scholarly journals Keratin Profiling by Single-Cell RNA-Sequencing Identifies Human Prostate Stem Cell Lineage Hierarchy and Cancer Stem-Like Cells

2021 ◽  
Vol 22 (15) ◽  
pp. 8109
Author(s):  
Wen-Yang Hu ◽  
Dan-Ping Hu ◽  
Lishi Xie ◽  
Larisa Nonn ◽  
Ranli Lu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Progenitor Cells ◽  
3D Culture ◽  
Cell Lineage ◽  
Gene Set Enrichment Analysis ◽  
Human Prostate ◽  
Stem Cell Lineage

Single prostate stem cells can generate stem and progenitor cells to form prostaspheres in 3D culture. Using a prostasphere-based label retention assay, we recently identified keratin 13 (KRT13)-enriched prostate stem cells at single-cell resolution, distinguishing them from daughter progenitors. Herein, we characterized the epithelial cell lineage hierarchy in prostaspheres using single-cell RNA-seq analysis. Keratin profiling revealed three clusters of label-retaining prostate stem cells; cluster I represents quiescent stem cells (PSCA, CD36, SPINK1, and KRT13/23/80/78/4 enriched), while clusters II and III represent active stem and bipotent progenitor cells (KRT16/17/6 enriched). Gene set enrichment analysis revealed enrichment of stem and cancer-related pathways in cluster I. In non-label-retaining daughter progenitor cells, three clusters were identified; cluster IV represents basal progenitors (KRT5/14/6/16 enriched), while clusters V and VI represent early and late-stage luminal progenitors, respectively (KRT8/18/10 enriched). Furthermore, MetaCore analysis showed enrichment of the “cytoskeleton remodeling–keratin filaments” pathway in cancer stem-like cells from human prostate cancer specimens. Along with common keratins (KRT13/23/80/78/4) in normal stem cells, unique keratins (KRT10/19/6C/16) were enriched in cancer stem-like cells. Clarification of these keratin profiles in human prostate stem cell lineage hierarchy and cancer stem-like cells can facilitate the identification and therapeutic targeting of prostate cancer stem-like cells.

scholarly journals Actions of Estrogenic Endocrine Disrupting Chemicals on Human Prostate Stem/Progenitor Cells and Prostate Carcinogenesis

2016 ◽  
Vol 10 (1) ◽  
pp. 76-97 ◽  
Author(s):  
Dan-Ping Hu ◽  
Wen-Yang Hu ◽  
Lishi Xie ◽  
Ye Li ◽  
Lynn Birch ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Endocrine Disrupting Chemicals ◽  
Human Prostate ◽  
Cancer Management ◽  
Prostate Carcinogenesis ◽  
Endocrine Disrupting ◽  
Cancer Initiation

Substantial evidences from epidemiological and animal-based studies indicate that early exposure to endocrine disrupting chemicals (EDCs) during the developmental stage results in a variety of disorders including cancer. Previous studies have demonstrated that early estrogen exposure results in life-long reprogramming of the prostate gland that leads to an increased incidence of prostatic lesions with aging. We have recently documented that bisphenol A (BPA), one of the most studied EDCs with estrogenic activity has similar effects in increasing prostate carcinogenic potential, supporting the connection between EDCs exposure and prostate cancer risk. It is well accepted that stem cells play a crucial role in development and cancer. Accumulating evidence suggest that stem cells are regulated by extrinsic factors and may be the potential target of hormonal carcinogenesis. Estrogenic EDCs which interfere with normal hormonal signaling may perturb prostate stem cell fate by directly reprogramming stem cells or breaking down the stem cell niche. Transformation of stem cells into cancer stem cells may underlie cancer initiation accounting for cancer recurrence, which becomes a critical therapeutic target of cancer management. We therefore propose that estrogenic EDCs may influence the development and progression of prostate cancer through reprogramming and transforming the prostate stem and early stage progenitor cells. In this review, we summarize our current studies and have updated recent advances highlighting estrogenic EDCs on prostate carcinogenesis by possible targeting prostate stem/progenitor cells. Using novel stem cell assays we have demonstrated that human prostate stem/progenitor cells express estrogen receptors (ER) and are directly modulated by estrogenic EDCs. Moreover, employing anin vivohumanized chimeric prostate model, we further demonstrated that estrogenic EDCs initiate and promote prostatic carcinogenesis in an androgen-supported environment. These findings support our hypothesis that prostate stem/progenitor cells may be the direct targets of estrogenic EDCs as a consequence of developmental exposure which carry permanent reprogrammed epigenetic and oncogenic events and subsequently deposit into cancer initiation and progression in adulthood.

The Neural Stem Cell Lineage Reveals Novel Relationships Among Spermatogonial Germ Stem Cells and Other Pluripotent Stem Cells

2014 ◽  
Vol 23 (7) ◽  
pp. 767-778 ◽  
Author(s):  
Anouk-Martine Teichert ◽  
Schreiber Pereira ◽  
Brenda Coles ◽  
Radha Chaddah ◽  
Susan Runciman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Neural Stem Cell ◽  
Pluripotent Stem Cells ◽  
Cell Lineage ◽  
Stem Cell Lineage

scholarly journals Single-Cell Transcriptomic Analysis Defines Heterogeneity and Transcriptional Dynamics in the Adult Neural Stem Cell Lineage

Cell Reports ◽  
2017 ◽  
Vol 18 (3) ◽  
pp. 777-790 ◽  
Author(s):  
Ben W. Dulken ◽  
Dena S. Leeman ◽  
Stéphane C. Boutet ◽  
Katja Hebestreit ◽  
Anne Brunet
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Neural Stem Cell ◽  
Cell Lineage ◽  
Transcriptomic Analysis ◽  
Adult Neural Stem Cell ◽  
Transcriptional Dynamics ◽  
Stem Cell Lineage

ID: 82: DISTINCT ACTIONS OF ERα AND ERβ IN HUMAN PROSTATE STEM AND PROGENITOR CELL SELF-RENEWAL AND DIFFERENTIATION

2016 ◽  
Vol 64 (4) ◽  
pp. 928.1-928 ◽  
Author(s):  
D Hu ◽  
W Hu ◽  
S Majumdar ◽  
T Gauntner ◽  
Y Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Side Population ◽  
Population Analysis ◽  
Human Prostate ◽  
Mrna Levels ◽  
Self Renewal ◽  
Prostate Carcinogenesis ◽  
Prostate Epithelial Cells

Estrogens are implicated in prostate development and cancer, while stem cells are essential in tissue homeostasis and carcinogenesis. We have previously demonstrated that estradiol-17β (E2) treatment augments prostaspheres (PS) number and size, implicating them as direct estrogen targets. The present studies sought to elucidate specific roles for ERα and ERβ in prostate stem and progenitor cells.Prostate stem-progenitor cells were identified and isolated from normal primary prostate epithelial cells (PrEC) using long term BrdU retention in 3-D PS culture. FACS analyses (BrdU/ERα or ERβ) showed prostate stem and progenitor populations were both ERα+ and ERβ+. BrdU-retaining stem cells expressed high levels of ERβ and lower ERα as compared to non-label-retaining progenitor cells, suggesting ERβ dominance in the prostate stem cell. Estradiol increased BrdU-retaining cell numbers by enhancing stem cell self-renewal through symmetric division. While ERα siRNA blocked the E2-stimulated BrdU-retaining cells, ERβ knockdown augmented the E2-induced increase of BrdU-retaining cells. Together these findings suggest that ERα stimulates whereas ERβ suppresses stem cell self-renew. This conclusion is supported by separate studies on 2-D cultured PrEC with FACS stem-like cell side-population analysis using selective ER antagonists and siRNA. Although ERβ siRNA did not influence ERα mRNA levels, ERα siRNA doubled ERβ expression suggesting a suppressive role of ERα on ERβ action.In total, the present findings identify distinct localization patterns and roles for ERα and ERβ in human prostate stem-like and daughter progenitor cells with ERα driving self-renewal and ERβ braking division. We propose that a delicate balance between ERα and ERβ contributes to prostate stem cell niche homeostasis and that their dysregulation may contribute to prostate carcinogenesis and progression.

scholarly journals Stem Cells, Diet, and Physiology

2020 ◽  
Vol 4 (Supplement_1) ◽  
pp. 740-740
Author(s):  
Daniela Drummond-Barbosa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Lineage ◽  
Germline Stem Cell ◽  
Stem Cell Regulation ◽  
Stem Cell Lineage ◽  
Sensor Control ◽  
Nutrient Signaling ◽  
Multicellular Organisms

Abstract Nutrient availability, stresses, and aging affect tissue stem cells in multicellular organisms; yet, the underlying physiological mechanisms in vivo remains largely unexplored. Dr. Drummond-Barbosa pioneered using Drosophila to study the physiology of tissue stem cell regulation. Her laboratory played a major role in delineating how diet, brain insulin-like peptides, and the TOR nutrient sensor control the germline stem cell (GSC) lineage. They also discovered that adipocyte-specific disruption of amino acid transport, other nutrient signaling, and metabolic pathways causes distinct germline phenotypes. They also showed that nuclear receptors act in multiple tissues to affect the GSC lineage through direct and indirect mechanisms. More recently, her group has been exploring how other physiological stresses affect the GSC lineage. Her group’s studies point to extensive communication between the brain, adipocytes, hepatocyte-like cells, and the germline, and underscore the complexity of the physiological network that modulates stem cell lineage behavior.

FC 038CRESCENTS DERIVE FROM SINGLE PODOCYTE PROGENITORS AND A DRUG ENHANCING THEIR DIFFERENTIATION ATTENUATES RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Maria Elena Melica ◽  
Giulia Antonelli ◽  
Roberto Semeraro ◽  
Maria Lucia Angelotti ◽  
Gianmarco Lugli ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Single Cell ◽  
Progenitor Cells ◽  
Rapidly Progressive Glomerulonephritis ◽  
Super Resolution ◽  
Crescent Formation ◽  
Hematopoietic Stem ◽  
Single Cell Rna Sequencing ◽  
Renal Progenitor

Abstract Background and Aims Rapidly progressive glomerulonephritis (RPGN) encompasses a group of diverse disorders characterized by the presence of massive hyperplasia of parietal epithelial cells (PEC) as the main histopathological lesion at kidney biopsy. It is associated with a rapid decline in kidney function referred to altogether as rapidly progressive glomerulonephritis. Typically, crescent formation is the consequence of diverse upstream pathomechanisms involving the specific activation of PEC. PEC normally reside peacefully along Bowman capsule and represent in part renal progenitor cells (RPC). Previous studies observed RPC markers in crescents from patients with different types of glomerulonephritis. Similarities between stem cell niches of bone marrow and kidney, prompted us to hypothesized that crescents result from monoclonal expansion of a single RPC clone conceptually similar to monoclonal diseases originating from hematopoietic stem cells. According to this analogy, we further hypothesized that drugs known to cure monoclonal disease of the hematopoietic stem cells by enforcing their terminal differentiation could also attenuate crescentic glomerulonephritis. Method To address this hypothesis, we established a RPGN disease model in a conditional transgenic mouse based on the mT/mG and the Confetti reporter that allows lineage tracing and clonal analysis of RPCs. Animals were treated with known pharmacological inhibitors of clonal stem cell proliferation in myeloproliferative disorders. Crescentic lesions were characterized by super-resolution STED microscopy. Finally, we employed single cell RNA sequencing of human renal progenitor cultures to identify the immature progenitor subset-generating crescent in human to identify putative new biomarker(s) of RPNG to validate in biopsy of patients. Results We observed that the crescentic lesions originated from the clonal expansion of single RPC, thus suggesting a clonal stem cell disorder. Therefore, we administrated a series of drugs known to ameliorates myeloproliferative neoplasms to our RPGN mouse model as potential therapeutic agents. In particular, treatment with one of the compounds induced a reduction in both proteinuria and crescent formation. 3D confocal microscopy and STED super-resolution imaging of glomeruli showed that this compound turned the uncontrolled hyperplasia of a specific immature PEC subset into a controlled differentiation into new podocytes thereby restoring the injured glomerular filtration barrier. Single cell RNA sequencing of human renal progenitor cultures identified a new marker of the crescent-generating progenitor cells. Expression of this marker in biopsies of patients with rapidly progressive glomerulonephritis associated with progression toward end stage kidney disease. Treatment of human PEC with the drug that in in vivo experiments showed a therapeutic effect on RPGN reduced proliferation of the immature progenitor subset promoting their differentiation into podocytes. Conclusion These results demonstrate that glomerular hyperplastic lesions derive from clonal amplification of a RPC subset and that shifting proliferation to podocyte differentiation reverses crescent formation and improves clinical outcome.

Lox2, a putative leech segment identity gene, is expressed in the same segmental domain in different stem cell lineages

Development ◽  
1992 ◽  
Vol 116 (3) ◽  
pp. 697-710 ◽  
Author(s):  
D. Nardelli-Haefliger ◽  
M. Shankland
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Gene Products ◽  
Cell Lineages ◽  
Stem Cell Lineage ◽  
Hybridization Reaction ◽  
Cell Segment

The segmented tissues of the adult leech arise from a set of five, bilaterally paired embryonic stem cells via a stereotyped sequence of cell lineage. Individual segments exhibit unique patterns of cell differentiation, and previous studies have suggested that each stem cell lineage establishes at least some aspects of its own segmental specificity autonomously. In this paper, we describe a putative leech segment identity gene, Lox2, and examine its expression in the various stem cell lineages. Both sequence analysis and the segmental pattern of Lox2 expression suggest a specific homology to the fruitfly segment identity genes Ubx and abdA. In situ hybridization reveals a cellular accumulation of Lox2 RNA over a contiguous domain of 16 midbody segments (M6-M21), including postmitotic neurons, muscles and the differentiating genitalia. Lox2 transcripts were not detected at the stage when segment identities are first established, suggesting that Lox2 gene products may not be part of the initial specification process. Individual stem cell lineages were labeled by intracellular injection of fluorescent tracers, and single cell colocalization of lineage tracer and hybridization reaction product revealed expression of Lox2 RNA in the progeny of four different stem cells. The segmental domain of Lox2 RNA was very similar in the various stem cell lineages, despite the fact that some stem cells generate one founder cell/segment, whereas other stem cells generate two founder cells/segment.

scholarly journals Division-independent differentiation mandates proliferative competition among stem cells

2018 ◽  
Vol 115 (14) ◽  
pp. E3182-E3191 ◽  
Author(s):  
Amy Reilein ◽  
David Melamed ◽  
Simon Tavaré ◽  
Daniel Kalderon
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Division ◽  
Cell Lineage ◽  
Proliferation Rate ◽  
Genetic Changes ◽  
Stem Cell Lineage ◽  
Stem Cell Division ◽  
Follicle Stem Cells ◽  
The Impact

Cancer-initiating gatekeeper mutations that arise in stem cells would be especially potent if they stabilize and expand an affected stem cell lineage. It is therefore important to understand how different stem cell organization strategies promote or prevent variant stem cell amplification in response to different types of mutation, including those that activate proliferation. Stem cell numbers can be maintained constant while producing differentiated products through individually asymmetrical division outcomes or by population asymmetry strategies in which individual stem cell lineages necessarily compete for niche space. We considered alternative mechanisms underlying population asymmetry and used quantitative modeling to predict starkly different consequences of altering proliferation rate: A variant, faster proliferating mutant stem cell should compete better only when stem cell division and differentiation are independent processes. For most types of stem cells, it has not been possible to ascertain experimentally whether division and differentiation are coupled. However, Drosophila follicle stem cells (FSCs) provided a favorable system with which to investigate population asymmetry mechanisms and also for measuring the impact of altered proliferation on competition. We found from detailed cell lineage studies that division and differentiation of an individual FSC are not coupled. We also found that FSC representation, reflecting maintenance and amplification, was highly responsive to genetic changes that altered only the rate of FSC proliferation. The FSC paradigm therefore provides definitive experimental evidence for the general principle that relative proliferation rate will always be a major determinant of competition among stem cells specifically when stem cell division and differentiation are independent.

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