimiento & desarrollo , Células Madre Pluripotentes/fisiología , Técnicas de Cultivo de Célula , Humanos , Modelos BiológicosRESUMEN
The distinct states of pluripotency in the pre- and post-implantation embryo can be captured in vitro as naive and primed pluripotent stem cell cultures, respectively. The study and application of the naive state remains hampered, particularly in humans, partially due to current culture protocols relying on extraneous undefined factors such as feeders. Here we performed a small-molecule screen to identify compounds that facilitate chemically defined establishment and maintenance of human feeder-independent naive embryonic (FINE) stem cells. The expression profile in genic and repetitive elements of FINE cells resembles the 8-cell-to-morula stage in vivo, and only differs from feeder-dependent naive cells in genes involved in cell-cell/cell-matrix interactions. FINE cells offer several technical advantages, such as increased amenability to transfection and a longer period of genomic stability, compared with feeder-dependent cells. Thus, FINE cells will serve as an accessible and useful system for scientific and translational applications of naïve pluripotent stem cells.
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Técnicas de Cultivo de Célula , Autorrenovación de las Células/efectos de los fármacos , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/efectos de los fármacos , Biomarcadores , Supervivencia Celular/efectos de los fármacos , Dasatinib/farmacología , Descubrimiento de Drogas/métodos , Células Nutrientes , Ensayos Analíticos de Alto Rendimiento , Células Madre Embrionarias Humanas/citología , Células Madre Embrionarias Humanas/metabolismo , Humanos , Imidazoles/farmacología , Células Madre Pluripotentes/metabolismo , Pirimidinas/farmacología , Bibliotecas de Moléculas PequeñasRESUMEN
Tissues have a natural capacity to replace dying cells and to heal wounds. This ability resides in resident stem cells, which self-renew, preserve, and repair their tissue during homeostasis and following injury. The skin epidermis and its appendages are subjected to daily assaults from the external environment. A high demand is placed on renewal and regeneration of the skin's barrier in order to protect the body from infection and dehydration and to heal wounds. This review focuses on the epithelial stem cells of skin, where they come from, where they reside, and how they function in normal homeostasis and wound repair.
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Diferenciación Celular/fisiología , Células Epiteliales/citología , Regeneración/fisiología , Piel/patología , Células Madre/patología , Animales , Epidermis/patología , HumanosRESUMEN
Genome architecture is associated with cellular identity, but how this organization changes during reprogramming is not well understood. Now in Cell Stem Cell, Krijger et al. (2016) and Beagan et al. (2016) report 3D chromatin interaction maps before and after reprogramming, providing evidence for topological memory in induced pluripotent stem cells.
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Reprogramación Celular , Células Madre Pluripotentes Inducidas , Cromatina , Genoma , HumanosRESUMEN
While distinct cell cycle structures have been known to correlate with pluripotent or differentiated cell states [1], there is no evidence on how the cell cycle machinery directly contributes to human embryonic stem cell (hESC) pluripotency. We established a determinant role of cell cycle machineries on the pluripotent state by demonstrating that the specific perturbation of the S and G2 phases can prevent pluripotent state dissolution (PSD) [2]. Active mechanisms in these phases, such as the DNA damage checkpoint and Cyclin B1, promote the pluripotent state [2]. To understand the mechanisms behind the effect on PSD by these pathways in hESCs, we performed comprehensive gene expression analysis by time-course microarray experiments. From these datasets, we observed expression changes in genes involved in the TGFß signaling pathway, which has a well-established role in hESC maintenance [3], [4], [5]. The microarray data have been deposited in NCBI's Gene Expression Omnibus (GEO) and can be accessed through GEO Series accession numbers GSE62062 and GSE63215.
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The repertoire of transcripts encoded by the genome contributes to the diversity of cellular states. Functional genomics aims to comprehensively uncover the roles of these transcripts to reconstruct biological networks and transform this information into useful knowledge. High-throughput functional screening has served as a powerful genetic discovery tool by enabling massively parallel implementation of biological assays. In recent years, high-throughput screening has unearthed crucial players in the regulation of different aspects of pluripotency, which is a unique property that enables a cell to differentiate into multiple cell types of the three major lineages. Pluripotency thus represents an interesting biological paradigm for studying the acquisition, maintenance, and dissolution of cellular states. In this review, we highlight the major findings of high-throughput studies to dissect these three aspects of pluripotency for the mouse and human systems. Collectively, they provide new insights into cell fate maintenance and transition. In addition, we also discuss the opportunities and challenges awaiting high-throughput screening in the future.
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Diferenciación Celular/genética , Genoma , Células Madre Pluripotentes/metabolismo , Animales , Regulación de la Expresión Génica , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Ensayos Analíticos de Alto Rendimiento , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , RatonesRESUMEN
During differentiation, human embryonic stem cells (hESCs) shut down the regulatory network conferring pluripotency in a process we designated pluripotent state dissolution (PSD). In a high-throughput RNAi screen using an inclusive set of differentiation conditions, we identify centrally important and context-dependent processes regulating PSD in hESCs, including histone acetylation, chromatin remodeling, RNA splicing, and signaling pathways. Strikingly, we detected a strong and specific enrichment of cell-cycle genes involved in DNA replication and G2 phase progression. Genetic and chemical perturbation studies demonstrate that the S and G2 phases attenuate PSD because they possess an intrinsic propensity toward the pluripotent state that is independent of G1 phase. Our data therefore functionally establish that pluripotency control is hardwired to the cell-cycle machinery, where S and G2 phase-specific pathways deterministically restrict PSD, whereas the absence of such pathways in G1 phase potentially permits the initiation of differentiation.
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Ciclo Celular , Células Madre Embrionarias/citología , Redes Reguladoras de Genes , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Diferenciación Celular , Ciclina B2/metabolismo , Células Madre Embrionarias/metabolismo , Epigénesis Genética , Humanos , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
The maintenance of mouse embryonic stem cells (mESCs) requires LIF and serum. However, a pluripotent "ground state," bearing resemblance to preimplantation mouse epiblasts, can be established through dual inhibition (2i) of both prodifferentiation Mek/Erk and Gsk3/Tcf3 pathways. While Gsk3 inhibition has been attributed to the transcriptional derepression of Esrrb, the molecular mechanism mediated by Mek inhibition remains unclear. In this study, we show that Krüppel-like factor 2 (Klf2) is phosphorylated by Erk2 and that phospho-Klf2 is proteosomally degraded. Mek inhibition hence prevents Klf2 protein phosphodegradation to sustain pluripotency. Indeed, while Klf2-null mESCs can survive under LIF/Serum, they are not viable under 2i, demonstrating that Klf2 is essential for ground state pluripotency. Importantly, we also show that ectopic Klf2 expression can replace Mek inhibition in mESCs, allowing the culture of Klf2-null mESCs under Gsk3 inhibition alone. Collectively, our study defines the Mek/Erk/Klf2 axis that cooperates with the Gsk3/Tcf3/Esrrb pathway in mediating ground state pluripotency.
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Factores de Transcripción de Tipo Kruppel/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Animales , Células Cultivadas , Células Madre Embrionarias/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , RatonesRESUMEN
Human embryonic stem cells (hESCs) are derived from the inner cell mass of the blastocyst. Despite sharing the common property of pluripotency, hESCs are notably distinct from epiblast cells of the preimplantation blastocyst. Here we use a combination of three small-molecule inhibitors to sustain hESCs in a LIF signaling-dependent hESC state (3iL hESCs) with elevated expression of NANOG and epiblast-enriched genes such as KLF4, DPPA3, and TBX3. Genome-wide transcriptome analysis confirms that the expression signature of 3iL hESCs shares similarities with native preimplantation epiblast cells. We also show that 3iL hESCs have a distinct epigenetic landscape, characterized by derepression of preimplantation epiblast genes. Using genome-wide binding profiles of NANOG and OCT4, we identify enhancers that contribute to rewiring of the regulatory circuitry. In summary, our study identifies a distinct hESC state with defined regulatory circuitry that will facilitate future analysis of human preimplantation embryogenesis and pluripotency.
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Blastocisto/metabolismo , Redes Reguladoras de Genes , Estratos Germinativos/metabolismo , Células Madre Pluripotentes/citología , Células Madre Pluripotentes/metabolismo , Animales , Blastocisto/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Células Madre Embrionarias/citología , Células Madre Embrionarias/efectos de los fármacos , Células Madre Embrionarias/metabolismo , Epigénesis Genética/efectos de los fármacos , Factor de Transcripción GATA6/metabolismo , Redes Reguladoras de Genes/efectos de los fármacos , Estratos Germinativos/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Humanos , Factor 4 Similar a Kruppel , Factor Inhibidor de Leucemia/farmacología , Ratones , Modelos Biológicos , Proteína Homeótica Nanog , Células Madre Pluripotentes/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Bibliotecas de Moléculas Pequeñas/farmacología , Transcriptoma/efectos de los fármacos , Transcriptoma/genéticaRESUMEN
The identity of a cell is determined by the concerted interplay of multiple molecular modulators such as transcription factors, chromatin modifiers and signalling mediators. Among these, the transcriptional circuitry holds great influence on the specification and maintenance of a cellular state, and its perturbation can trigger a transition to another cell state. This is particularly striking in the field of pluripotency, where tempering the expression levels of one or few transcription factors is sufficient to induce the loss or acquisition of the pluripotent state. Recently, nuclear receptors, a class of transcription factors, have emerged as major players in the molecular network governing pluripotency. In this review, we discuss the importance of nuclear receptors in embryonic stem cell self-renewal, differentiation and cellular reprogramming, highlighting recent discoveries as well as providing an outlook in stem cell and nuclear receptor research.
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Reprogramación Celular , Células Madre Pluripotentes/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Humanos , Células Madre Pluripotentes/citologíaRESUMEN
BACKGROUND: The cyclic AMP-Protein Kinase A (cAMP-PKA) pathway is an evolutionarily conserved signal transduction mechanism that regulates cellular growth and differentiation in animals and fungi. We present a mathematical model that recapitulates the short-term and long-term dynamics of this pathway in the budding yeast, Saccharomyces cerevisiae. Our model is aimed at recapitulating the dynamics of cAMP signaling for wild-type cells as well as single (pde1Δ and pde2Δ) and double (pde1Δpde2Δ) phosphodiesterase mutants. RESULTS: Our model focuses on PKA-mediated negative feedback on the activity of phosphodiesterases and the Ras branch of the cAMP-PKA pathway. We show that both of these types of negative feedback are required to reproduce the wild-type signaling behavior that occurs on both short and long time scales, as well as the the observed responses of phosphodiesterase mutants. A novel feature of our model is that, for a wide range of parameters, it predicts that intracellular cAMP concentrations should exhibit decaying oscillatory dynamics in their approach to steady state following glucose stimulation. Experimental measurements of cAMP levels in two genetic backgrounds of S. cerevisiae confirmed the presence of decaying cAMP oscillations as predicted by the model. CONCLUSIONS: Our model of the cAMP-PKA pathway provides new insights into how yeast respond to alterations in their nutrient environment. Because the model has both predictive and explanatory power it will serve as a foundation for future mathematical and experimental studies of this important signaling network.
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Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , AMP Cíclico/metabolismo , Modelos Biológicos , Mutación , Fenotipo , Saccharomyces cerevisiae/citología , Transducción de Señal , Retroalimentación Fisiológica/efectos de los fármacos , Glucosa/farmacología , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/metabolismo , Reproducibilidad de los Resultados , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genéticaRESUMEN
The forkhead box O (FoxO) family is involved in diverse cellular processes such as tumor suppression, stress response, and metabolism. In a recent Nature Cell Biology Letter, Zhang et al. (2011) uncover a novel role for FoxO proteins in regulating the identity of human ESCs.
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Desarrollo Embrionario , Células Madre Embrionarias/metabolismo , Factores de Transcripción Forkhead/metabolismo , Células Madre Pluripotentes/metabolismo , Animales , Ciclo Celular , Supervivencia Celular , Desarrollo Embrionario/genética , Células Madre Embrionarias/patología , Proteína Forkhead Box O1 , Proteína Forkhead Box O3 , Factores de Transcripción Forkhead/genética , Regulación del Desarrollo de la Expresión Génica , Humanos , Ratones , Factor 3 de Transcripción de Unión a Octámeros/genética , Factor 3 de Transcripción de Unión a Octámeros/metabolismo , Células Madre Pluripotentes/patología , Factores de Transcripción SOXB1/genética , Factores de Transcripción SOXB1/metabolismo , Especificidad de la EspecieRESUMEN
The cellular identity of both pluripotent and differentiated cells is defined by the concerted interplay of transcriptional factors as well as other modulators such as epigenetic and signaling mediators. Therefore, the manipulation of a cell's transcriptional network directly facilitates inter-conversion between cellular identities. Understanding the molecular regulation of cell fate changes, including those involved in pluripotency, is crucial in realizing the practical potential of pluripotent and induced cell types. Here we review the advancements in the role of transcription factors in pluripotency, as well as in the conversion between and within pluripotent and somatic cell types.