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stem cell heterogeneity

Abby Spangler, Emily Y Su, April M Craft, Patrick Cahan
Directed differentiation of pluripotent stem cells provides an accessible system to model development. However, the distinct cell types that emerge, their dynamics, and their relationship to progenitors in the early embryo has been difficult to decipher because of the cellular heterogeneity inherent to differentiation. Here, we used a combination of bulk RNA-Seq, single cell RNA-Seq, and bioinformatics analyses to dissect the cell types that emerge during directed differentiation of mouse embryonic stem cells as embryoid bodies and we compared them to spatially and temporally resolved transcriptional profiles of early embryos...
July 29, 2018: Stem Cell Research
Takashi Yamazaki, Lizhi Liu, Denis Lazarev, Amr Al-Zain, Vitalay Fomin, Percy Luk Yeung, Stuart M Chambers, Chi-Wei Lu, Lorenz Studer, James L Manley
Alternative splicing (AS) plays important roles in embryonic stem cell (ESC) differentiation. In this study, we first identified transcripts that display specific AS patterns in pluripotent human ESCs (hESCs) relative to differentiated cells. One of these encodes T-cell factor 3 (TCF3), a transcription factor that plays important roles in ESC differentiation. AS creates two TCF3 isoforms, E12 and E47, and we identified two related splicing factors, heterogeneous nuclear ribonucleoproteins (hnRNPs) H1 and F (hnRNP H/F), that regulate TCF3 splicing...
August 16, 2018: Genes & Development
Eithne M Maguire, Stuart W A Pearce, Qingzhong Xiao
During atherosclerosis, the gradual accumulation of lipids into the subendothelial space of damaged arteries results in several lipid modification processes followed by macrophage uptake in the arterial wall. The way in which these modified lipoproteins are dealt with determines the likelihood of cholesterol accumulation within the monocyte-derived macrophage and thus its transformation into the foam cell that makes up the characteristic fatty streak observed in the early stages of atherosclerosis. The unique expression of chemokine receptors and cellular adhesion molecules expressed on the cell surface of monocytes points to a particular extravasation route that they can take to gain entry into atherosclerotic site, in order to undergo differentiation into the phagocytic macrophage...
August 13, 2018: Vascular Pharmacology
Luca Trotta, Anna Norberg, Mervi Taskinen, Vivien Béziat, Sofie Degerman, Ulla Wartiovaara-Kautto, Hannamari Välimaa, Kirsi Jahnukainen, Jean-Laurent Casanova, Mikko Seppänen, Janna Saarela, Minna Koskenvuo, Timi Martelius
BACKGROUND: The telomere biology disorders (TBDs) include a range of multisystem diseases characterized by mucocutaneous symptoms and bone marrow failure. In dyskeratosis congenita (DKC), the clinical features of TBDs stem from the depletion of crucial stem cell populations in highly proliferative tissues, resulting from abnormal telomerase function. Due to the wide spectrum of clinical presentations and lack of a conclusive laboratory test it may be challenging to reach a clinical diagnosis, especially if patients lack the pathognomonic clinical features of TBDs...
August 17, 2018: Orphanet Journal of Rare Diseases
Ivana Jovčevska
Glioblastomas account for the majority of primary brain tumors. Although glioblastomas are considered as rare diseases, they represent 60%-70% of all gliomas and in most cases have fatal consequences. Genetic analyses show great heterogeneity both intratumor and intertumor. This notion opens up debates about glioblastoma origin. Different brain cells including astrocytes, neural stem cells, oligodendrocyte precursor cells and glioblastoma stem cells are proposed as capable of initiation and reseeding a tumor; however data is still inconclusive...
August 14, 2018: Bosnian Journal of Basic Medical Sciences
Mahboobeh Razmkhah, Shabnam Abtahi, Abbas Ghaderi
Mesenchymal Stem Cells [MSCs] are a heterogeneous population of fibroblast-like cells which maintain self-renewability and pluripotency. Many studies have demonstrated the immunomodulatory effects of MSCs on the innate and adaptive immune cells. As a result of interactions with tumor cells, microenvironment and immune-stimulating milieu, MSCs contribute to tumor progression by several mechanisms, including sustained proliferative signal in cancer stem cells [CSCs], inhibition of tumor cell apoptosis, transition to tumor associated fibroblasts [TAFs], promotion of angiogenesis, stimulation of epithelial-mesenchymal transition [EMT], suppression of immune responses, and consequential promotion of tumor metastasis...
August 15, 2018: Current Stem Cell Research & Therapy
Eliza Gordon-Lipkin, Ali Fatemi
Leukodystrophies are a heterogeneous class of genetic diseases affecting the white matter in the central nervous system with a broad range of clinical manifestations and a frequently progressive course. An interest in precision medicine has emerged over the last several decades, and biomedical research in leukodystrophies has made exciting advances along this front through therapeutic target discovery and novel disease model systems. In this review, we discuss current and emerging therapeutic approaches in leukodystrophies, including gene therapy, antisense oligonucleotide therapy, CRISPR/CAS-based gene editing, and cell and stem cell based therapies...
August 16, 2018: Journal of Child Neurology
Chiara Di Stefano, Paola Grazioli, Rosaria Anna Fontanella, Paola De Cesaris, Antonella D'Amore, Michele Regno, Donatella Starace, Fabrizio Padula, Micol Elena Fiori, Rita Canipari, Antonella Stoppacciaro, Margherita Pesce, Antonio Filippini, Antonio Francesco Campese, Elio Ziparo, Anna Riccioli
In human prostate cancer (PCa), the neuroendocrine cells, expressing the prostate cancer stem cell (CSC) marker CD44, may be resistant to androgen ablation and promote tumor recurrence. During the study of heterogeneity of the highly aggressive neuroendocrine PCa cell lines PC3 and DU-145, we isolated and expanded in vitro a minor subpopulation of very small cells lacking CD44 (CD44neg ). Unexpectedly, these sorted CD44neg cells rapidly and spontaneously converted to a stable CD44high phenotype specifically expressing the CD44v8-10 isoform which the sorted CD44high subpopulation failed to express...
July 20, 2018: Oncotarget
Elizabeth P Lackey, Detlef H Heck, Roy V Sillitoe
The cerebellum is the focus of an emergent series of debates because its circuitry is now thought to encode an unexpected level of functional diversity. The flexibility that is built into the cerebellar circuit allows it to participate not only in motor behaviors involving coordination, learning, and balance but also in non-motor behaviors such as cognition, emotion, and spatial navigation. In accordance with the cerebellum's diverse functional roles, when these circuits are altered because of disease or injury, the behavioral outcomes range from neurological conditions such as ataxia, dystonia, and tremor to neuropsychiatric conditions, including autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder...
2018: F1000Research
Karolin Holzwarth, Ralf Köhler, Lars Philipsen, Koji Tokoyoda, Valeriia Ladyhina, Carolina Wählby, Raluca A Niesner, Anja E Hauser
The bone marrow (BM) consists of multiple, structured micro-environmental entities-the so called niches, which contain hematopoietic cells as well as stromal cells. These niches fulfill a variety of functions, such as control of the hematopoietic stem cell pool, differentiation of hematopoietic cells, and maintenance of immunological memory. However, due to the molecular and cellular complexity and a lack of suitable histological multiplexing methods, the composition of the various BM niches is still elusive...
August 14, 2018: Cytometry. Part A: the Journal of the International Society for Analytical Cytology
Taeyong Kim, Oscar H Echeagaray, Bingyan J Wang, Alexandria Casillas, Kathleen M Broughton, Bong-Hyun Kim, Mark A Sussman
Regenerative therapeutic approaches for myocardial diseases often involve delivery of stem cells expanded ex vivo. Prior studies indicate that cell culture conditions affect functional and phenotypic characteristics, but relationship(s) of cultured cells derived from freshly isolated populations and the heterogeneity of the cultured population remain poorly defined. Functional and phenotypic characteristics of ex vivo expanded cells will determine outcomes of interventional treatment for disease, necessitating characterization of the impact that ex vivo expansion has upon isolated stem cell populations...
August 13, 2018: Scientific Reports
Oluwaseun Adebayo Bamodu, Ching-Kuo Yang, Wei-Hong Cheng, David T W Tzeng, Kuang-Tai Kuo, Chun-Chih Huang, Li Deng, Michael Hsiao, Wei-Hwa Lee, Chi-Tai Yeh
BACKGROUND: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality in both sexes globally. This is not unconnected with the heterogeneity and plasticity of CRC stem cells (CRC-SCs) which stealthily exploit the niche-related and (epi)genetic factors to facilitate metastasis, chemoresistance, tumor recurrence, and disease progression. Despite the accumulating evidence of the role of dysregulated microRNAs in malignancies, the therapeutic efficacy of pharmacological-targeting of CRC-SC-associated microRNAs is relatively under-explored...
August 10, 2018: Cancers
Lindy Zhang, Allison M Martin, Kathy Ruble
Pediatric oncology patients treated with antineoplastic therapy have impaired immune systems that lead to loss of protective antibodies. They require reimmunization to protect against vaccine-preventable diseases. There are a paucity of studies on the clinical practice of pediatric oncologists and the available recommendations are heterogenous. This study describes current reimmunization practices among pediatric oncologists. We surveyed the Children's Oncology Group (COG)-identified principle investigators to capture clinical practices among pediatric oncologists within their institutions regarding reimmunization of non-hematopoietic stem cell transplantation patients...
August 10, 2018: Journal of Pediatric Hematology/oncology
Ahn R Lee, Yu Gan, Yuxin Tang, Xuesen Dong
BACKGROUND: Prostate adenocarcinoma (AdPC) cells can undergo lineage switching to neuroendocrine cells and develop into therapy-resistant neuroendocrine prostate cancer (NEPC). While genomic/epigenetic alterations are shown to induce neuroendocrine differentiation via an intermediate stem-like state, RNA splicing factor SRRM4 can transform AdPC cells into NEPC xenografts through a direct neuroendocrine transdifferentiation mechanism. Whether SRRM4 can also regulate a stem-cell gene network for NEPC development remains unclear...
August 10, 2018: EBioMedicine
Kazuko Okamoto, Arno Germond, Hideaki Fujita, Chikara Furusawa, Yasushi Okada, Tomonobu M Watanabe
In the stem cell research field, the molecular regulatory network used to define cellular states has been extensively studied, however, the general driving force guiding the collective state dynamics remains to be identified from biophysical aspects. Here we monitored the time-development of the cell-state transition at the single-cell and colony levels, simultaneously, during the early differentiation process in mouse embryonic stem cells. Our quantitative analyses revealed that cellular heterogeneity was a result of spontaneous fluctuation of cellular state and cell-cell cooperativity...
August 10, 2018: Scientific Reports
Kosaku Nanki, Kohta Toshimitsu, Ai Takano, Masayuki Fujii, Mariko Shimokawa, Yuki Ohta, Mami Matano, Takashi Seino, Shingo Nishikori, Keiko Ishikawa, Kenta Kawasaki, Kazuhiro Togasaki, Sirirat Takahashi, Yasutaka Sukawa, Hiroki Ishida, Shinya Sugimoto, Hirofumi Kawakubo, Jihoon Kim, Yuko Kitagawa, Shigeki Sekine, Bon-Kyoung Koo, Takanori Kanai, Toshiro Sato
Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency...
August 9, 2018: Cell
Nisi Zhang, Xiaolong Liang, Chuang Gao, Min Chen, Yiming Zhou, Christopher J Krueger, Gang Bao, Zhuoran Gong, Zhifei Dai
Triple-negative breast cancer (TNBC) is a malignant and refractory disease with high morbidity and mortality. TNBC shows no response to hormonal therapy nor targeted therapy, due to the lack of known targetable biomarkers. Furthermore, TNBC also exhibits a high degree of heterogeneity that leads to cancer evolution, drug resistance, metastatic progression, and recurrence, arising from the tumor-initiating properties of cancer stem cells (CSCs). Thus, the development of radical therapeutic regimens with high efficacy and limited side effects is crucial...
August 10, 2018: ACS Applied Materials & Interfaces
Birte Friedrichs, Matthias Stelljes, Norbert Schmitz
PURPOSE OF REVIEW: T - and natural killer (NK) cell neoplasms are a heterogeneous group of rare diseases with often inferior outcome. Only few studies exist, clarifying the role of allogeneic transplantation in different clinical scenarios. Larger prospective randomized studies are largely missing even for the more frequent entities. Mostly retrospective analysis and anecdotal reports of patients with advanced disease are available, hampering direct conclusions on the significance of allogeneic stem cell transplantation (alloSCT)...
September 2018: Current Opinion in Oncology
Zheng Chen, Tsung-Chin Lin, Xiaohong Bi, Guijin Lu, Brian C Dawson, Roberto Miranda, L Jeffrey Medeiros, Ian McNiece, Nami McCarty
Despite progress in the treatment of MM, including the use of high-dose chemotherapy and autologous stem cell transplantation, a considerable proportion of patients are refractory to all therapies. This resistance is related to the molecular genetic heterogeneity in MM cells as well as to the contributions from the BM, which is one of the key determinants of treatment outcome. Our previous studies using fluorescent tracers revealed that MM heterogeneity is correlated with the presence of quiescent stem-like cancer cells, which prefer to reside within the osteoblastic niche of the BM...
August 8, 2018: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
Rajshekhar R Giraddi, Chi-Yeh Chung, Richard E Heinz, Ozlen Balcioglu, Mark Novotny, Christy L Trejo, Christopher Dravis, Berhane M Hagos, Elnaz Mirzaei Mehrabad, Luo Wei Rodewald, Jae Y Hwang, Cheng Fan, Roger Lasken, Katherine E Varley, Charles M Perou, Geoffrey M Wahl, Benjamin T Spike
The mammary gland consists of cells with gene expression patterns reflecting their cellular origins, function, and spatiotemporal context. However, knowledge of developmental kinetics and mechanisms of lineage specification is lacking. We address this significant knowledge gap by generating a single-cell transcriptome atlas encompassing embryonic, postnatal, and adult mouse mammary development. From these data, we map the chronology of transcriptionally and epigenetically distinct cell states and distinguish fetal mammary stem cells (fMaSCs) from their precursors and progeny...
August 7, 2018: Cell Reports
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