Sensing the Environment: Extracellular Lactate Levels Control Adult Neurogenesis.
Abstract Metabolism has emerged as a key player for stem cell behavior; however, the role of metabolism in the microenvironment remains poorly understood. In this issue of Cell Stem Cell, Wang et al. (2019) show that brain endothelial cells directly affect adult neural stem cells and maintain a healthy metabolic environment by regulating lactate levels. PMID: 31809733 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Scandella V, Knobloch M Tags: Cell Stem Cell Source Type: research

Mutualism in the Marrow.
Abstract Cross-talk between hematopoietic stem cells (HSCs) and the HSC niche is likely important in hematopoiesis but not well demonstrated. Now in Cell Stem Cell, Chen et al. (2019) describe how specialized endothelial cells regulate hematopoietic stem cell maintenance and how hematopoietic stem/progenitor cells facilitate vascular regeneration in return. PMID: 31809734 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Chute JP, Termini CM Tags: Cell Stem Cell Source Type: research

The Seed Tends to the Soil: Hair Follicle Stem Cells Remodel Their Lymphatic Niche.
Abstract Hair follicle stem cells may themselves regulate the niche environment for hair follicle regrowth. A recent Science paper from Elaine Fuchs and colleagues (Gur-Cohen et al., 2019) suggests that this involves regulation of the lymphatic system and may have implications in understanding tissue regeneration. PMID: 31809735 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Gay D, Ito M Tags: Cell Stem Cell Source Type: research

Gene Editing Expands the Donor Pool for CCR5-Negative Stem Cell Transplants.
Abstract Cell therapy efforts for treating HIV+ patients are challenged by limited availability of donors with naturally occurring CCR5 mutations conferring resistance. Xu et al. (2019) report a CRISPR-based method for disrupting CCR5 in hematopoietic stem cells prior to transplant, providing a proof of concept for expanding the pool of potential donors. PMID: 31809736 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Cannon PM Tags: Cell Stem Cell Source Type: research

Identification of Functionally Distinct Mx1+ αSMA+ Periosteal Skeletal Stem Cells.
Identification of Functionally Distinct Mx1+αSMA+ Periosteal Skeletal Stem Cells. Cell Stem Cell. 2019 Dec 05;25(6):784-796.e5 Authors: Ortinau LC, Wang H, Lei K, Deveza L, Jeong Y, Hara Y, Grafe I, Rosenfeld SB, Lee D, Lee B, Scadden DT, Park D Abstract The periosteum is critical for bone maintenance and healing. However, the in vivo identity and specific regulatory mechanisms of adult periosteum-resident skeletal stem cells are unknown. Here, we report animal models that selectively and durably label postnatal Mx1+αSMA+ periosteal stem cells (P-SSCs) and establish that P-SSCs are a ...
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Ortinau LC, Wang H, Lei K, Deveza L, Jeong Y, Hara Y, Grafe I, Rosenfeld SB, Lee D, Lee B, Scadden DT, Park D Tags: Cell Stem Cell Source Type: research

Hic1 Defines Quiescent Mesenchymal Progenitor Subpopulations with Distinct Functions and Fates in Skeletal Muscle Regeneration.
Abstract Many adult tissues contain resident stem cells, such as the Pax7+ satellite cells within skeletal muscle, that regenerate parenchymal elements following damage. Tissue-resident mesenchymal progenitors (MPs) also participate in regeneration, although their function and fate in this process are unclear. Here, we identify Hypermethylated in cancer 1 (Hic1) as a marker of MPs in skeletal muscle and further show that Hic1 deletion leads to MP hyperplasia. Single-cell RNA-seq and ATAC-seq analysis of Hic1+ MPs in skeletal muscle shows multiple subpopulations, which we further show have distinct functions and li...
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Scott RW, Arostegui M, Schweitzer R, Rossi FMV, Underhill TM Tags: Cell Stem Cell Source Type: research

Heterogeneity within Stratified Epithelial Stem Cell Populations Maintains the Oral Mucosa in Response to Physiological Stress.
Abstract Stem cells in stratified epithelia are generally believed to adhere to a non-hierarchical single-progenitor model. Using lineage tracing and genetic label-retention assays, we show that the hard palatal epithelium of the oral cavity is unique in displaying marked proliferative heterogeneity. We identify a previously uncharacterized, infrequently-dividing stem cell population that resides within a candidate niche, the junctional zone (JZ). JZ stem cells tend to self-renew by planar symmetric divisions, respond to masticatory stresses, and promote wound healing, whereas frequently-dividing cells reside outs...
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Byrd KM, Piehl NC, Patel JH, Huh WJ, Sequeira I, Lough KJ, Wagner BL, Marangoni P, Watt FM, Klein OD, Coffey RJ, Williams SE Tags: Cell Stem Cell Source Type: research

A 3D Tissue-wide Digital Imaging Pipeline for Quantitation of Secreted Molecules Shows Absence of CXCL12 Gradients in Bone Marrow.
Abstract Technological limitations have hampered understanding of how individual molecules, including putative stem cell regulators, are distributed throughout tissues and stem cell niches. Here, we report adaptation of the proximity ligation assay (PLA) for large-volume, in situ imaging of individual proteins with multiple additional fluorescent channels with integrated 3D quantification strategies and software. Using this platform, we quantified the bone marrow (BM) distribution of individual CXCL12 chemokine proteins, both before and after their depletion by granulocyte-colony stimulating factor (G-CSF) tr...
Source: Cell Stem Cell - December 5, 2019 Category: Stem Cells Authors: Kunz L, Schroeder T Tags: Cell Stem Cell Source Type: research

Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy.
Swartling FJ Abstract Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling sho...
Source: Cell Stem Cell - November 20, 2019 Category: Stem Cells Authors: Čančer M, Hutter S, Holmberg KO, Rosén G, Sundström A, Tailor J, Bergström T, Garancher A, Essand M, Wechsler-Reya RJ, Falk A, Weishaupt H, Swartling FJ Tags: Cell Stem Cell Source Type: research

Apelin+ Endothelial Niche Cells Control Hematopoiesis and Mediate Vascular Regeneration after Myeloablative Injury.
Abstract Radiotherapy and chemotherapy disrupt bone vasculature, but the underlying causes and mechanisms enabling vessel regeneration after bone marrow (BM) transplantation remain poorly understood. Here, we show that loss of hematopoietic cells per se, in response to irradiation and other treatments, triggers vessel dilation, permeability, and endothelial cell (EC) proliferation. We further identify a small subpopulation of Apelin-expressing (Apln+) ECs, representing 0.003% of BM cells, that is critical for physiological homeostasis and transplant-induced BM regeneration. Genetic ablation of Apln+ ECs or Apln-Cr...
Source: Cell Stem Cell - November 20, 2019 Category: Stem Cells Authors: Chen Q, Liu Y, Jeong HW, Stehling M, Dinh VV, Zhou B, Adams RH Tags: Cell Stem Cell Source Type: research

Patient-Derived Organoids Predict Chemoradiation Responses of Locally Advanced Rectal Cancer.
Abstract Accumulating evidence indicates that patient-derived organoids (PDOs) can predict drug responses in the clinic, but the ability of PDOs to predict responses to chemoradiation in cancer patients remains an open question. Here we generate a living organoid biobank from patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (NACR) enrolled in a phase III clinical trial. Our co-clinical trial data confirm that rectal cancer organoids (RCOs) closely recapitulate the pathophysiology and genetic changes of corresponding tumors. Chemoradiation responses in patients are hi...
Source: Cell Stem Cell - November 19, 2019 Category: Stem Cells Authors: Yao Y, Xu X, Yang L, Zhu J, Wan J, Shen L, Xia F, Fu G, Deng Y, Pan M, Guo Q, Gao X, Li Y, Rao X, Zhou Y, Liang L, Wang Y, Zhang J, Zhang H, Li G, Zhang L, Peng J, Cai S, Hu C, Gao J, Clevers H, Zhang Z, Hua G Tags: Cell Stem Cell Source Type: research

Brain Endothelial Cells Maintain Lactate Homeostasis and Control Adult Hippocampal Neurogenesis.
Abstract Increased understanding of the functions of lactate has suggested a close relationship between lactate homeostasis and normal brain activity because of its importance as an energy source and signaling molecule. Here we show that lactate levels affect adult hippocampal neurogenesis. Cerebrovascular-specific deletion of PTEN causes learning and memory deficits and disrupts adult neurogenesis with accompanying lactate accumulation. Consistently, administering lactate to wild-type animals impairs adult hippocampal neurogenesis. The endothelial PTEN/Akt pathway increases monocarboxylic acid transporter 1 (MCT1...
Source: Cell Stem Cell - November 11, 2019 Category: Stem Cells Authors: Wang J, Cui Y, Yu Z, Wang W, Cheng X, Ji W, Guo S, Zhou Q, Wu N, Chen Y, Chen Y, Song X, Jiang H, Wang Y, Lan Y, Zhou B, Mao L, Li J, Yang H, Guo W, Yang X Tags: Cell Stem Cell Source Type: research

Evaluation of Xie et  al.: Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal.
This article shows an example of the peer review process for "Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal" (Xie et al., 2019). PMID: 31703766 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 7, 2019 Category: Stem Cells Authors: Morrison SJ, Meacham CE Tags: Cell Stem Cell Source Type: research

From Mother or Father: Uniparental Embryos Uncover Parent-of-Origin Effects in Humans.
Abstract In mammals, both parents make unique contributions to the offspring and maternal and paternal genomes are required for development. Two recent papers in Cell Stem Cell (Leng et al., 2019; Sagi et al., 2019) study uniparental embryos and uniparental embryonic stem cells to interrogate parent-of-origin effects in human embryogenesis. PMID: 31703767 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 7, 2019 Category: Stem Cells Authors: Aizawa E, Wutz A Tags: Cell Stem Cell Source Type: research

The Princess and the P: Pluripotent Stem Cells and P-Bodies.
Abstract In this issue of Cell Stem Cell, Di Stefano et al. (2019) identify the RNA helicase DDX6 as a regulator of stem cell pluripotency and differentiation. DDX6 depletion leads to P-body disruption, which, in turn, inhibits or promotes stem and progenitor cell differentiation, depending on their cellular context. PMID: 31703768 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - November 7, 2019 Category: Stem Cells Authors: Viegas JO, Meshorer E Tags: Cell Stem Cell Source Type: research

In  Vivo Selection for Gene-Corrected HSPCs Advances Gene Therapy for a Rare Stem Cell Disease.
In Vivo Selection for Gene-Corrected HSPCs Advances Gene Therapy for a Rare Stem Cell Disease. Cell Stem Cell. 2019 Nov 07;25(5):592-593 Authors: Gentner B, Naldini L Abstract Two recent papers (one by Román-Rodríguez et al., 2019 in this issue of Cell Stem Cell) highlight how the power of biological selection on hematopoietic stem cell fitness can facilitate gene therapies for Fanconi Anemia. A clinical trial using lentiviral gene replacement and a proof-of-concept targeted genome editing study show robust engraftment and expansion of gene-corrected cells at levels reaching th...
Source: Cell Stem Cell - November 7, 2019 Category: Stem Cells Authors: Gentner B, Naldini L Tags: Cell Stem Cell Source Type: research

Clinical Translation of Pluripotent Stem Cell Therapies: Challenges and Considerations.
te; P Abstract Although the clinical outcomes of cell therapy trials have not met initial expectations, emerging evidence suggests that injury-mediated tissue damage might benefit from the delivery of cells or their secreted products. Pluripotent stem cells (PSCs) are promising cell sources primarily because of their capacity to generate stage- and lineage-specific differentiated derivatives. However, they carry inherent challenges for safe and efficacious clinical translation. This Review describes completed or ongoing trials of PSCs, discusses their potential mechanisms of action, and considers how to address th...
Source: Cell Stem Cell - November 7, 2019 Category: Stem Cells Authors: Desgres M, Menasché P Tags: Cell Stem Cell Source Type: research

Identification and Massively Parallel Characterization of Regulatory Elements Driving Neural Induction.
Abstract Epigenomic regulation and lineage-specific gene expression act in concert to drive cellular differentiation, but the temporal interplay between these processes is largely unknown. Using neural induction from human pluripotent stem cells (hPSCs) as a paradigm, we interrogated these dynamics by performing RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and assay for transposase accessible chromatin using sequencing (ATAC-seq) at seven time points during early neural differentiation. We found that changes in DNA accessibility precede H3K27ac, which is followed by gene expressio...
Source: Cell Stem Cell - October 14, 2019 Category: Stem Cells Authors: Inoue F, Kreimer A, Ashuach T, Ahituv N, Yosef N Tags: Cell Stem Cell Source Type: research

Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal.
Abstract Cellular stress responses serve as crucial decision points balancing persistence or culling of hematopoietic stem cells (HSCs) for lifelong blood production. Although strong stressors cull HSCs, the linkage between stress programs and self-renewal properties that underlie human HSC maintenance remains unknown, particularly at quiescence exit when HSCs must also dynamically shift metabolic state. Here, we demonstrate distinct wiring of the sphingolipidome across the human hematopoietic hierarchy and find that genetic or pharmacologic modulation of the sphingolipid enzyme DEGS1 regulates lineage differentia...
Source: Cell Stem Cell - October 11, 2019 Category: Stem Cells Authors: Xie SZ, Garcia-Prat L, Voisin V, Ferrari R, Gan OI, Wagenblast E, Kaufmann KB, Zeng AGX, Takayanagi SI, Patel I, Lee EK, Jargstorf J, Holmes G, Romm G, Pan K, Shoong M, Vedi A, Luberto C, Minden MD, Bader GD, Laurenti E, Dick JE Tags: Cell Stem Cell Source Type: research

Smelling Danger: Olfactory Stem Cells Control Immune Defense during Chronic Inflammation.
Abstract Neurogenesis is critical to continuously replacie olfactory neurons but is impaired during chronic inflammatory rhinosinusitis. In this issue of Cell Stem Cell, Chen et al. (2019) describe the inflammation-induced switching of olfactory stem cells from a regenerative phenotype to one participating in immune defense; this process contributes to deficient replacement of olfactory sensory neurons. PMID: 31585089 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Rustenhoven J, Kipnis J Tags: Cell Stem Cell Source Type: research

Collisions on the Busy DNA Highway Set Up Barriers for Reprogramming.
Abstract Why most cells remain refractory to transcription factor (TF)-induced fate conversion remains largely mysterious, with the answers holding important instructions on how to effectively direct cell identities. In this issue of Cell Stem Cell, Babos et al. (2019) show that conflicts caused by simultaneous high transcription and high replication rates are to blame. PMID: 31585090 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Hu X, Guo S Tags: Cell Stem Cell Source Type: research

Engineered Stem Cells Provide Cancer-Killing iNKT Cells.
Abstract Invariant natural killer T (iNKT) cells have been tested for their potential use in cancer immune therapy, but their low frequency has limited their use. In this issue, Zhu and colleagues propose to overcome this by engineering hematopoietic stem cells (HSCs) to provide a continual source of iNKT cells. (Zhu et al., 2019). PMID: 31585091 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Murray MP, Kronenberg M Tags: Cell Stem Cell Source Type: research

Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras.
Abstract Recent demonstrations of human brain organoid transplantation in rodents have accentuated ethical concerns associated with these entities, especially as they relate to potential "humanization" of host animals. Consideration of established scientific principles can help define the realistic range of expected outcomes in such transplantation studies. This practical approach suggests that augmentation of discrete brain functions in transplant hosts is a more relevant ethical question in the near term than the possibility of "conscious" chimeric animals. We hope that this framework contrib...
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Chen HI, Wolf JA, Blue R, Song MM, Moreno JD, Ming GL, Song H Tags: Cell Stem Cell Source Type: research

Metformin Restores CNS Remyelination Capacity by Rejuvenating Aged Stem Cells.
Abstract The age-related failure to produce oligodendrocytes from oligodendrocyte progenitor cells (OPCs) is associated with irreversible neurodegeneration in multiple sclerosis (MS). Consequently, regenerative approaches have significant potential for treating chronic demyelinating diseases. Here, we show that the differentiation potential of adult rodent OPCs decreases with age. Aged OPCs become unresponsive to pro-differentiation signals, suggesting intrinsic constraints on therapeutic approaches aimed at enhancing OPC differentiation. This decline in functional capacity is associated with hallmarks of cellular...
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Neumann B, Baror R, Zhao C, Segel M, Dietmann S, Rawji KS, Foerster S, McClain CR, Chalut K, van Wijngaarden P, Franklin RJM Tags: Cell Stem Cell Source Type: research

Oligodendrocyte Death in Pelizaeus-Merzbacher Disease Is Rescued by Iron Chelation.
Abstract Pelizaeus-Merzbacher disease (PMD) is an X-linked leukodystrophy caused by mutations in Proteolipid Protein 1 (PLP1), encoding a major myelin protein, resulting in profound developmental delay and early lethality. Previous work showed involvement of unfolded protein response (UPR) and endoplasmic reticulum (ER) stress pathways, but poor PLP1 genotype-phenotype associations suggest additional pathogenetic mechanisms. Using induced pluripotent stem cell (iPSC) and gene-correction, we show that patient-derived oligodendrocytes can develop to the pre-myelinating stage, but subsequently undergo cell death. Mut...
Source: Cell Stem Cell - October 3, 2019 Category: Stem Cells Authors: Nobuta H, Yang N, Ng YH, Marro SG, Sabeur K, Chavali M, Stockley JH, Killilea DW, Walter PB, Zhao C, Huie P, Goldman SA, Kriegstein AR, Franklin RJM, Rowitch DH, Wernig M Tags: Cell Stem Cell Source Type: research

Asymmetric Centromeres Differentially Coordinate with Mitotic Machinery to Ensure Biased Sister Chromatid Segregation in Germline Stem Cells.
Abstract Many stem cells utilize asymmetric cell division (ACD) to produce a self-renewed stem cell and a differentiating daughter cell. How non-genic information could be inherited differentially to establish distinct cell fates is not well understood. Here, we report a series of spatiotemporally regulated asymmetric components, which ensure biased sister chromatid attachment and segregation during ACD of Drosophila male germline stem cells (GSCs). First, sister centromeres are differentially enriched with proteins involved in centromere specification and kinetochore function. Second, temporally asymmetric microt...
Source: Cell Stem Cell - September 25, 2019 Category: Stem Cells Authors: Ranjan R, Snedeker J, Chen X Tags: Cell Stem Cell Source Type: research

PRDM16 Maintains Homeostasis of the Intestinal Epithelium by Controlling Region-Specific Metabolism.
Abstract Metabolic pathways dynamically regulate tissue development and maintenance. However, the mechanisms that govern the metabolic adaptation of stem or progenitor cells to their local niche are poorly understood. Here, we define the transcription factor PRDM16 as a region-specific regulator of intestinal metabolism and epithelial renewal. PRDM16 is selectively expressed in the upper intestine, with enrichment in crypt-resident progenitor cells. Acute Prdm16 deletion in mice triggered progenitor apoptosis, leading to diminished epithelial differentiation and severe intestinal atrophy. Genomic and metabolic ana...
Source: Cell Stem Cell - September 21, 2019 Category: Stem Cells Authors: Stine RR, Sakers AP, TeSlaa T, Kissig M, Stine ZE, Kwon CW, Cheng L, Lim HW, Kaestner KH, Rabinowitz JD, Seale P Tags: Cell Stem Cell Source Type: research

NHEJ-Mediated Repair of CRISPR-Cas9-Induced DNA Breaks Efficiently Corrects Mutations in HSPCs from Patients with Fanconi Anemia.
Torres-Ruiz R, Surrallés J, Bueren JA, Río P Abstract Non-homologous end-joining (NHEJ) is the preferred mechanism used by hematopoietic stem cells (HSCs) to repair double-stranded DNA breaks and is particularly increased in cells deficient in the Fanconi anemia (FA) pathway. Here, we show feasible correction of compromised functional phenotypes in hematopoietic cells from multiple FA complementation groups, including FA-A, FA-C, FA-D1, and FA-D2. NHEJ-mediated repair of targeted CRISPR-Cas9-induced DNA breaks generated compensatory insertions and deletions that restore the coding frame of the mutat...
Source: Cell Stem Cell - September 17, 2019 Category: Stem Cells Authors: Román-Rodríguez FJ, Ugalde L, Álvarez L, Díez B, Ramírez MJ, Risueño C, Cortón M, Bogliolo M, Bernal S, March F, Ayuso C, Hanenberg H, Sevilla J, Rodríguez-Perales S, Torres-Ruiz R, Surrallés J, Bueren JA, Río P Tags: Cell Stem Cell Source Type: research

Cancer-Related Mutations Identified in Primed and Naive Human Pluripotent Stem Cells.
Abstract Human pluripotent stem cells (hPSCs) are known to harbor chromosomal aberrations, affecting their tumorigenic potential. We established a strategy to identify cancer-related point mutations in hPSCs, detecting recurrent mutations in over 20 genes, alongside those previously detected in p53. Importantly, naive hPSCs harbor, on average, four times more mutations than their primed counterparts, which appear primarily in pathways inhibited during naive conversion. Such cancer-related mutations should be taken into consideration in future applications, especially in clinical contexts. PMID: 31543368 [PubM...
Source: Cell Stem Cell - September 11, 2019 Category: Stem Cells Authors: Avior Y, Eggan K, Benvenisty N Tags: Cell Stem Cell Source Type: research

Loss of SATB1 Induces p21-Dependent Cellular Senescence in Post-mitotic Dopaminergic Neurons.
We report that SATB1 prevents cellular senescence in post-mitotic dopaminergic neurons. Loss of SATB1 causes activation of a cellular senescence transcriptional program in dopamine neurons both in human stem cell-derived dopaminergic neurons and in mice. We observed phenotypes that are central to cellular senescence in SATB1 knockout dopamine neurons in vitro and in vivo. Moreover, we found that SATB1 directly represses expression of the pro-senescence factor p21 in dopaminergic neurons. Our data implicate senescence of dopamine neurons as a contributing factor in the pathology of Parkinson's disease. PMID: ...
Source: Cell Stem Cell - September 10, 2019 Category: Stem Cells Authors: Riessland M, Kolisnyk B, Kim TW, Cheng J, Ni J, Pearson JA, Park EJ, Dam K, Acehan D, Ramos-Espiritu LS, Wang W, Zhang J, Shim JW, Ciceri G, Brichta L, Studer L, Greengard P Tags: Cell Stem Cell Source Type: research

Evaluation of Stuart et  al.: Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.
Evaluation of Stuart et al.: Distinct Molecular Trajectories Converge to Induce Naive Pluripotency. Cell Stem Cell. 2019 Sep 05;25(3):297-298 Authors: Stadtfeld M Abstract An example of the peer review process for "Distinct molecular trajectories converge to induce naive pluripotency" (Stuart et al., 2019) is presented here. PMID: 31491390 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Stadtfeld M Tags: Cell Stem Cell Source Type: research

Changing the Rules of the Game: How Winners Become Losers during Oncogenic Cell Selection.
Abstract As we age, our tissues become a mosaic of random mutations, many of which are oncogenic and promote the expansion of their carrier cells. In this issue of Cell Stem Cell, Fernandez-Antoran et al. (2019) show how commonly used medical procedures modify cell selection dynamics to either expand or eliminate cells carrying oncogenic p53 mutations. PMID: 31491391 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Villa Del Campo C, Torres M Tags: Cell Stem Cell Source Type: research

Aging of the Hematopoietic Stem Cell Niche: An Unnerving Matter.
Abstract The drivers of aging in the hematopoietic system remain incompletely understood. In this issue of Cell Stem Cell, Ho et al. (2019) report that functional switching of β-adrenergic nerve signaling underlies remodeling of stem cell niches, driving age-associated alterations in hematopoiesis. PMID: 31491392 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Raaijmakers MHGP Tags: Cell Stem Cell Source Type: research

Stem Cell Businesses and Right to Try Laws.
PMID: 31491393 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Sipp D, Turner L, Rasko JEJ Tags: Cell Stem Cell Source Type: research

Institutional Report Cards for Gender Equality: Lessons Learned from Benchmarking Efforts for Women in STEM.
PMID: 31491394 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Beeler WH, Smith-Doody KA, Ha R, Aiyar RS, Schwarzbach E, Solomon SL, Jagsi R Tags: Cell Stem Cell Source Type: research

Human Pluripotent Stem Cell-Derived Cardiovascular Cells: From Developmental Biology to Therapeutic Applications.
Abstract Advances in our understanding of cardiovascular development have provided a roadmap for the directed differentiation of human pluripotent stem cells (hPSCs) to the major cell types found in the heart. In this Perspective, we review the state of the field in generating and maturing cardiovascular cells from hPSCs based on our fundamental understanding of heart development. We then highlight their applications for studying human heart development, modeling disease-performing drug screening, and cell replacement therapy. With the advancements highlighted here, the promise that hPSCs will deliver new treatmen...
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Protze SI, Lee JH, Keller GM Tags: Cell Stem Cell Source Type: research

Distinct Imprinting Signatures and Biased Differentiation of Human Androgenetic and Parthenogenetic Embryonic Stem Cells.
Abstract Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs e...
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Sagi I, De Pinho JC, Zuccaro MV, Atzmon C, Golan-Lev T, Yanuka O, Prosser R, Sadowy A, Perez G, Cabral T, Glaser B, Tsang SH, Goland R, Sauer MV, Lobo R, Benvenisty N, Egli D Tags: Cell Stem Cell Source Type: research

Design Approaches for Generating Organ Constructs.
PMID: 31491397 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - September 5, 2019 Category: Stem Cells Authors: Xia Y, Izpisua Belmonte JC Tags: Cell Stem Cell Source Type: research

Complex Oscillatory Waves Emerging from Cortical Organoids Model Early Human Brain Network Development.
Abstract Structural and transcriptional changes during early brain maturation follow fixed developmental programs defined by genetics. However, whether this is true for functional network activity remains unknown, primarily due to experimental inaccessibility of the initial stages of the living human brain. Here, we developed human cortical organoids that dynamically change cellular populations during maturation and exhibited consistent increases in electrical activity over the span of several months. The spontaneous network formation displayed periodic and regular oscillatory events that were dependent on glutama...
Source: Cell Stem Cell - August 23, 2019 Category: Stem Cells Authors: Trujillo CA, Gao R, Negraes PD, Gu J, Buchanan J, Preissl S, Wang A, Wu W, Haddad GG, Chaim IA, Domissy A, Vandenberghe M, Devor A, Yeo GW, Voytek B, Muotri AR Tags: Cell Stem Cell Source Type: research

Distinct Molecular Trajectories Converge to Induce Naive Pluripotency.
JCR Abstract Understanding how cell identity transitions occur and whether there are multiple paths between the same beginning and end states are questions of wide interest. Here we show that acquisition of naive pluripotency can follow transcriptionally and mechanistically distinct routes. Starting from post-implantation epiblast stem cells (EpiSCs), one route advances through a mesodermal state prior to naive pluripotency induction, whereas another transiently resembles the early inner cell mass and correspondingly gains greater developmental potency. These routes utilize distinct signaling networks and transcri...
Source: Cell Stem Cell - August 13, 2019 Category: Stem Cells Authors: Stuart HT, Stirparo GG, Lohoff T, Bates LE, Kinoshita M, Lim CY, Sousa EJ, Maskalenka K, Radzisheuskaya A, Malcolm AA, Alves MRP, Lloyd RL, Nestorowa S, Humphreys P, Mansfield W, Reik W, Bertone P, Nichols J, Göttgens B, Silva JCR Tags: Cell Stem Cell Source Type: research

Defining the Identity and Dynamics of Adult Gastric Isthmus Stem Cells.
BK Abstract The gastric corpus epithelium is the thickest part of the gastrointestinal tract and is rapidly turned over. Several markers have been proposed for gastric corpus stem cells in both isthmus and base regions. However, the identity of isthmus stem cells (IsthSCs) and the interaction between distinct stem cell populations is still under debate. Here, based on unbiased genetic labeling and biophysical modeling, we show that corpus glands are compartmentalized into two independent zones, with slow-cycling stem cells maintaining the base and actively cycling stem cells maintaining the pit-isthmus-neck regio...
Source: Cell Stem Cell - August 8, 2019 Category: Stem Cells Authors: Han S, Fink J, Jörg DJ, Lee E, Yum MK, Chatzeli L, Merker SR, Josserand M, Trendafilova T, Andersson-Rolf A, Dabrowska C, Kim H, Naumann R, Lee JH, Sasaki N, Mort RL, Basak O, Clevers H, Stange DE, Philpott A, Kim JK, Simons BD, Koo BK Tags: Cell Stem Cell Source Type: research

Evaluation of Tung et  al.: Mir-17∼92 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration.
Evaluation of Tung et al.: Mir-17∼92 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration. Cell Stem Cell. 2019 Aug 01;25(2):165-166 Authors: Liu Y, Yoo AS Abstract An example of the peer review process for "Mir-17∼92 Confers Differential Vulnerability of Motor Neuron Subtypes to ALS-Associated Degeneration" (Tung et al., 2019) is presented here. PMID: 31374193 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Liu Y, Yoo AS Tags: Cell Stem Cell Source Type: research

Cutting Off Leukemogenesis: Hydra-like Plasticity of Mature Leukemic Cells.
Abstract Leukemic stem cells (LSCs) in acute myeloid leukemia (AML) can drive tumor growth and relapse. In this issue of Cell Stem Cell, McKenzie et al. (2019) report that some mature leukemic cells can de-differentiate and contribute to AML tumorigenesis, a finding with important implications for therapies focused on eradicating LSCs. PMID: 31374194 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Bamezai S, Buske C Tags: Cell Stem Cell Source Type: research

Calcium: A New Guardian of Naive Pluripotency.
Abstract In this issue of Cell Stem Cell, MacDougall et al. (2019) utilized a CRISPR mutagenesis screen to identify factors for mESC self-renewal and found that intracellular calcium and nuclear export act in naive pluripotency exit. Combined knockout of Tcf7l1 and the calcium transporter Atp2b1 enabled mESCs to self-renew in the absence of LIF and 2i. PMID: 31374195 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Zhu Y, Zhang J Tags: Cell Stem Cell Source Type: research

Hematopoietic Stem Cell Intracellular Levels of Ca2+ to the Rescue! What Next?
Abstract Calcium ions (Ca2+), ubiquitous signaling and second messenger molecules, are communicators for the transmission of messages in numerous cell functions. In this issue of Cell Stem Cell, Luchsinger et al. (2019) provide evidence through the use of transplantation and mechanistic studies for the finding that, "Harnessing Hematopoietic Stem Cell Low Intracellular Calcium Improves Their Maintenance In Vitro." PMID: 31374196 [PubMed - in process] (Source: Cell Stem Cell)
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Broxmeyer HE Tags: Cell Stem Cell Source Type: research

Defining Adult Stem Cell Function at Its Simplest: The Ability to Replace Lost Cells through Mitosis.
Abstract Classic studies on hematopoiesis indicate that blood cell numbers are maintained by rare, hard-wired, transplantable stem cells (SCs). Subsequent studies in other organs have implicitly assumed that all SC hierarchies follow the design of the hematopoietic system. Lineage tracing techniques have revolutionized the study of solid tissue SCs. It thus appears that key characteristics of the hematopoietic SC hierarchy (rarity of SCs, specific marker expression, quiescence, asymmetric division, and unidirectional differentiation) are not generalizable to other tissues. In light of these insights, we offer a re...
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Post Y, Clevers H Tags: Cell Stem Cell Source Type: research

Interconversion between Tumorigenic and Differentiated States in Acute Myeloid Leukemia.
, Metcalf D, Johnstone RW, Croker BA, Lancaster GI, Murphy AJ, Naik SH, Nutt SL, Pospisil V, Schroeder T, Wall M, Dawson MA, Wei AH, de Thé H, Ritchie ME, Zuber J, Dickins RA Abstract Tumors are composed of phenotypically heterogeneous cancer cells that often resemble various differentiation states of their lineage of origin. Within this hierarchy, it is thought that an immature subpopulation of tumor-propagating cancer stem cells (CSCs) differentiates into non-tumorigenic progeny, providing a rationale for therapeutic strategies that specifically eradicate CSCs or induce their differentiation. The cli...
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: McKenzie MD, Ghisi M, Oxley EP, Ngo S, Cimmino L, Esnault C, Liu R, Salmon JM, Bell CC, Ahmed N, Erlichster M, Witkowski MT, Liu GJ, Chopin M, Dakic A, Simankowicz E, Pomilio G, Vu T, Krsmanovic P, Su S, Tian L, Baldwin TM, Zalcenstein DA, DiRago L, Wang Tags: Cell Stem Cell Source Type: research

Modeling Monogenic Diabetes using Human ESCs Reveals Developmental and Metabolic Deficiencies Caused by Mutations in HNF1A.
Abstract Human monogenic diabetes, caused by mutations in genes involved in beta cell development and function, has been a challenge to study because multiple mouse models have not fully recapitulated the human disease. Here, we use genome edited human embryonic stem cells to understand the most common form of monogenic diabetes, MODY3, caused by mutations in the transcription factor HNF1A. We found that HNF1A is necessary to repress an alpha cell gene expression signature, maintain endocrine cell function, and regulate cellular metabolism. In addition, we identified the human-specific long non-coding RNA, LI...
Source: Cell Stem Cell - August 1, 2019 Category: Stem Cells Authors: Cardenas-Diaz FL, Osorio-Quintero C, Diaz-Miranda MA, Kishore S, Leavens K, Jobaliya C, Stanescu D, Ortiz-Gonzalez X, Yoon C, Chen CS, Haliyur R, Brissova M, Powers AC, French DL, Gadue P Tags: Cell Stem Cell Source Type: research

Outcompeting p53-Mutant Cells in the Normal Esophagus by Redox Manipulation.
Abstract As humans age, normal tissues, such as the esophageal epithelium, become a patchwork of mutant clones. Some mutations are under positive selection, conferring a competitive advantage over wild-type cells. We speculated that altering the selective pressure on mutant cell populations may cause them to expand or contract. We tested this hypothesis by examining the effect of oxidative stress from low-dose ionizing radiation (LDIR) on wild-type and p53 mutant cells in the transgenic mouse esophagus. We found that LDIR drives wild-type cells to stop proliferating and differentiate. p53 mutant cells are insensit...
Source: Cell Stem Cell - July 9, 2019 Category: Stem Cells Authors: Fernandez-Antoran D, Piedrafita G, Murai K, Ong SH, Herms A, Frezza C, Jones PH Tags: Cell Stem Cell Source Type: research

Remodeling of Bone Marrow Hematopoietic Stem Cell Niches Promotes Myeloid Cell Expansion during Premature or Physiological Aging.
W, Louache F, Andrés V, Méndez-Ferrer S Abstract Hematopoietic stem cells (HSCs) residing in the bone marrow (BM) accumulate during aging but are functionally impaired. However, the role of HSC-intrinsic and -extrinsic aging mechanisms remains debated. Megakaryocytes promote quiescence of neighboring HSCs. Nonetheless, whether megakaryocyte-HSC interactions change during pathological/natural aging is unclear. Premature aging in Hutchinson-Gilford progeria syndrome recapitulates physiological aging features, but whether these arise from altered stem or niche cells is unknown. Here, we show that the BM...
Source: Cell Stem Cell - July 4, 2019 Category: Stem Cells Authors: Ho YH, Del Toro R, Rivera-Torres J, Rak J, Korn C, García-García A, Macías D, González-Gómez C, Del Monte A, Wittner M, Waller AK, Foster HR, López-Otín C, Johnson RS, Nerlov C, Ghevaert C, Vainchenker W, Louache F, Andrés V, Méndez-Ferrer S Tags: Cell Stem Cell Source Type: research