Mapping Gene Circuits Essential for Germ Layer Differentiation via Loss-of-Function Screens in Haploid Human Embryonic Stem Cells.
Abstract Pluripotent stem cells can differentiate into all embryonic germ layers, yet the genes essential for these cell fate transitions in human remain elusive. Here, we mapped the essential genes for the differentiation of human pluripotent stem cells (hPSCs) into the three germ layers by using a genome-wide loss-of-function library established in haploid hPSCs. Strikingly, we observed a high fraction of essential genes associated with plasma membrane, highlighting signaling pathways needed for each lineage differentiation. Interestingly, analysis of all hereditary neurological disorders uncovered high essentia...
Source: Cell Stem Cell - July 28, 2020 Category: Stem Cells Authors: Yilmaz A, Braverman-Gross C, Bialer-Tsypin A, Peretz M, Benvenisty N Tags: Cell Stem Cell Source Type: research

Regenerative Reprogramming of the Intestinal Stem Cell State via Hippo Signaling Suppresses Metastatic Colorectal Cancer.
FD Abstract Although the Hippo transcriptional coactivator YAP is considered oncogenic in many tissues, its roles in intestinal homeostasis and colorectal cancer (CRC) remain controversial. Here, we demonstrate that the Hippo kinases LATS1/2 and MST1/2, which inhibit YAP activity, are required for maintaining Wnt signaling and canonical stem cell function. Hippo inhibition induces a distinct epithelial cell state marked by low Wnt signaling, a wound-healing response, and transcription factor Klf6 expression. Notably, loss of LATS1/2 or overexpression of YAP is sufficient to reprogram Lgr5+ cancer stem cells to th...
Source: Cell Stem Cell - July 24, 2020 Category: Stem Cells Authors: Cheung P, Xiol J, Dill MT, Yuan WC, Panero R, Roper J, Osorio FG, Maglic D, Li Q, Gurung B, Calogero RA, Yilmaz ÖH, Mao J, Camargo FD Tags: Cell Stem Cell Source Type: research

Aging and Rejuvenation of Neural Stem Cells and Their Niches.
Abstract Aging has a profound and devastating effect on the brain. Old age is accompanied by declining cognitive function and enhanced risk of brain diseases, including cancer and neurodegenerative disorders. A key question is whether cells with regenerative potential contribute to brain health and even brain "rejuvenation." This review discusses mechanisms that regulate neural stem cells (NSCs) during aging, focusing on the effect of metabolism, genetic regulation, and the surrounding niche. We also explore emerging rejuvenating strategies for old NSCs. Finally, we consider how new technologies may help...
Source: Cell Stem Cell - July 21, 2020 Category: Stem Cells Authors: Navarro Negredo P, Yeo RW, Brunet A Tags: Cell Stem Cell Source Type: research

Distinct Spatiotemporally Dynamic Wnt-Secreting Niches Regulate Proximal Airway Regeneration and Aging.
Abstract Our understanding of dynamic interactions between airway basal stem cells (ABSCs) and their signaling niches in homeostasis, injury, and aging remains elusive. Using transgenic mice and pharmacologic studies, we found that Wnt/β-catenin within ABSCs was essential for proliferation post-injury in vivo. ABSC-derived Wnt ligand production was dispensable for epithelial proliferation. Instead, the PDGFRα+ lineage in the intercartilaginous zone (ICZ) niche transiently secreted Wnt ligand necessary for ABSC proliferation. Strikingly, ABSC-derived Wnt ligand later drove early progenitor different...
Source: Cell Stem Cell - July 20, 2020 Category: Stem Cells Authors: Aros CJ, Vijayaraj P, Pantoja CJ, Bisht B, Meneses LK, Sandlin JM, Tse JA, Chen MW, Purkayastha A, Shia DW, Sucre JMS, Rickabaugh TM, Vladar EK, Paul MK, Gomperts BN Tags: Cell Stem Cell Source Type: research

BMI1 Inhibition Eliminates Residual Cancer Stem Cells after PD1 Blockade and Activates Antitumor Immunity to Prevent Metastasis and Relapse.
Abstract PD1 blockade-based combination therapy has been approved as a first-line treatment for head and neck squamous cell carcinoma (HNSCC). However, the response rate remains relatively low, and patients with HNSCC eventually relapse. Here, we show that the combination treatment of anti-PD1 and cisplatin enriched BMI1+ CSCs in HNSCC while inhibiting HNSCC growth. In contrast, the pharmacological and genetic inhibition of BMI1 eliminated BMI1+ CSCs and enabled PD1 blockade therapy, resulting in the inhibition of metastatic HNSCC and prevention of HNSCC relapses. BMI1 inhibition strongly induced tumor cell-i...
Source: Cell Stem Cell - July 20, 2020 Category: Stem Cells Authors: Jia L, Zhang W, Wang CY Tags: Cell Stem Cell Source Type: research

Mesenchymal Niche-Derived Neuregulin-1 Drives Intestinal Stem Cell Proliferation and Regeneration of Damaged Epithelium.
ud HE Abstract Epidermal growth factor (EGF) maintains intestinal stem cell (ISC) proliferation and is a key component of organoid growth media yet is dispensable for intestinal homeostasis, suggesting roles for multiple EGF family ligands in ISC function. Here, we identified neuregulin 1 (NRG1) as a key EGF family ligand that drives tissue repair following injury. NRG1, but not EGF, is upregulated upon damage and is expressed in mesenchymal stromal cells, macrophages, and Paneth cells. NRG1 deletion reduces proliferation in intestinal crypts and compromises regeneration capacity. NRG1 robustly stimulates prolifer...
Source: Cell Stem Cell - July 14, 2020 Category: Stem Cells Authors: Jardé T, Chan WH, Rossello FJ, Kaur Kahlon T, Theocharous M, Kurian Arackal T, Flores T, Giraud M, Richards E, Chan E, Kerr G, Engel RM, Prasko M, Donoghue JF, Abe SI, Phesse TJ, Nefzger CM, McMurrick PJ, Powell DR, Daly RJ, Polo JM, Abud HE Tags: Cell Stem Cell Source Type: research

LEFTY1 Is a Dual-SMAD Inhibitor that Promotes Mammary Progenitor Growth and Tumorigenesis.
Abstract SMAD pathways govern epithelial proliferation, and transforming growth factor β (TGF-β and BMP signaling through SMAD members has distinct effects on mammary development and homeostasis. Here, we show that LEFTY1, a secreted inhibitor of NODAL/SMAD2 signaling, is produced by mammary progenitor cells and, concomitantly, suppresses SMAD2 and SMAD5 signaling to promote long-term proliferation of normal and malignant mammary epithelial cells. In contrast, BMP7, a NODAL antagonist with context-dependent functions, is produced by basal cells and restrains progenitor cell proliferation. In normal mouse...
Source: Cell Stem Cell - July 14, 2020 Category: Stem Cells Authors: Zabala M, Lobo NA, Antony J, Heitink LS, Gulati GS, Lam J, Parashurama N, Sanchez K, Adorno M, Sikandar SS, Kuo AH, Qian D, Kalisky T, Sim S, Li L, Dirbas FM, Somlo G, Newman A, Quake SR, Clarke MF Tags: Cell Stem Cell Source Type: research

Tissue-Biased Expansion of DNMT3A-Mutant Clones in a Mosaic Individual Is Associated with Conserved Epigenetic Erosion.
Abstract DNA methyltransferase 3A (DNMT3A) is the most commonly mutated gene in clonal hematopoiesis (CH). Somatic DNMT3A mutations arise in hematopoietic stem cells (HSCs) many years before malignancies develop, but difficulties in comparing their impact before malignancy with wild-type cells have limited the understanding of their contributions to transformation. To circumvent this limitation, we derived normal and DNMT3A mutant lymphoblastoid cell lines from a germline mosaic individual in whom these cells co-existed for nearly 6 decades. Mutant cells dominated the blood system, but not other tissues. Deep sequ...
Source: Cell Stem Cell - July 14, 2020 Category: Stem Cells Authors: Tovy A, Reyes JM, Gundry MC, Brunetti L, Lee-Six H, Petljak M, Park HJ, Guzman AG, Rosas C, Jeffries AR, Baple E, Mill J, Crosby AH, Sency V, Xin B, Machado HE, Castillo D, Weitzel JN, Li W, Stratton MR, Campbell PJ, Wang H, Sanders MA, Goodell MA Tags: Cell Stem Cell Source Type: research

Overcoming Autocrine FGF Signaling-Induced Heterogeneity in Naive Human ESCs Enables Modeling of Random X Chromosome Inactivation.
Abstract Primed and naive human embryonic stem cells (hESCs) do not fully recapitulate the X chromosome status observed in human preimplantation epiblast and fail to initiate random X chromosome inactivation (XCI) upon differentiation. Therefore, an ideal system for studying XCI during early human development is yet to be established. We show that incomplete blocking of autocrine fibroblast growth factor 2 (FGF2) signaling in naive hESCs drives significant heterogeneity in X chromosome and pluripotency status. We derived homozygous XaXa naive hESCs with dual allelic XIST expression and high levels of TFCP2L1, whos...
Source: Cell Stem Cell - July 8, 2020 Category: Stem Cells Authors: An C, Feng G, Zhang J, Cao S, Wang Y, Wang N, Lu F, Zhou Q, Wang H Tags: Cell Stem Cell Source Type: research

One for All: A Pooled Approach to Classify Functional Impacts of Multiple Mutations.
Abstract Understanding common biological consequences of heterogenous mutations in complex polygenic conditions is challenging. In this issue of Cell Stem Cell, Cederquist et al. (2020) implement an in vitro pooled assay where 30 high-confidence ASD mutations engineered in subclones of a human pluripotent stem cell line can be investigated in parallel to reveal their effects on prefrontal cortex neurogenesis. PMID: 32619508 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Jourdon A, Vaccarino FM Tags: Cell Stem Cell Source Type: research

Effects of Diet Choice on Stem Cell Function Necessitate Clarity in Selection and Reporting.
PMID: 32619509 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Li W, Houston M, Peregrina K, Ye K, Augenlicht LH 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: 32619510 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Tags: Cell Stem Cell Source Type: research

Is Obesity a Disease of Stem Cells?
We present growing evidence that reveals the bidirectionality of obesity-induced stem cell dysfunction and how the molecular changes in stem cells residing in obese environments may accelerate disease severity. PMID: 32619511 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Oestreich AK, Collins KH, Harasymowicz NS, Wu CL, Guilak F Tags: Cell Stem Cell Source Type: research

Pathogen-Induced TLR4-TRIF Innate Immune Signaling in Hematopoietic Stem Cells Promotes Proliferation but Reduces Competitive Fitness.
nz MG PMID: 32619512 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Takizawa H, Fritsch K, Kovtonyuk LV, Saito Y, Yakkala C, Jacobs K, Ahuja AK, Lopes M, Hausmann A, Hardt WD, Gomariz Á, Nombela-Arrieta C, Manz MG Tags: Cell Stem Cell Source Type: research

Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.
PMID: 32619513 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Toyohara T, Roudnicky F, Florido MHC, Nakano T, Yu H, Katsuki S, Lee M, Meissner T, Friesen M, Davidow LS, Ptaszek L, Abe T, Rubin LL, Pereira AC, Aikawa M, Cowan CA Tags: Cell Stem Cell Source Type: research

A Human Skeletal Muscle Atlas Identifies the Trajectories of Stem and Progenitor Cells across Development and from Human Pluripotent Stem Cells.
PMID: 32619514 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Xi H, Langerman J, Sabri S, Chien P, Young CS, Younesi S, Hicks M, Gonzalez K, Fujiwara W, Marzi J, Liebscher S, Spencer M, Van Handel B, Evseenko D, Schenke-Layland K, Plath K, Pyle AD Tags: Cell Stem Cell Source Type: research

Cell-by-Cell Deconstruction of Stem Cell Niches.
Abstract Single-cell sequencing approaches offer exploration of tissue architecture at unprecedented resolution. These tools are especially powerful when deconvoluting highly specialized microenvironments, such as stem cell (SC) niches. Here, we review single-cell studies that map the cellular and transcriptional makeup of stem and progenitor niches and discuss how these high-resolution analyses fundamentally advance our understanding of how niche factors shape SC biology and activity. In-depth characterization of the blueprint of SC-niche crosstalk, as well as understanding how it becomes dysregulated, will undou...
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Tikhonova AN, Lasry A, Austin R, Aifantis I Tags: Cell Stem Cell Source Type: research

Rubbing Out Leukemia Stem Cells by Erasing the Eraser.
Abstract In this issue of Cell Stem Cell, Shen et al. (2020) and Wang et al. (2020) independently identify the essential function of m6A demethylase ALKBH5 in maintaining myeloid leukemia stem cells. These studies expand the regulators of the epitranscriptome that are required for acute myeloid leukemia (AML) development. PMID: 32619516 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Cheng Y, Luo H, Kharas MG Tags: Cell Stem Cell Source Type: research

A Multiplex Human Pluripotent Stem Cell Platform Defines Molecular and Functional Subclasses of Autism-Related Genes.
Abstract Autism is a clinically heterogeneous neurodevelopmental disorder characterized by impaired social interactions, restricted interests, and repetitive behaviors. Despite significant advances in the genetics of autism, understanding how genetic changes perturb brain development and affect clinical symptoms remains elusive. Here, we present a multiplex human pluripotent stem cell (hPSC) platform, in which 30 isogenic disease lines are pooled in a single dish and differentiated into prefrontal cortex (PFC) lineages to efficiently test early-developmental hypotheses of autism. We define subgroups of autism muta...
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Cederquist GY, Tchieu J, Callahan SJ, Ramnarine K, Ryan S, Zhang C, Rittenhouse C, Zeltner N, Chung SY, Zhou T, Chen S, Betel D, White RM, Tomishima M, Studer L Tags: Cell Stem Cell Source Type: research

Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes.
en C, Hesse M, Serpooshan V, Jovinge S, Fleischmann BK, Doevendans PA, van der Velden J, Garcia KC, Wu JC, Sluijter JPG, Wu SM Abstract Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Buikema JW, Lee S, Goodyer WR, Maas RG, Chirikian O, Li G, Miao Y, Paige SL, Lee D, Wu H, Paik DT, Rhee S, Tian L, Galdos FX, Puluca N, Beyersdorf B, Hu J, Beck A, Venkamatran S, Swami S, Wijnker P, Schuldt M, Dorsch LM, van Mil A, Red-Horse K, Wu JY, Gei Tags: Cell Stem Cell Source Type: research

Translational Research in Culture: AADAC, Diabetes, and Cardiovascular Disease.
Abstract Many type 2 diabetes patients develop cardiovascular disease (CVD) while some are protected. Toyohara et al. (2020) find that elevated arylacetamide deacetylase (AADAC) expression in vascular smooth muscle cells (dVSMCs) differentiated from patient-derived induced pluripotent stem cells is associated with cardioprotection. AADAC overexpression alters multiple dVSMC properties and decreases murine CVD. PMID: 32619519 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Misra A, Fisher EA Tags: Cell Stem Cell Source Type: research

From Skin to Brain: A Parkinson's Disease Patient Transplanted with His Own Cells.
d A Abstract In a pioneering study in New England Journal of Medicine, Schweitzer et al. (2020) report on a patient with Parkinson's disease who received a graft of dopamine neurons obtained from in vitro differentiated induced pluripotent stem cells, derived from the patient's own skin fibroblasts, showing the feasibility of autologous transplantation for dopamine cell replacement. PMID: 32619520 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - July 2, 2020 Category: Stem Cells Authors: Parmar M, Björklund A Tags: Cell Stem Cell Source Type: research

Histone Acetyltransferase MOF Blocks Acquisition of Quiescence in Ground-State ESCs through Activating Fatty Acid Oxidation.
Abstract Self-renewing embryonic stem cells (ESCs) respond to environmental cues by exiting pluripotency or entering a quiescent state. The molecular basis underlying this fate choice remains unclear. Here, we show that histone acetyltransferase MOF plays a critical role in this process through directly activating fatty acid oxidation (FAO) in the ground-state ESCs. We further show that the ground-state ESCs particularly rely on elevated FAO for oxidative phosphorylation (OXPHOS) and energy production. Mof deletion or FAO inhibition induces bona fide quiescent ground-state ESCs with an intact core pluripotency net...
Source: Cell Stem Cell - June 24, 2020 Category: Stem Cells Authors: Khoa LTP, Tsan YC, Mao F, Kremer DM, Sajjakulnukit P, Zhang L, Zhou B, Tong X, Bhanu NV, Choudhary C, Garcia BA, Yin L, Smith GD, Saunders TL, Bielas SL, Lyssiotis CA, Dou Y Tags: Cell Stem Cell Source Type: research

A Human Pluripotent Stem Cell-based Platform to Study SARS-CoV-2 Tropism and Model Virus Infection in Human Cells and Organoids.
We present an experimental platform comprised of cell and organoid derivatives from human pluripotent stem cells (hPSCs). A Spike-enabled pseudo-entry virus infects pancreatic endocrine cells, liver organoids, cardiomyocytes, and dopaminergic neurons. Recent clinical studies show a strong association with COVID-19 and diabetes. We find that human pancreatic beta cells and liver organoids are highly permissive to SARS-CoV-2 infection, further validated using adult primary human islets and adult hepatocyte and cholangiocyte organoids. SARS-CoV-2 infection caused striking expression of chemokines, as also seen in primary huma...
Source: Cell Stem Cell - June 19, 2020 Category: Stem Cells Authors: Yang L, Han Y, Nilsson-Payant BE, Gupta V, Wang P, Duan X, Tang X, Zhu J, Zhao Z, Jaffré F, Zhang T, Kim TW, Harschnitz O, Redmond D, Houghton S, Liu C, Naji A, Ciceri G, Guttikonda S, Bram Y, Nguyen DT, Cioffi M, Chandar V, Hoagland DA, Huang Y, Xiang J Tags: Cell Stem Cell Source Type: research

Overcoming Intrinsic H3K27me3 Imprinting Barriers Improves Post-implantation Development after Somatic Cell Nuclear Transfer.
Abstract Successful cloning by somatic cell nuclear transfer (SCNT) requires overcoming significant epigenetic barriers. Genomic imprinting is not generally regarded as such a barrier, although H3K27me3-dependent imprinting is differentially distributed in E6.5 epiblast and extraembryonic tissues. Here we report significant enhancement of SCNT efficiency by deriving somatic donor cells carrying simultaneous monoallelic deletion of four H3K27me3-imprinted genes from haploid mouse embryonic stem cells. Quadruple monoallelic deletion of Sfmbt2, Jade1, Gab1, and Smoc1 normalized H3K27me3-imprinted expression patterns ...
Source: Cell Stem Cell - June 13, 2020 Category: Stem Cells Authors: Wang LY, Li ZK, Wang LB, Liu C, Sun XH, Feng GH, Wang JQ, Li YF, Qiao LY, Nie H, Jiang LY, Sun H, Xie YL, Ma SN, Wan HF, Lu FL, Li W, Zhou Q Tags: Cell Stem Cell Source Type: research

Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In  Vivo Persistence and Enhances Anti-tumor Activity.
Metabolic Reprograming via Deletion of CISH in Human iPSC-Derived NK Cells Promotes In Vivo Persistence and Enhances Anti-tumor Activity. Cell Stem Cell. 2020 Jun 10;: Authors: Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, Meng Z, Wu C, Guan KL, Malmberg KJ, Kaufman DS Abstract Cytokine-inducible SH2-containing protein (CIS; encoded by the gene CISH) is a key negative regulator of interleukin-15 (IL-15) signaling in natural killer (NK) cells. Here, we develop human CISH-knockout (CISH-/-) NK cells using an induced pluripotent stem cell-derived NK cell (iPSC-NK cell) platform. CISH-/- iPSC-...
Source: Cell Stem Cell - June 10, 2020 Category: Stem Cells Authors: Zhu H, Blum RH, Bernareggi D, Ask EH, Wu Z, Hoel HJ, Meng Z, Wu C, Guan KL, Malmberg KJ, Kaufman DS Tags: Cell Stem Cell Source Type: research

What Is Cell Stem Cell Doing to Support the Global Stem Cell Community during the COVID-19 Pandemic?
PMID: 32502397 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Chari S, Rajan P, Saxe J, Wang Q Tags: Cell Stem Cell Source Type: research

Colon Cancer Heterogeneity: Welcome to the RiboZone.
Abstract In this issue of Cell Stem Cell, Morral et al. (2020) shed new light on the hierarchical organization of cells within colorectal cancer. They show that tumor cells at the apex of this hierarchy reside in particular tumor zones and possess high protein synthesis activity. Interference with their biosynthetic activity results in an irreversible growth arrest of CRC. PMID: 32502398 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Piskol R, de Sousa E Melo F Tags: Cell Stem Cell Source Type: research

There's No I in Team: Cellular Crosstalk Enhances In  Vitro Cardiac Maturation.
There's No I in Team: Cellular Crosstalk Enhances In Vitro Cardiac Maturation. Cell Stem Cell. 2020 Jun 04;26(6):799-801 Authors: Mills RJ, Hudson JE Abstract Organoids and microtissues offer the unique opportunity to dissect cell-cell interactions in an organ-specific context without confounding effects of organ failure or organism viability. In a study in this issue of Cell Stem Cell, Giacomelli et al. (2020) add human cardiac fibroblasts into cardiac microtissues and reveal striking fibroblast-endothelial-cardiomyocyte crosstalk that promotes advanced cardiomyocyte maturation. PMID: ...
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Mills RJ, Hudson JE Tags: Cell Stem Cell Source Type: research

Skinny Fat Cells Stimulate Wound Healing.
Abstract In this issue of Cell Stem Cell, Shook et al. (2020) reveal that dermal adipocytes regulate skin wound repair via release of fatty acids that promote macrophage recruitment and accelerated revascularization. Furthermore, mature dermal adipocytes dedifferentiate into migratory extracellularmatrix-producing myofibroblasts. PMID: 32502400 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Merrick D, Seale P Tags: Cell Stem Cell Source Type: research

End Products of Telomere Research.
Abstract Most rare inherited telomere biology disorders and some common aging-related diseases are associated with shortened telomeres. In this issue of Cell Stem Cell, insights into one of the rarest genetic causes of these disorders led to the discovery (Nagpal et al., 2020) of small molecules that lengthen telomeres. PMID: 32502401 [PubMed - as supplied by publisher] (Source: Cell Stem Cell)
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Reddel RR, MacKenzie KL, Bryan TM Tags: Cell Stem Cell Source Type: research

Circadian Regulation of Adult Stem Cell Homeostasis and Aging.
Abstract The circadian clock temporally organizes cellular physiology throughout the day, allowing daily environmental changes to be anticipated and potentially harmful physiologic processes to be temporally separated. By synchronizing all cells at the tissue level, the circadian clock ensures coherent temporal organismal physiology. Recent advances in our understanding of adult stem cell physiology suggest that aging and perturbations in circadian rhythmicity in stem cells are tightly intertwined. Here we discuss how circadian rhythms regulate and synchronize adult stem cell functions and how alterations in clock...
Source: Cell Stem Cell - June 4, 2020 Category: Stem Cells Authors: Benitah SA, Welz PS Tags: Cell Stem Cell Source Type: research

The Rational Development of CD133-Targeting Immunotherapies for Glioblastoma.
on J, Hope K, Moffat J, Singh S Abstract CD133 marks self-renewing cancer stem cells (CSCs) in a variety of solid tumors, and CD133+ tumor-initiating cells are known markers of chemo- and radio-resistance in multiple aggressive cancers, including glioblastoma (GBM), that may drive intra-tumoral heterogeneity. Here, we report three immunotherapeutic modalities based on a human anti-CD133 antibody fragment that targets a unique epitope present in glycosylated and non-glycosylated CD133 and studied their effects on targeting CD133+ cells in patient-derived models of GBM. We generated an immunoglobulin G (IgG) (RW03-I...
Source: Cell Stem Cell - May 22, 2020 Category: Stem Cells Authors: Vora P, Venugopal C, Salim SK, Tatari N, Bakhshinyan D, Singh M, Seyfrid M, Upreti D, Rentas S, Wong N, Williams R, Qazi MA, Chokshi C, Ding A, Subapanditha M, Savage N, Mahendram S, Ford E, Adile AA, McKenna D, McFarlane N, Huynh V, Wylie RG, Pan J, Bram Tags: Cell Stem Cell Source Type: research

A Multiplexed Barcodelet Single-Cell RNA-Seq Approach Elucidates Combinatorial Signaling Pathways that Drive ESC Differentiation.
Abstract Empirical optimization of stem cell differentiation protocols is time consuming, is laborintensive, and typically does not comprehensively interrogate all relevant signaling pathways. Here we describe barcodelet single-cell RNA sequencing (barRNA-seq), which enables systematic exploration of cellular perturbations by tagging individual cells with RNA "barcodelets" to identify them on the basis of the treatments they receive. We apply barRNA-seq to simultaneously manipulate up to seven developmental pathways and study effects on embryonic stem cell (ESC) germ layer specification and mesodermal sp...
Source: Cell Stem Cell - May 21, 2020 Category: Stem Cells Authors: Yeo GHT, Lin L, Qi CY, Cha M, Gifford DK, Sherwood RI Tags: Cell Stem Cell Source Type: research

Human-iPSC-Derived Cardiac Stromal Cells Enhance Maturation in 3D Cardiac Microtissues and Reveal Non-cardiomyocyte Contributions to Heart Disease.
CF, Slieker RC, Sommariva E, de Vries AAF, Giera M, Semrau S, Tertoolen LGJ, Orlova VV, Bellin M, Mummery CL Abstract Cardiomyocytes (CMs) from human induced pluripotent stem cells (hiPSCs) are functionally immature, but this is improved by incorporation into engineered tissues or forced contraction. Here, we showed that tri-cellular combinations of hiPSC-derived CMs, cardiac fibroblasts (CFs), and cardiac endothelial cells also enhance maturation in easily constructed, scaffold-free, three-dimensional microtissues (MTs). hiPSC-CMs in MTs with CFs showed improved sarcomeric structures with T-tubules, enhanced cont...
Source: Cell Stem Cell - May 20, 2020 Category: Stem Cells Authors: Giacomelli E, Meraviglia V, Campostrini G, Cochrane A, Cao X, van Helden RWJ, Krotenberg Garcia A, Mircea M, Kostidis S, Davis RP, van Meer BJ, Jost CR, Koster AJ, Mei H, Míguez DG, Mulder AA, Ledesma-Terrón M, Pompilio G, Sala L, Salvatori DCF, Slieker Tags: Cell Stem Cell Source Type: research

A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line.
Abstract GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation. Screening the regulatory regions of the GATA6 gene in these patient cells and 32 additional agenesis patients revealed a higher minor allele frequency of a SNP 3' ...
Source: Cell Stem Cell - May 20, 2020 Category: Stem Cells Authors: Kishore S, De Franco E, Cardenas-Diaz FL, Letourneau-Freiberg LR, Sanyoura M, Osorio-Quintero C, French DL, Greeley SAW, Hattersley AT, Gadue P Tags: Cell Stem Cell Source Type: research

Disrupting Mitochondrial Copper Distribution Inhibits Leukemic Stem Cell Self-Renewal.
, Lupien M, Schimmer AD Abstract Leukemic stem cells (LSCs) rely on oxidative metabolism and are differentially sensitive to targeting mitochondrial pathways, which spares normal hematopoietic cells. A subset of mitochondrial proteins is folded in the intermembrane space via the mitochondrial intermembrane assembly (MIA) pathway. We found increased mRNA expression of MIA pathway substrates in acute myeloid leukemia (AML) stem cells. Therefore, we evaluated the effects of inhibiting this pathway in AML. Genetic and chemical inhibition of ALR reduces AML growth and viability, disrupts LSC self-renewal, and induces t...
Source: Cell Stem Cell - May 12, 2020 Category: Stem Cells Authors: Singh RP, Jeyaraju DV, Voisin V, Hurren R, Xu C, Hawley JR, Barghout SH, Khan DH, Gronda M, Wang X, Jitkova Y, Sharon D, Liyanagae S, MacLean N, Seneviratene AK, Mirali S, Borenstein A, Thomas GE, Soriano J, Orouji E, Minden MD, Arruda A, Chan SM, Bader G Tags: Cell Stem Cell Source Type: research

Patient hiPSCs Identify Vascular Smooth Muscle Arylacetamide Deacetylase as Protective against Atherosclerosis.
Abstract Although susceptibility to cardiovascular disease (CVD) is different for every patient, why some patients with type 2 diabetes mellitus (T2DM) develop CVD while others are protected has not yet been clarified. Using T2DM-patient-derived human induced pluripotent stem cells (hiPSCs), we found that in patients protected from CVD, there was significantly elevated expression of an esterase, arylacetamide deacetylase (AADAC), in vascular smooth muscle cells (VSMCs). We overexpressed this esterase in human primary VSMCs and VSMCs differentiated from hiPSCs and observed that the number of lipid droplets was sign...
Source: Cell Stem Cell - May 12, 2020 Category: Stem Cells Authors: Toyohara T, Roudnicky F, Florido MHC, Nakano T, Yu H, Katsuki S, Lee M, Torsten M, Friesen M, Davidow LS, Ptaszek L, Abe T, Rubin LL, Pereira AC, Aikawa M, Cowan CA Tags: Cell Stem Cell Source Type: research

Integrin-Linked Kinase Mediates Therapeutic Resistance of Quiescent CML Stem Cells to Tyrosine Kinase Inhibitors.
Abstract Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from pa...
Source: Cell Stem Cell - May 10, 2020 Category: Stem Cells Authors: Rothe K, Babaian A, Nakamichi N, Chen M, Chafe SC, Watanabe A, Forrest DL, Mager DL, Eaves CJ, Dedhar S, Jiang X Tags: Cell Stem Cell Source Type: research

RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia.
Abstract N6-methyladenosine (m6A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m6A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of ...
Source: Cell Stem Cell - May 10, 2020 Category: Stem Cells Authors: Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, Chen H, Su R, Yin Z, Li W, Deng X, Chen Y, Hu YC, Weng H, Huang H, Prince E, Cogle CR, Sun M, Zhang B, Chen CW, Marcucci G, He C, Qian Z, Chen J Tags: Cell Stem Cell Source Type: research

Zonation of Ribosomal DNA Transcription Defines a Stem Cell Hierarchy in Colorectal Cancer.
cho E, Heyn H, Batlle E Abstract Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RN...
Source: Cell Stem Cell - May 10, 2020 Category: Stem Cells Authors: Morral C, Stanisavljevic J, Hernando-Momblona X, Mereu E, Álvarez-Varela A, Cortina C, Stork D, Slebe F, Turon G, Whissell G, Sevillano M, Merlos-Suárez A, Casanova-Martí À, Moutinho C, Lowe SW, Dow LE, Villanueva A, Sancho E, Heyn H, Batlle E Tags: Cell Stem Cell Source Type: research

A Human Skeletal Muscle Atlas Identifies the Trajectories of Stem and Progenitor Cells across Development and from Human Pluripotent Stem Cells.
Abstract The developmental trajectory of human skeletal myogenesis and the transition between progenitor and stem cell states are unclear. We used single-cell RNA sequencing to profile human skeletal muscle tissues from embryonic, fetal, and postnatal stages. In silico, we identified myogenic as well as other cell types and constructed a "roadmap" of human skeletal muscle ontogeny across development. In a similar fashion, we also profiled the heterogeneous cell cultures generated from multiple human pluripotent stem cell (hPSC) myogenic differentiation protocols and mapped hPSC-derived myogenic progenito...
Source: Cell Stem Cell - May 10, 2020 Category: Stem Cells Authors: Xi H, Langerman J, Sabri S, Chien P, Young CS, Younesi S, Hicks M, Gonzalez K, Fujiwara W, Marzi J, Liebscher S, Spencer M, Van Handel B, Evseenko D, Schenke-Layland K, Plath K, Pyle AD Tags: Cell Stem Cell Source Type: research

Can a Cell Put Its Arms around a Memory?
Abstract Johnny Thunders once wrote, "You can't put your arms around a memory…" and the song continues, "don't try." Yet, when complex morphogenetic movements accompany differentiation, the cellular memory of signaling becomes essential. In this issue of Cell Stem Cell, Gunne-Braden et al. (2020) report a network wrapping its arms around the memory of BMP signaling, a phenomenon known as hysteresis. PMID: 32386548 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Knudsen TE, Brickman JM Tags: Cell Stem Cell Source Type: research

Inflammation's Epigenetic Footprint in Hematopoietic Stem Cells.
Abstract Immune memory was thought to be unique to cells of the adaptive immune system. In this issue of Cell Stem Cell, de Laval et al. (2020) describe persistent epigenetic modifications in hematopoietic stem cells following an inflammatory insult with LPS as a mechanism by which immune memory may be established. PMID: 32386549 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Geiger SS, Essers MAG Tags: Cell Stem Cell Source Type: research

Tales from the Cryptkeeper: New Roles for Lats1/2 in Wnt-driven Homeostasis.
Abstract In this issue of Cell Stem Cell, Li et al. (2020) reveal pivotal roles for Lats1/2 in adult, Wnt-mediated intestinal homeostasis through TEAD-dependent and -independent transcription. Loss of Lats1/2 mobilizes a previously unrecognized YAP/TAZ-Groucho/TLE interaction to suppress Wnt/TCF-mediated transcription, thereby resulting in intestinal stem cell depletion and Wnt-uncoupled progenitor expansion. PMID: 32386550 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Fu V, Guan KL Tags: Cell Stem Cell Source Type: research

APA Makes a Short Cut for Ramping up HSC Metabolism.
Abstract The physiological role of alternative polyadenylation (APA) in controlling hematopoietic stem cell (HSC) behavior in vivo, and the mechanistic implications of this association, remain elusive. Now in Cell Stem Cell, Sommerkamp et al. (2020) provide evidence that APA regulates HSC self-renewal and multi-potency by affecting stem cell activation and glutaminolysis. PMID: 32386551 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Jiang S Tags: Cell Stem Cell Source Type: research

Problems and Pitfalls of Identifying Remyelination in Multiple Sclerosis.
ranklin RJM Abstract Regenerative medicines that promote remyelination in multiple sclerosis (MS) are making the transition from laboratory to clinical trials. While animal models provide the experimental flexibility to analyze mechanisms of remyelination, here we discuss the challenges in understanding where and how remyelination occurs in MS. PMID: 32386552 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Neumann B, Foerster S, Zhao C, Bodini B, Reich DS, Bergles DE, Káradóttir RT, Lubetzki C, Lairson LL, Zalc B, Stankoff B, Franklin RJM Tags: Cell Stem Cell Source Type: research

The Advocate's Adventure.
PMID: 32386553 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Reed DC Tags: Cell Stem Cell Source Type: research

High-Fidelity Modeling of Human Microglia with Pluripotent Stem Cells.
Abstract Gosselin et al. (2017) reported that a tissue-environment-dependent transcriptional network specifies human microglia identity and that in vitro environments drastically alter the human microglia transcriptome. Recent 3-dimensional culture and human-mouse chimeric brain modeling systems developed using human pluripotent stem cells help us understand the complex properties of human microglia. PMID: 32386554 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: Jiang P, Turkalj L, Xu R Tags: Cell Stem Cell Source Type: research

Tools and Concepts for Interrogating and Defining Cellular Identity.
Abstract Defining the mechanisms that generate specialized cell types and coordinate their functions is critical for understanding organ development and renewal. New tools and discoveries are challenging and refining our definitions of a cell type. A rapidly growing toolkit for single-cell analyses has expanded the number of markers that can be assigned to a cell simultaneously, revealing heterogeneity within cell types that were previously regarded as homogeneous populations. Additionally, cell types defined by specific molecular markers can exhibit distinct, context-dependent functions; for example, between tiss...
Source: Cell Stem Cell - May 7, 2020 Category: Stem Cells Authors: McKinley KL, Castillo-Azofeifa D, Klein OD Tags: Cell Stem Cell Source Type: research