Histone crotonylation promotes mesoendodermal commitment of human embryonic stem cells.
Abstract Histone crotonylation is a non-acetyl histone lysine modification that is as widespread as acetylation. However, physiological functions associated with histone crotonylation remain almost completely unknown. Here we report that histone crotonylation is crucial for endoderm differentiation. We demonstrate that key crotonyl-coenzyme A (CoA)-producing enzymes are specifically induced in endodermal cells during differentiation of human embryonic stem cells (hESCs) in vitro and in mouse embryos, where they function to increase histone crotonylation and enhance endodermal gene expression. Chemical enhance...
Source: Cell Stem Cell - January 8, 2021 Category: Stem Cells Authors: Fang Y, Xu X, Ding J, Yang L, Doan MT, Karmaus PWF, Snyder NW, Zhao Y, Li JL, Li X Tags: Cell Stem Cell Source Type: research

Surface antigen-guided CRISPR screens identify regulators of myeloid leukemia differentiation.
Abstract Lack of cellular differentiation is a hallmark of many human cancers, including acute myeloid leukemia (AML). Strategies to overcome such a differentiation blockade are an approach for treating AML. To identify targets for differentiation-based therapies, we applied an integrated cell surface-based CRISPR platform to assess genes involved in maintaining the undifferentiated state of leukemia cells. Here we identify the RNA-binding protein ZFP36L2 as a critical regulator of AML maintenance and differentiation. Mechanistically, ZFP36L2 interacts with the 3' untranslated region of key myeloid maturation gene...
Source: Cell Stem Cell - January 8, 2021 Category: Stem Cells Authors: Wang E, Zhou H, Nadorp B, Cayanan G, Chen X, Yeaton AH, Nomikou S, Witkowski MT, Narang S, Kloetgen A, Thandapani P, Ravn-Boess N, Tsirigos A, Aifantis I Tags: Cell Stem Cell Source Type: research

Single-cell analysis of the developing human testis reveals somatic niche cell specification and fetal germline stem cell establishment.
Abstract Human testis development in prenatal life involves complex changes in germline and somatic cell identity. To better understand, we profiled and analyzed ∼32,500 single-cell transcriptomes of testicular cells from embryonic, fetal, and infant stages. Our data show that at 6-7 weeks postfertilization, as the testicular cords are established, the Sertoli and interstitial cells originate from a common heterogeneous progenitor pool, which then resolves into fetal Sertoli cells (expressing tube-forming genes) or interstitial cells (including Leydig-lineage cells expressing steroidogenesis genes). ...
Source: Cell Stem Cell - January 8, 2021 Category: Stem Cells Authors: Guo J, Sosa E, Chitiashvili T, Nie X, Rojas EJ, Oliver E, DonorConnect, Plath K, Hotaling JM, Stukenborg JB, Clark AT, Cairns BR Tags: Cell Stem Cell Source Type: research

Retraction Notice to: Cancer-Related Mutations Identified in Primed and Naive Human Pluripotent Stem Cells.
PMID: 33433329 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Avior Y, Eggan K, Benvenisty N Tags: Cell Stem Cell Source Type: research

One Big Step to a Neuron, Two Small Steps for miRNAs.
Abstract Direct cell fate conversion of human somatic cells into induced neurons (iNs) is often regarded as a highly concerted one-step process. In this issue of Cell Stem Cell, Cates et al. (2021) dissect the iN conversion trajectory into two largely independent steps and identify key players at each stage. PMID: 33417865 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Herdy JR, Karbacher L, Mertens J Tags: Cell Stem Cell Source Type: research

Balancing Scientific Advice with Political Realities during the Campaign to Pass California's Ballot Proposition 14.
PMID: 33417866 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Goldstein LSB Tags: Cell Stem Cell Source Type: research

Introductions to the Community: Early-Career Researchers in the Time of COVID-19.
Authors: Abstract COVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers. PMID: 33417867 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Tags: Cell Stem Cell Source Type: research

Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/ β-Catenin Signaling.
Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/β-Catenin Signaling. Cell Stem Cell. 2021 Jan 07;28(1):170-172 Authors: Li Y, Chen M, Hu J, Sheng R, Lin Q, He X, Guo M PMID: 33417868 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Li Y, Chen M, Hu J, Sheng R, Lin Q, He X, Guo M Tags: Cell Stem Cell Source Type: research

Computational Stem Cell Biology: Open Questions and Guiding Principles.
Abstract Computational biology is enabling an explosive growth in our understanding of stem cells and our ability to use them for disease modeling, regenerative medicine, and drug discovery. We discuss four topics that exemplify applications of computation to stem cell biology: cell typing, lineage tracing, trajectory inference, and regulatory networks. We use these examples to articulate principles that have guided computational biology broadly and call for renewed attention to these principles as computation becomes increasingly important in stem cell biology. We also discuss important challenges for this field ...
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Cahan P, Cacchiarelli D, Dunn SJ, Hemberg M, de Sousa Lopes SMC, Morris SA, Rackham OJL, Del Sol A, Wells CA Tags: Cell Stem Cell Source Type: research

Growth Competition in Interspecies Chimeras: A New Paradigm for Blastocyst Complementation.
Abstract Blastocyst complementation represents a powerful technique for interspecies organogenesis but is limited by low chimerism due to developmental incompatibilities. In this issue of Cell Stem Cell,Nishimura et al. (2021) circumvent early developmental barriers by disabling Igf1r in host embryos, conferring donor cells with a growth advantage from mid-gestation onward. PMID: 33417870 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Ballard EB, Wu J Tags: Cell Stem Cell Source Type: research

UM171 Preserves Epigenetic Marks that Are Reduced in Ex Vivo Culture of Human HSCs via Potentiation of the CLR3-KBTBD4 Complex.
Abstract Human hematopoietic stem cells (HSCs) exhibit attrition of their self-renewal capacity when cultured ex vivo, a process that is partially reversed upon treatment with epigenetic modifiers, most notably inhibitors of histone deacetylases (HDACs) or lysine-specific demethylase LSD1. A recent study showed that the human HSC self-renewal agonist UM171 modulates the CoREST complex, leading to LSD1 degradation, whose inhibition mimics the activity of UM171. The mechanism underlying the UM171-mediated loss of CoREST function remains undetermined. We now report that UM171 potentiates the activity of a CULLIN...
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Chagraoui J, Girard S, Spinella JF, Simon L, Bonneil E, Mayotte N, MacRae T, Coulombe-Huntington J, Bertomeu T, Moison C, Tomellini E, Thibault P, Tyers M, Marinier A, Sauvageau G Tags: Cell Stem Cell Source Type: research

Unlocking Tissue Regenerative Potential by Epigenetic Reprogramming.
Abstract The regeneration potential of axons projecting from retinal ganglion cells (RGCs) is lost shortly after birth. In Nature, Lu et al. (2020) demonstrate that epigenetic reprogramming of RGCs by overexpression of Oct4, Sox2, and Klf4 leads to axon regeneration and restoration of vision in a glaucoma model and aged mice. PMID: 33417872 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Reddy P, Memczak S, Izpisua Belmonte JC Tags: Cell Stem Cell Source Type: research

Tipping the Scale: MYC Gains Weight in Fanconi Anemia Bone Marrow Failure Progression.
Abstract Fanconi anemia (FA) is an inherited syndrome of bone marrow failure (BMF) due to disrupted DNA repair. In this issue of Cell Stem Cell, Rodríguez et al. (2021) show that blood stem cells from FA patients have abnormal and inflammation-induced MYC expression, which promotes their proliferation in the face of increasing DNA damage. PMID: 33417873 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - January 7, 2021 Category: Stem Cells Authors: Renaudin X, Rosselli F Tags: Cell Stem Cell Source Type: research

Plasticity of distal nephron epithelia from human kidney organoids enables the induction of ureteric tip and stalk.
Abstract During development, distinct progenitors contribute to the nephrons versus the ureteric epithelium of the kidney. Indeed, previous human pluripotent stem-cell-derived models of kidney tissue either contain nephrons or pattern specifically to the ureteric epithelium. By re-analyzing the transcriptional distinction between distal nephron and ureteric epithelium in human fetal kidney, we show here that, while existing nephron-containing kidney organoids contain distal nephron epithelium and no ureteric epithelium, this distal nephron segment alone displays significant in vitro plasticity and can adopt a...
Source: Cell Stem Cell - December 21, 2020 Category: Stem Cells Authors: Howden SE, Wilson SB, Groenewegen E, Starks L, Forbes TA, Tan KS, Vanslambrouck JM, Holloway EM, Chen YH, Jain S, Spence JR, Little MH Tags: Cell Stem Cell Source Type: research

Generation of Functional Organs Using a Cell-Competitive Niche in Intra- and Inter-species Rodent Chimeras.
Abstract Interspecies organ generation via blastocyst complementation has succeeded in rodents, but not yet in evolutionally more distant species. Early developmental arrest hinders the formation of highly chimeric fetuses. We demonstrate that the deletion of insulin-like growth factor 1 receptor (Igf1r) in mouse embryos creates a permissive "cell-competitive niche" in several organs, significantly augmenting both mouse intraspecies and mouse/rat interspecies donor chimerism that continuously increases from embryonic day 11 onward, sometimes even taking over entire organs within intraspecies chimeras. Si...
Source: Cell Stem Cell - December 16, 2020 Category: Stem Cells Authors: Nishimura T, Suchy FP, Bhadury J, Igarashi KJ, Charlesworth CT, Nakauchi H Tags: Cell Stem Cell Source Type: research

Dcaf11 activates Zscan4-mediated alternative telomere lengthening in early embryos and embryonic stem cells.
Abstract Telomeres play vital roles in ensuring chromosome stability and are thus closely linked with the onset of aging and human disease. Telomeres undergo extensive lengthening during early embryogenesis. However, the detailed molecular mechanism of telomere resetting in early embryos remains unknown. Here, we show that Dcaf11 (Ddb1- and Cul4-associated factor 11) participates in telomere elongation in early embryos and 2-cell-like embryonic stem cells (ESCs). The deletion of Dcaf11 in embryos and ESCs leads to reduced telomere sister-chromatid exchange (T-SCE) and impairs telomere lengthening. Importantly, Dca...
Source: Cell Stem Cell - December 15, 2020 Category: Stem Cells Authors: Le R, Huang Y, Zhang Y, Wang H, Lin J, Dong Y, Li Z, Guo M, Kou X, Zhao Y, Chen M, Zhu Q, Zhao A, Yin J, Sun J, Su Z, Shi K, Gao Y, Chen J, Liu W, Kang L, Wang Y, Li C, Liu X, Gao R, Wang H, Ju Z, Gao S Tags: Cell Stem Cell Source Type: research

Integrative Single-Cell RNA-Seq and ATAC-Seq Analysis of Human Developmental Hematopoiesis.
Abstract Regulation of hematopoiesis during human development remains poorly defined. Here we applied single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) to over 8,000 human immunophenotypic blood cells from fetal liver and bone marrow. We inferred their differentiation trajectory and identified three highly proliferative oligopotent progenitor populations downstream of hematopoietic stem cells (HSCs)/multipotent progenitors (MPPs). Along this trajectory, we observed opposing patterns of chromatin accessibility and differentiation that coincided...
Source: Cell Stem Cell - December 15, 2020 Category: Stem Cells Authors: Ranzoni AM, Tangherloni A, Berest I, Riva SG, Myers B, Strzelecka PM, Xu J, Panada E, Mohorianu I, Zaugg JB, Cvejic A Tags: Cell Stem Cell Source Type: research

Cancer-Related Mutations Identified in Primed Human Pluripotent Stem Cells.
PMID: 33321073 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 10, 2020 Category: Stem Cells Authors: Avior Y, Lezmi E, Eggan K, Benvenisty N Tags: Cell Stem Cell Source Type: research

Cancer-Related Mutations Are Not Enriched in Naive Human Pluripotent Stem Cells.
Abstract Previous analysis of RNA sequencing (RNA-seq) data from human naive pluripotent stem cells reported multiple point "mutations" in cancer-related genes and implicated selective culture conditions. We observed, however, that those mutations were only present in co-cultures with mouse feeder cells. Inspection of reads containing the polymorphisms revealed complete identity to the mouse reference genome. After we filtered reads to remove sequences of mouse origin, the actual incidence of oncogenic polymorphisms arising in naive pluripotent stem cells is close to zero. PMID: 33321074 [PubMed - a...
Source: Cell Stem Cell - December 10, 2020 Category: Stem Cells Authors: Stirparo GG, Smith A, Guo G Tags: Cell Stem Cell Source Type: research

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis.
els E, Kramann R, Costa IG, Schneider RK Abstract Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-f...
Source: Cell Stem Cell - December 9, 2020 Category: Stem Cells Authors: Leimkühler NB, Gleitz HFE, Ronghui L, Snoeren IAM, Fuchs SNR, Nagai JS, Banjanin B, Lam KH, Vogl T, Kuppe C, Stalmann USA, Büsche G, Kreipe H, Gütgemann I, Krebs P, Banz Y, Boor P, Tai EW, Brümmendorf TH, Koschmieder S, Crysandt M, Bindels E, Kramann Tags: Cell Stem Cell Source Type: research

Introductions to the Community: Early-Career Researchers in the Time of COVID-19.
Abstract COVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers. PMID: 33275897 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 3, 2020 Category: Stem Cells Authors: Takayama K, Weaver LN, Lummertz da Rocha E, Lo Sardo V, Gehart H, Vu LP Tags: Cell Stem Cell Source Type: research

Scientific Collaboration and Communication in the Time of COVID-19: A Chat with Christine Mummery.
Authors: Abstract COVID-19 has impacted scientific efforts in laboratories and clinical facilities globally. In keeping with these exigencies, creative ways of scientific collaboration and communication have come to the fore. Cell Stem Cell asked Christine Mummery, President of the ISSCR 2020-2021, to share her perspectives on the successes and challenges of the ISSCR COVID-networking series. PMID: 33275898 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 3, 2020 Category: Stem Cells Tags: Cell Stem Cell Source Type: research

Modeling Multi-organ Infection by SARS-CoV-2  Using Stem Cell Technology.
Modeling Multi-organ Infection by SARS-CoV-2 Using Stem Cell Technology. Cell Stem Cell. 2020 Dec 03;27(6):859-868 Authors: Simoneau CR, Ott M Abstract SARS-CoV-2, the virus causing the current COVID-19 pandemic, primarily targets the airway epithelium and in lungs can lead to acute respiratory distress syndrome. Clinical studies in recent months have revealed that COVID-19 is a multi-organ disease causing characteristic complications. Stem cell models of various organ systems-most prominently, lung, gut, heart, and brain-are at the forefront of studies aimed at understanding the role of direct i...
Source: Cell Stem Cell - December 3, 2020 Category: Stem Cells Authors: Simoneau CR, Ott M Tags: Cell Stem Cell Source Type: research

ROS Dynamics Delineate Functional States of Hippocampal Neural Stem Cells and Link to Their Activity-Dependent Exit from Quiescence.
n G Abstract Cellular redox states regulate the balance between stem cell maintenance and activation. Increased levels of intracellular reactive oxygen species (ROS) are linked to proliferation and lineage specification. In contrast to this general principle, we here show that in the hippocampus of adult mice, quiescent neural precursor cells (NPCs) maintain the highest ROS levels (hiROS). Classifying NPCs on the basis of cellular ROS content identified distinct functional states. Shifts in ROS content primed cells for a subsequent state transition, with lower ROS content marking proliferative activity and differe...
Source: Cell Stem Cell - November 25, 2020 Category: Stem Cells Authors: Adusumilli VS, Walker TL, Overall RW, Klatt GM, Zeidan SA, Zocher S, Kirova DG, Ntitsias K, Fischer TJ, Sykes AM, Reinhardt S, Dahl A, Mansfeld J, Rünker AE, Kempermann G Tags: Cell Stem Cell Source Type: research

Differentiated Daughter Cells Regulate Stem Cell Proliferation and Fate through Intra-tissue Tension.
Abstract Basal stem cells fuel development, homeostasis, and regeneration of the epidermis. The proliferation and fate decisions of these cells are highly regulated by their microenvironment, including the basement membrane and underlying mesenchymal cells. Basal progenitors give rise to differentiated progeny that generate the epidermal barrier. Here, we present data that differentiated progeny also regulate the proliferation, differentiation, and migration of basal progenitor cells. Using two distinct mouse lines, we found that increasing contractility of differentiated cells resulted in non-cell-autonomous hype...
Source: Cell Stem Cell - November 24, 2020 Category: Stem Cells Authors: Ning W, Muroyama A, Li H, Lechler T Tags: Cell Stem Cell Source Type: research

Capture of Mouse and Human Stem Cells with Features of Formative Pluripotency.
Abstract Pluripotent cells emerge as a naive founder population in the blastocyst, acquire capacity for germline and soma formation, and then undergo lineage priming. Mouse embryonic stem cells (ESCs) and epiblast-derived stem cells (EpiSCs) represent the initial naive and final primed phases of pluripotency, respectively. Here, we investigate the intermediate formative stage. Using minimal exposure to specification cues, we derive stem cells from formative mouse epiblast. Unlike ESCs or EpiSCs, formative stem (FS) cells respond directly to germ cell induction. They colonize somatic tissues and germline in chimera...
Source: Cell Stem Cell - November 24, 2020 Category: Stem Cells Authors: Kinoshita M, Barber M, Mansfield W, Cui Y, Spindlow D, Stirparo GG, Dietmann S, Nichols J, Smith A Tags: Cell Stem Cell Source Type: research

Derivation of Intermediate Pluripotent Stem Cells Amenable to Primordial Germ Cell Specification.
Abstract Dynamic pluripotent stem cell (PSC) states are in vitro adaptations of pluripotency continuum in vivo. Previous studies have generated a number of PSCs with distinct properties. To date, however, no known PSCs have demonstrated dual competency for chimera formation and direct responsiveness to primordial germ cell (PGC) specification, a unique functional feature of formative pluripotency. Here, by modulating fibroblast growth factor (FGF), transforming growth factor β (TGF-β), and WNT pathways, we derived PSCs from mice, horses, and humans (designated as XPSCs) that are permissive for ...
Source: Cell Stem Cell - November 23, 2020 Category: Stem Cells Authors: Yu L, Wei Y, Sun HX, Mahdi AK, Pinzon Arteaga CA, Sakurai M, Schmitz DA, Zheng C, Ballard ED, Li J, Tanaka N, Kohara A, Okamura D, Mutto AA, Gu Y, Ross PJ, Wu J Tags: Cell Stem Cell Source Type: research

Direct Exposure to SARS-CoV-2 and Cigarette Smoke Increases Infection Severity and Alters the Stem Cell-Derived Airway Repair Response.
Abstract Current smoking is associated with increased risk of severe COVID-19, but it is not clear how cigarette smoke (CS) exposure affects SARS-CoV-2 airway cell infection. We directly exposed air-liquid interface (ALI) cultures derived from primary human nonsmoker airway basal stem cells (ABSCs) to short term CS and then infected them with SARS-CoV-2. We found an increase in the number of infected airway cells after CS exposure with a lack of ABSC proliferation. Single-cell profiling of the cultures showed that the normal interferon response was reduced after CS exposure with infection. Treatment of CS-exposed ...
Source: Cell Stem Cell - November 17, 2020 Category: Stem Cells Authors: Purkayastha A, Sen C, Garcia G, Langerman J, Shia DW, Meneses LK, Vijayaraj P, Durra A, Koloff CR, Freund DR, Chi J, Rickabaugh TM, Mulay A, Konda B, Sim MS, Stripp BR, Plath K, Arumugaswami V, Gomperts BN Tags: Cell Stem Cell Source Type: research

The Transition from Quiescent to Activated States in Human Hematopoietic Stem Cells Is Governed by Dynamic 3D Genome Reorganization.
, Lupien M Abstract Lifelong blood production requires long-term hematopoietic stem cells (LT-HSCs), marked by stemness states involving quiescence and self-renewal, to transition into activated short-term HSCs (ST-HSCs) with reduced stemness. As few transcriptional changes underlie this transition, we used single-cell and bulk assay for transposase-accessible chromatin sequencing (ATAC-seq) on human HSCs and hematopoietic stem and progenitor cell (HSPC) subsets to uncover chromatin accessibility signatures, one including LT-HSCs (LT/HSPC signature) and another excluding LT-HSCs (activated HSPC [Act/HSPC] signatur...
Source: Cell Stem Cell - November 17, 2020 Category: Stem Cells Authors: Takayama N, Murison A, Takayanagi SI, Arlidge C, Zhou S, Garcia-Prat L, Chan-Seng-Yue M, Zandi S, Gan OI, Boutzen H, Kaufmann KB, Trotman-Grant A, Schoof E, Kron K, Díaz N, Lee JJY, Medina T, De Carvalho DD, Taylor MD, Vaquerizas JM, Xie SZ, Dick JE, Lup Tags: Cell Stem Cell Source Type: research

Androgen Signaling Regulates SARS-CoV-2 Receptor Levels and Is Associated with Severe COVID-19 Symptoms in Men.
H, Fattahi F Abstract SARS-CoV-2 infection has led to a global health crisis, and yet our understanding of the disease and potential treatment options remains limited. The infection occurs through binding of the virus with angiotensin converting enzyme 2 (ACE2) on the cell membrane. Here, we established a screening strategy to identify drugs that reduce ACE2 levels in human embryonic stem cell (hESC)-derived cardiac cells and lung organoids. Target analysis of hit compounds revealed androgen signaling as a key modulator of ACE2 levels. Treatment with antiandrogenic drugs reduced ACE2 expression and protected hESC...
Source: Cell Stem Cell - November 17, 2020 Category: Stem Cells Authors: Samuel RM, Majd H, Richter MN, Ghazizadeh Z, Zekavat SM, Navickas A, Ramirez JT, Asgharian H, Simoneau CR, Bonser LR, Koh KD, Garcia-Knight M, Tassetto M, Sunshine S, Farahvashi S, Kalantari A, Liu W, Andino R, Zhao H, Natarajan P, Erle DJ, Ott M, Goodarz Tags: Cell Stem Cell Source Type: research

Inherited DNA Repair Defects Disrupt the Structure and Function of Human Skin.
Abstract Squamous cell carcinoma (SCC) is a global public health burden originating in epidermal stem and progenitor cells (ESPCs) of the skin and mucosa. To understand how genetic risk factors contribute to SCC, studies of ESPC biology are imperative. Children with Fanconi anemia (FA) are a paradigm for extreme SCC susceptibility caused by germline loss-of-function mutations in FA DNA repair pathway genes. To discover epidermal vulnerabilities, patient-derived pluripotent stem cells (PSCs) conditional for the FA pathway were differentiated into ESPCs and PSC-derived epidermal organotypic rafts (PSC-EORs). FA PSC-...
Source: Cell Stem Cell - November 12, 2020 Category: Stem Cells Authors: Ruiz-Torres S, Brusadelli MG, Witte DP, Wikenheiser-Brokamp KA, Sauter S, Nelson AS, Sertorio M, Chlon TM, Lane A, Mehta PA, Myers KC, Bedard MC, Pal B, Supp DM, Lambert PF, Komurov K, Kovacic MB, Davies SM, Wells SI Tags: Cell Stem Cell Source Type: research

Cell Surface Mechanics Gate Embryonic Stem Cell Differentiation.
ilde;oz A Abstract Cell differentiation typically occurs with concomitant shape transitions to enable specialized functions. To adopt a different shape, cells need to change the mechanical properties of their surface. However, whether cell surface mechanics control the process of differentiation has been relatively unexplored. Here we show that membrane mechanics gate exit from naive pluripotency of mouse embryonic stem cells. By measuring membrane tension during early differentiation, we find that naive stem cells release their plasma membrane from the underlying actin cortex when transitioning to a primed state....
Source: Cell Stem Cell - November 12, 2020 Category: Stem Cells Authors: Bergert M, Lembo S, Sharma S, Russo L, Milovanović D, Gretarsson KH, Börmel M, Neveu PA, Hackett JA, Petsalaki E, Diz-Muñoz A Tags: Cell Stem Cell Source Type: research

Membrane Tension Gates ERK-Mediated Regulation of Pluripotent Cell Fate.
Abstract Cell fate transitions are frequently accompanied by changes in cell shape and mechanics. However, how cellular mechanics affects the instructive signaling pathways controlling cell fate is poorly understood. To probe the interplay between shape, mechanics, and fate, we use mouse embryonic stem cells (ESCs), which change shape as they undergo early differentiation. We find that shape change is regulated by a β-catenin-mediated decrease in RhoA activity and subsequent decrease in the plasma membrane tension. Strikingly, preventing a decrease in membrane tension results in early differentiation defects ...
Source: Cell Stem Cell - November 11, 2020 Category: Stem Cells Authors: De Belly H, Stubb A, Yanagida A, Labouesse C, Jones PH, Paluch EK, Chalut KJ Tags: Cell Stem Cell Source Type: research

CRISPR-Mediated Induction of Neuron-Enriched Mitochondrial Proteins Boosts Direct Glia-to-Neuron Conversion.
z M Abstract Astrocyte-to-neuron conversion is a promising avenue for neuronal replacement therapy. Neurons are particularly dependent on mitochondrial function, but how well mitochondria adapt to the new fate is unknown. Here, we determined the comprehensive mitochondrial proteome of cortical astrocytes and neurons, identifying about 150 significantly enriched mitochondrial proteins for each cell type, including transporters, metabolic enzymes, and cell-type-specific antioxidants. Monitoring their transition during reprogramming revealed late and only partial adaptation to the neuronal identity. Early dCas9-media...
Source: Cell Stem Cell - November 9, 2020 Category: Stem Cells Authors: Russo GL, Sonsalla G, Natarajan P, Breunig CT, Bulli G, Merl-Pham J, Schmitt S, Giehrl-Schwab J, Giesert F, Jastroch M, Zischka H, Wurst W, Stricker SH, Hauck SM, Masserdotti G, Götz M Tags: Cell Stem Cell Source Type: research

A Hierarchy of Proliferative and Migratory Keratinocytes Maintains the Tympanic Membrane.
Abstract The tympanic membrane (TM) is critical for hearing and requires continuous clearing of cellular debris, but little is known about homeostatic mechanisms in the TM epidermis. Using single-cell RNA sequencing, lineage tracing, whole-organ explant, and live-cell imaging, we show that homeostatic TM epidermis is distinct from other epidermal sites and has discrete proliferative zones with a three-dimensional hierarchy of multiple keratinocyte populations. TM stem cells reside in a discrete location of the superior TM and generate long-lived clones and committed progenitors (CPs). CP clones exhibit lateral mig...
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Frumm SM, Yu SK, Chang J, Artichoker JA, Scaria SM, Lee KP, Byrnes LE, Sneddon JB, Tward AD Tags: Cell Stem Cell Source Type: research

Targeting LSCs: Peeling Back the Curtain on the Metabolic Complexities of AML.
Abstract Most patients with AML succumb to chemoresistant leukemia stem cells (LSCs), which persist and reinitiate disease years after clinical remission. In this issue of Cell Stem Cell, Jones et al. (2020) identify a therapeutically targetable mechanism of resistance to venetoclax in relapsed and refractory AML LSCs mediated by nicotinamide metabolism. PMID: 33157042 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Zhang TY, Majeti R Tags: Cell Stem Cell Source Type: research

A "Switch" in Time through Genes Aligned: Unraveling the Genomic Landscape of HSC Development.
A "Switch" in Time through Genes Aligned: Unraveling the Genomic Landscape of HSC Development. Cell Stem Cell. 2020 Nov 05;27(5):695-697 Authors: Apostol AC, López DA, Beaudin AE Abstract Seeking to define the "switch" from fetal to adult hematopoiesis, Li et al. (2020) performed extensive genomic and epigenomic profiling of hematopoietic stem and progenitor cells across ontogeny (as explored in this issue of Cell Stem Cell). Gradual and stochastic changes in genomic and epigenomic regulation suggest the absence of any specific regulator. PMID: 33157043 [PubMed - i...
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Apostol AC, López DA, Beaudin AE Tags: Cell Stem Cell Source Type: research

Dynamic Hydrogels for Investigating Vascularization.
Abstract Extracellular matrix is known to regulate vascularization by a sequence of multiple factors including mechanical forces. In this issue of Cell Stem Cell, Wei et al. (2020) investigate the roles of matrix biomechanics on early stages of vasculogenesis by using hydrogels with tunable stiffness and stress relaxation. PMID: 33157044 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Vunjak-Novakovic G Tags: Cell Stem Cell Source Type: research

A Purpose in Liquidity: Perfusing 3D Open Scaffolds Improves "Mini-gut" Morphogenesis and Longevity.
A Purpose in Liquidity: Perfusing 3D Open Scaffolds Improves "Mini-gut" Morphogenesis and Longevity. Cell Stem Cell. 2020 Nov 05;27(5):699-701 Authors: Schlieve CR, Grikscheit TC Abstract Channeling morphogenic signaling gradients intrinsic to intestinal epithelial stem cells, Nikolaev et al. (2020) optimized a three-dimensional microchip perfusion system that augments growth, maturation, and longevity of tubular intestinal enteroids. Reported in Nature, this system may ultimately pave the way to study human intestinal development and pathophysiology, perhaps for therapeutic discovery. ...
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Schlieve CR, Grikscheit TC Tags: Cell Stem Cell Source Type: research

Introductions to the Community: Early-Career Researchers in the Time of COVID-19.
Abstract COVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers. PMID: 33157046 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Smith Q, McKinley KL, Chan CJ, Sikandar S, Xiang Y, Passaro D Tags: Cell Stem Cell Source Type: research

CRISPR-Cas Tools and Their Application in Genetic Engineering of Human Stem Cells and Organoids.
Abstract CRISPR-Cas technology has revolutionized biological research and holds great therapeutic potential. Here, we review CRISPR-Cas systems and their latest developments with an emphasis on application to human cells. We also discuss how different CRISPR-based strategies can be used to accomplish a particular genome engineering goal. We then review how different CRISPR tools have been used in genome engineering of human stem cells in vitro, covering both the pluripotent (iPSC/ESC) and somatic adult stem cell fields and, in particular, 3D organoid cultures. Finally, we discuss the progress and challenges a...
Source: Cell Stem Cell - November 5, 2020 Category: Stem Cells Authors: Hendriks D, Clevers H, Artegiani B Tags: Cell Stem Cell Source Type: research

Multimerization of Zika Virus-NS5 Causes Ciliopathy and Forces Premature Neurogenesis.
aguer N, Martí E Abstract Zika virus (ZikV) is a flavivirus that infects neural tissues, causing congenital microcephaly. ZikV has evolved multiple mechanisms to restrict proliferation and enhance cell death, although the underlying cellular events involved remain unclear. Here we show that the ZikV-NS5 protein interacts with host proteins at the base of the primary cilia in neural progenitor cells, causing an atypical non-genetic ciliopathy and premature neuron delamination. Furthermore, in human microcephalic fetal brain tissue, ZikV-NS5 persists at the base of the motile cilia in ependymal cells, which a...
Source: Cell Stem Cell - October 27, 2020 Category: Stem Cells Authors: Saade M, Ferrero DS, Blanco-Ameijeiras J, Gonzalez-Gobartt E, Flores-Mendez M, Ruiz-Arroyo VM, Martínez-Sáez E, Ramón Y Cajal S, Akizu N, Verdaguer N, Martí E Tags: Cell Stem Cell Source Type: research

BMP10 Signaling Promotes the Development of Endocardial Cells from Human Pluripotent Stem Cell-Derived Cardiovascular Progenitors.
Abstract The embryonic endocardium is essential for early heart development as it functions to induce trabecular myocardium, the first heart tissue to form, and is the source of the cells that make up the valves and a portion of the coronary vasculature. With this potential, human endocardial cells could provide unique therapeutic opportunities that include engineering biological valves and cell-based therapy strategies to replace coronary vasculature in damaged hearts. To access human endocardial cells, we generated a human pluripotent stem cell (hPSC)-derived endothelial population that displays many characteris...
Source: Cell Stem Cell - October 27, 2020 Category: Stem Cells Authors: Mikryukov AA, Mazine A, Wei B, Yang D, Miao Y, Gu M, Keller GM Tags: Cell Stem Cell Source Type: research

Three-Dimensional Human Alveolar Stem Cell Culture Models Reveal Infection Response to SARS-CoV-2.
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the cause of a present pandemic, infects human lung alveolar type 2 (hAT2) cells. Characterizing pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hAT2 cells limits the study. Here, we develop a feeder-free, long-term, three-dimensional (3D) culture technique for hAT2 cells derived from primary human lung tissue and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid...
Source: Cell Stem Cell - October 21, 2020 Category: Stem Cells Authors: Youk J, Kim T, Evans KV, Jeong YI, Hur Y, Hong SP, Kim JH, Yi K, Kim SY, Na KJ, Bleazard T, Kim HM, Fellows M, Mahbubani KT, Saeb-Parsy K, Kim SY, Kim YT, Koh GY, Choi BS, Ju YS, Lee JH Tags: Cell Stem Cell Source Type: research

Human Lung Stem Cell-Based Alveolospheres Provide Insights into SARS-CoV-2-Mediated Interferon Responses and Pneumocyte Dysfunction.
Abstract Coronavirus infection causes diffuse alveolar damage leading to acute respiratory distress syndrome. The absence of ex vivo models of human alveolar epithelium is hindering an understanding of coronavirus disease 2019 (COVID-19) pathogenesis. Here, we report a feeder-free, scalable, chemically defined, and modular alveolosphere culture system for the propagation and differentiation of human alveolar type 2 cells/pneumocytes derived from primary lung tissue. Cultured pneumocytes express the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor angiotensin-converting enzyme receptor typ...
Source: Cell Stem Cell - October 21, 2020 Category: Stem Cells Authors: Katsura H, Sontake V, Tata A, Kobayashi Y, Edwards CE, Heaton BE, Konkimalla A, Asakura T, Mikami Y, Fritch EJ, Lee PJ, Heaton NS, Boucher RC, Randell SH, Baric RS, Tata PR Tags: Cell Stem Cell Source Type: research

Derivation of Airway Basal Stem Cells from Human Pluripotent Stem Cells.
er EJ, Horani A, Brody SL, Davis BR, Kotton DN Abstract The derivation of tissue-specific stem cells from human induced pluripotent stem cells (iPSCs) would have broad reaching implications for regenerative medicine. Here, we report the directed differentiation of human iPSCs into airway basal cells ("iBCs"), a population resembling the stem cell of the airway epithelium. Using a dual fluorescent reporter system (NKX2-1GFP;TP63tdTomato), we track and purify these cells as they first emerge as developmentally immature NKX2-1GFP+ lung progenitors and subsequently augment a TP63 program during proximal airw...
Source: Cell Stem Cell - October 19, 2020 Category: Stem Cells Authors: Hawkins FJ, Suzuki S, Beermann ML, Barillà C, Wang R, Villacorta-Martin C, Berical A, Jean JC, Le Suer J, Matte T, Simone-Roach C, Tang Y, Schlaeger TM, Crane AM, Matthias N, Huang SXL, Randell SH, Wu J, Spence JR, Carraro G, Stripp BR, Rab A, Sorsher EJ Tags: Cell Stem Cell Source Type: research

Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/ β-Catenin Signaling.
Volumetric Compression Induces Intracellular Crowding to Control Intestinal Organoid Growth via Wnt/β-Catenin Signaling. Cell Stem Cell. 2020 Oct 13;: Authors: Li Y, Chen M, Hu J, Sheng R, Lin Q, He X, Guo M Abstract Enormous amounts of essential intracellular events are crowdedly packed inside picoliter-sized cellular space. However, the significance of the physical properties of cells remains underappreciated because of a lack of evidence of how they affect cellular functionalities. Here, we show that volumetric compression regulates the growth of intestinal organoids by modifying intracellular...
Source: Cell Stem Cell - October 13, 2020 Category: Stem Cells Authors: Li Y, Chen M, Hu J, Sheng R, Lin Q, He X, Guo M Tags: Cell Stem Cell Source Type: research

Dux-Mediated Corrections of Aberrant H3K9ac during 2-Cell Genome Activation Optimize Efficiency of Somatic Cell Nuclear Transfer.
Abstract Differentiated somatic cells can be reprogrammed to totipotent embryos through somatic cell nuclear transfer (SCNT) with low efficiency. The histone deacetylase inhibitor trichostatin A (TSA) has been found to improve SCNT efficiency, but the underlying mechanism remains undetermined. Here, we examined genome-wide H3K9ac during SCNT embryo development and found that aberrant H3K9ac regions resulted in reduced 2-cell genome activation. TSA treatment largely corrects aberrant acetylation in SCNT embryos with an efficiency that is dictated by the native epigenetic environment. We further identified that the ...
Source: Cell Stem Cell - October 5, 2020 Category: Stem Cells Authors: Yang G, Zhang L, Liu W, Qiao Z, Shen S, Zhu Q, Gao R, Wang M, Wang M, Li C, Liu M, Sun J, Wang L, Liu W, Cui X, Zhao K, Zang R, Chen M, Liang Z, Wang L, Kou X, Zhao Y, Wang H, Wang Y, Gao S, Chen J, Jiang C Tags: Cell Stem Cell Source Type: research

Defining the First Part of the Oncogenic KRAS Journey.
Abstract Discovered as a proto-oncogene 40 years ago, mutations in KRAS exist in ∼30% of all human cancers. In this issue of Cell Stem Cell,Dost et al. (2020) combine the power of analyzing organoid cultures, patient samples, and mouse models with scRNA-seq to elucidate early events occurring with oncogenic KRAS activation. PMID: 33007229 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 30, 2020 Category: Stem Cells Authors: Osborne JK, Minna JD Tags: Cell Stem Cell Source Type: research

The Hippo Show Must Go On: YAP Activation as a Therapeutic Strategy in Colorectal Cancer.
Abstract The role of Hippo pathway in colorectal cancer (CRC) initiation and progression has been controversial. In this issue of Cell Stem Cell, Cheung et al. (2020) shed new light on a distinct function of the transcriptional co-activator YAP as a tumor suppressor and Wnt pathway inhibitor in CRC. PMID: 33007230 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 30, 2020 Category: Stem Cells Authors: Veschi V, Stassi G Tags: Cell Stem Cell Source Type: research