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Cell Stem Cell

Kun Zhang, Ludi Zhang, Wenming Liu, Xiaolong Ma, Jin Cen, Zhen Sun, Chenhua Wang, Sisi Feng, Zhengtao Zhang, Liyun Yue, Lulu Sun, Zhenfeng Zhu, Xiaotao Chen, Anqi Feng, Jiaying Wu, Zhiwu Jiang, Peng Li, Xin Cheng, Dong Gao, Luying Peng, Lijian Hui
Transplantation of human hepatocytes (HHs) holds significant potential for treating liver diseases. However, the supply of transplantable HHs is severely constrained by limited donor availability and compromised capacity for in vitro expansion. In response to chronic injury, some HHs are reprogrammed into proliferative cells that express both hepatocyte and progenitor markers, suggesting exploitable strategies for expanding HHs in vitro. Here, we report defined medium conditions that allow 10,000-fold expansion of HHs...
October 30, 2018: Cell Stem Cell
Meryem B Baghdadi, Joao Firmino, Kartik Soni, Brendan Evano, Daniela Di Girolamo, Philippos Mourikis, David Castel, Shahragim Tajbakhsh
Critical features of stem cells include anchoring within a niche and activation upon injury. Notch signaling maintains skeletal muscle satellite (stem) cell quiescence by inhibiting differentiation and inducing expression of extracellular components of the niche. However, the complete spectrum of how Notch safeguards quiescence is not well understood. Here, we perform Notch ChIP-sequencing and small RNA sequencing in satellite cells and identify the Notch-induced microRNA-708, which is a mirtron that is highly expressed in quiescent cells and sharply downregulated in activated cells...
October 25, 2018: Cell Stem Cell
Carolina Petrillo, Lucy G Thorne, Giulia Unali, Giulia Schiroli, Anna M S Giordano, Francesco Piras, Ivan Cuccovillo, Sarah J Petit, Fatima Ahsan, Mahdad Noursadeghi, Simon Clare, Pietro Genovese, Bernhard Gentner, Luigi Naldini, Greg J Towers, Anna Kajaste-Rudnitski
Innate immune factors may restrict hematopoietic stem cell (HSC) genetic engineering and contribute to broad individual variability in gene therapy outcomes. Here, we show that HSCs harbor an early, constitutively active innate immune block to lentiviral transduction that can be efficiently overcome by cyclosporine H (CsH). CsH potently enhances gene transfer and editing in human long-term repopulating HSCs by inhibiting interferon-induced transmembrane protein 3 (IFITM3), which potently restricts VSV glycoprotein-mediated vector entry...
October 24, 2018: Cell Stem Cell
Helen H N Yan, Hoi Cheong Siu, Simon Law, Siu Lun Ho, Sarah S K Yue, Wai Yin Tsui, Dessy Chan, April S Chan, Stephanie Ma, Ka On Lam, Sina Bartfeld, Alice H Y Man, Bernard C H Lee, Annie S Y Chan, Jason W H Wong, Priscilla S W Cheng, Anthony K W Chan, Jiangwen Zhang, Jue Shi, Xiaodan Fan, Dora L W Kwong, Tak W Mak, Siu Tsan Yuen, Hans Clevers, Suet Yi Leung
Gastric cancer displays marked molecular heterogeneity with aggressive behavior and treatment resistance. Therefore, good in vitro models that encompass unique subtypes are urgently needed for precision medicine development. Here, we have established a primary gastric cancer organoid (GCO) biobank that comprises normal, dysplastic, cancer, and lymph node metastases (n = 63) from 34 patients, including detailed whole-exome and transcriptome analysis. The cohort encompasses most known molecular subtypes (including EBV, MSI, intestinal/CIN, and diffuse/GS, with CLDN18-ARHGAP6 or CTNND1-ARHGAP26 fusions or RHOA mutations), capturing regional heterogeneity and subclonal architecture, while their morphology, transcriptome, and genomic profiles remain closely similar to in vivo tumors, even after long-term culture...
October 13, 2018: Cell Stem Cell
Jack-Christophe Cossec, Ilan Theurillat, Claudia Chica, Sabela Búa Aguín, Xavier Gaume, Alexandra Andrieux, Ane Iturbide, Gregory Jouvion, Han Li, Guillaume Bossis, Jacob-Sebastian Seeler, Maria-Elena Torres-Padilla, Anne Dejean
Understanding general principles that safeguard cellular identity should reveal critical insights into common mechanisms underlying specification of varied cell types. Here, we show that SUMO modification acts to stabilize cell fate in a variety of contexts. Hyposumoylation enhances pluripotency reprogramming in vitro and in vivo, increases lineage transdifferentiation, and facilitates leukemic cell differentiation. Suppressing sumoylation in embryonic stem cells (ESCs) promotes their conversion into 2-cell-embryo-like (2C-like) cells...
November 1, 2018: Cell Stem Cell
Joanne I Hsu, Tajhal Dayaram, Ayala Tovy, Etienne De Braekeleer, Mira Jeong, Feng Wang, Jianhua Zhang, Timothy P Heffernan, Sonal Gera, Jeffrey J Kovacs, Joseph R Marszalek, Christopher Bristow, Yuanqing Yan, Guillermo Garcia-Manero, Hagop Kantarjian, George Vassiliou, P Andrew Futreal, Lawrence A Donehower, Koichi Takahashi, Margaret A Goodell
Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+ /Mg2+ -dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure...
November 1, 2018: Cell Stem Cell
Peter Feige, Caroline E Brun, Morten Ritso, Michael A Rudnicki
Muscle stem cells, or satellite cells, are required for skeletal muscle maintenance, growth, and repair. Following satellite cell activation, several factors drive asymmetric cell division to generate a stem cell and a proliferative progenitor that forms new muscle. The balance between symmetric self-renewal and asymmetric division significantly impacts the efficiency of regeneration. In this Review, we discuss the relationship of satellite cell heterogeneity and the establishment of polarity to asymmetric division, as well as how these processes are impacted in homeostasis, aging, and disease...
November 1, 2018: Cell Stem Cell
Tenneille E Ludwig, Angela Kujak, Antonio Rauti, Steven Andrzejewski, Susan Langbehn, James Mayfield, Jacqueline Fuller, Yoshimi Yashiro, Yasushi Hara, Anita Bhattacharyya
November 2018 marks the 20th anniversary of the seminal human embryonic stem cell (hESC) publication, which reported the initial hESC derivations and launched the field of human pluripotent stem cell research. To commemorate this significant milestone, we reflect on the scientific, economic, and clinically relevant impact of this groundbreaking achievement.
November 1, 2018: Cell Stem Cell
(no author information available yet)
Overcoming the widening "Valley of Death" between stem cell laboratory discoveries and clinical translation is imperative to develop the next generation of effective therapies. We asked 9 clinical experts to share their perspectives on how to bridge this gap and increase the clinical impact of basic research.
November 1, 2018: Cell Stem Cell
Roi Ankawa, Yaron Fuchs
Large cutaneous and non-healing ulcers exhibit impaired epithelialization, which represents a major therapeutic challenge. Recently in Nature, Kurita et al. (2018) reported a surprising potential source of epithelial cells. The authors demonstrate that wound-resident mesenchymal cells can be reprogrammed to generate expandable epithelial tissues and facilitate wound closure.
November 1, 2018: Cell Stem Cell
Megan E McNerney, Michelle M Le Beau
Clonal hematopoiesis of indeterminate potential (CHIP) describes clonal selection of a hematopoietic stem cell with a somatic mutation that confers increased fitness, influenced by a selective environment such as aging, inflammation, or therapeutic exposure. In this issue of Cell Stem Cell, Hsu et al. (2018) explore the role of cytotoxic therapy in disease-relevant CHIP.
November 1, 2018: Cell Stem Cell
Charles G Mullighan
Hematopoietic progenitors undergo marked shifts during transition from fetal to postnatal life, and the implication of these changes for the cell-of-origin of childhood leukemia are unclear. In this issue of Cell Stem Cell, Giambra et al. (2018) show that epigenetically regulated IGF1 signaling regulates the ability of fetal-liver- or bone-marrow-derived cells to initiate T-ALL.
November 1, 2018: Cell Stem Cell
Michael V Sofroniew
Gain-of-function mutations in the canonical astrocyte protein, GFAP, cause a fatal neurodevelopmental disorder with myelination abnormalities, seizures, and psychomotor disturbances. Recently, Li et al. (2018) (in Cell Stem Cell) and Jones et al. (2018) (in Cell Reports) have shown that patient iPSC-derived astrocytes with mutant GFAP have disrupted astrocyte functions, revealing disease mechanisms and potential roles of GFAP.
November 1, 2018: Cell Stem Cell
Mingxing Lei, Cheng-Ming Chuong
In normal homeostasis, cancer defense, or stem cell therapy, epidermal progenitors undergo constant competition to reach an equilibrium state. In this issue of Cell Stem Cell, Mesa et al. (2018) and Murai et al. (2018) show that skin epidermal progenitors maintain tissue homeostasis through competitive equilibrium under physiological self-renewal or oncogenic conditions.
November 1, 2018: Cell Stem Cell
Ido Sagi, Shiran Bar, Nissim Benvenisty
Genomic imprinting results in the molecular and functional inequality of maternal and paternal alleles, precluding mammalian unisexual development. In this issue of Cell Stem Cell, Li et al. (2018) employ sophisticated manipulations of gametes and engineered haploid embryonic stem cells to successfully generate both all-maternal and all-paternal mice, effectively overcoming the roadblocks of imprinting.
November 1, 2018: Cell Stem Cell
Shashank S Tiwari, Pranav N Desai
Hundreds of clinics in India offer unproven stem cell therapies despite having remarkably stringent guidelines and regulations for fraudulent advertisements and clinical practice. We discuss the challenges with current regulations, how a recently proposed amendment may further legitimize unproven stem cell therapies, and discuss paths forward in a global context.
November 1, 2018: Cell Stem Cell
Zhi-Kun Li, Le-Yun Wang, Li-Bin Wang, Gui-Hai Feng, Xue-Wei Yuan, Chao Liu, Kai Xu, Yu-Huan Li, Hai-Feng Wan, Ying Zhang, Yu-Fei Li, Xin Li, Wei Li, Qi Zhou, Bao-Yang Hu
Unisexual reproduction is widespread among lower vertebrates, but not in mammals. Deletion of the H19 imprinted region in immature oocytes produced bimaternal mice with defective growth; however, bipaternal reproduction has not been previously achieved in mammals. We found that cultured parthenogenetic and androgenetic haploid embryonic stem cells (haESCs) display DNA hypomethylation resembling that of primordial germ cells. Through MII oocyte injection or sperm coinjection with hypomethylated haploid ESCs carrying specific imprinted region deletions, we obtained live bimaternal and bipaternal mice...
November 1, 2018: Cell Stem Cell
Yanxia Liu, Chen Yu, Timothy Patrick Daley, Fangyuan Wang, William S Cao, Salil Bhate, Xueqiu Lin, Chris Still, Honglei Liu, Dehua Zhao, Haifeng Wang, Xinmin S Xie, Sheng Ding, Wing Hung Wong, Marius Wernig, Lei S Qi
Comprehensive identification of factors that can specify neuronal fate could provide valuable insights into lineage specification and reprogramming, but systematic interrogation of transcription factors, and their interactions with each other, has proven technically challenging. We developed a CRISPR activation (CRISPRa) approach to systematically identify regulators of neuronal-fate specification. We activated expression of all endogenous transcription factors and other regulators via a pooled CRISPRa screen in embryonic stem cells, revealing genes including epigenetic regulators such as Ezh2 that can induce neuronal fate...
November 1, 2018: Cell Stem Cell
Kasumi Murai, Greta Skrupskelyte, Gabriel Piedrafita, Michael Hall, Vasiliki Kostiou, Swee Hoe Ong, Tibor Nagy, Alex Cagan, David Goulding, Allon M Klein, Benjamin A Hall, Philip H Jones
Aging human tissues, such as sun-exposed epidermis, accumulate a high burden of progenitor cells that carry oncogenic mutations. However, most progenitors carrying such mutations colonize and persist in normal tissue without forming tumors. Here, we investigated tissue-level constraints on clonal progenitor behavior by inducing a single-allele p53 mutation (Trp53R245W ; p53∗/wt ), prevalent in normal human epidermis and squamous cell carcinoma, in transgenic mouse epidermis. p53∗/wt progenitors initially outcompeted wild-type cells due to enhanced proliferation, but subsequently reverted toward normal dynamics and homeostasis...
November 1, 2018: Cell Stem Cell
Kailin R Mesa, Kyogo Kawaguchi, Katie Cockburn, David Gonzalez, Jonathan Boucher, Tianchi Xin, Allon M Klein, Valentina Greco
Maintenance of adult tissues depends on sustained activity of resident stem cell populations, but the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of 1 to 2 days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa...
November 1, 2018: Cell Stem Cell
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