A Transient Niche Regulates the Specification of Drosophila Intestinal Stem Cells

Stem cell niches are locations where stem cells reside and self-renew. Although studies have shown how niches maintain stem cell fate during tissue homeostasis, less is known about their roles in establishing stem cells. The adult Drosophila midgut is maintained by intestinal stem cells (ISCs); however, how they are established is unknown. Here, we show that an ISC progenitor generates a niche cell via Notch signaling. This niche uses the bone morphogenetic protein 2/4 homolog, decapentaplegic, to allow progenitors to divide in an undifferentiated state and subsequently breaks down and dies, resulting in the specification of ISCs in the adult midgut. Our results demonstrate a paradigm for stem cell–niche biology, where progenitors generate transient niches that determine stem cell fate and may give insights into stem cell specification in other tissues.

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Mitochondria-enriched protrusions are associated with brain and intestinal stem cells in Drosophila

Communications Biology ◽

10.1038/s42003-019-0671-4 ◽

2019 ◽

Vol 2 (1) ◽

Author(s):

Sharyn A. Endow ◽

Sara E. Miller ◽

Phuong Thao Ly

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Niche ◽

Brain Regions ◽

Intestinal Stem Cells ◽

Undifferentiated State ◽

Cytoplasmic Protrusion ◽

Microtubule Growth ◽

Cell Niche ◽

Early Larvae

AbstractBrain stem cells stop dividing in late Drosophila embryos and begin dividing again in early larvae after feeding induces reactivation. Quiescent neural stem cells (qNSCs) display an unusual cytoplasmic protrusion that is no longer present in reactivated NSCs. The protrusions join the qNSCs to the neuropil, brain regions that are thought to maintain NSCs in an undifferentiated state, but the function of the protrusions is not known. Here we show that qNSC protrusions contain clustered mitochondria that are likely maintained in position by slow forward-and-backward microtubule growth. Larvae treated with a microtubule-stabilizing drug show bundled microtubules and enhanced mitochondrial clustering in NSCs, together with reduced qNSC reactivation. We further show that intestinal stem cells contain mitochondria-enriched protrusions. The qNSC and intestinal stem-cell protrusions differ from previously reported cytoplasmic extensions by forming stem-cell-to-niche mitochondrial bridges that could potentially both silence genes and sense signals from the stem cell niche.

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Immunostaining of Lgr5, an Intestinal Stem Cell Marker, in Normal and Premalignant Human Gastrointestinal Tissue

The Scientific World JOURNAL ◽

10.1100/tsw.2008.148 ◽

2008 ◽

Vol 8 ◽

pp. 1168-1176 ◽

Cited By ~ 76

Author(s):

Laren Becker ◽

Qin Huang ◽

Hiroshi Mashimo

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Niche ◽

Intestinal Stem Cells ◽

Stem Cell Marker ◽

Tumor Initiating Cells ◽

Colonic Adenomas ◽

Potential Marker ◽

Cell Niche ◽

Crypt Base

Lgr5 has recently been identified as a murine marker of intestinal stem cells. Its expression has not been well characterized in human gastrointestinal tissues, but has been reported in certain cancers. With the increasing appreciation for the role of cancer stem cells or tumor-initiating cells in certain tumors, we sought to explore the expression of Lgr5 in normal and premalignant human gastrointestinal tissues. Using standard immunostaining, we compared expression of Lgr5 in normal colon and small intestine vs. small intestinal and colonic adenomas and Barrett's esophagus. In the normal tissue, Lgr5 was expressed in the expected stem cell niche, at the base of crypts, as seen in mice. However, in premalignant lesions, Lgr5+cells were not restricted to the crypt base. Additionally, their overall numbers were increased. In colonic adenomas, Lgr5+cells were commonly found clustered at the luminal surface and rarely at the crypt base. Finally, we compared immunostaining of Lgr5 with that of CD133, a previously characterized marker for tumor-initiating cells in colon cancer, and found that they identified distinct subpopulations of cells that were in close proximity, but did not costain. Our findings suggest that (1) Lgr5 is a potential marker of intestinal stem cells in humans and (2) loss of restriction to the stem cell niche is an early event in the premalignant transformation of stem cells and may play a role in carcinogenesis.

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Asymmetric organelle inheritance predicts human blood stem cell fate

Blood ◽

10.1182/blood.2020009778 ◽

2021 ◽

Author(s):

Dirk Loeffler ◽

Florin Schneiter ◽

Weijia Wang ◽

Arne Wehling ◽

Tobias Kull ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Division ◽

Cell Fate ◽

Human Blood ◽

Asymmetric Cell Division ◽

Cell Fates ◽

Hematopoietic Stem ◽

Stem Cell Fate ◽

Blood Stem Cells

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.

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N6-Methyladenosine in RNA and DNA: An Epitranscriptomic and Epigenetic Player Implicated in Determination of Stem Cell Fate

Stem Cells International ◽

10.1155/2018/3256524 ◽

2018 ◽

Vol 2018 ◽

pp. 1-18 ◽

Cited By ~ 16

Author(s):

Pengfei Ji ◽

Xia Wang ◽

Nina Xie ◽

Yujing Li

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Direct Interaction ◽

Limited Information ◽

Stem Cell Fate ◽

Base Modification ◽

Dna And Rna ◽

Proliferation And Differentiation

Vast emerging evidences are linking the base modifications and determination of stem cell fate such as proliferation and differentiation. Among the base modification markers extensively studied, 5-methylcytosine (5-mC) and its oxidative derivatives (5-hydroxymethylcytosine (5-hmC), 5-formylcytosine (5-fC), and 5-carboxylcytosine (5-caC)) dynamically occur in DNA and RNA and have been acknowledged as important epigenetic markers involved in regulation of cellular biological processes. N6-Methyladenosine modification in DNA (m6dA), mRNA (m6A), tRNA, and other noncoding RNAs has been defined as another important epigenetic and epitranscriptomic marker in eukaryotes in recent years. The mRNA m6A modification has been characterized biochemically, molecularly, and phenotypically, including elucidation of its methyltransferase complexes (m6A writer), demethylases (m6A eraser), and direct interaction proteins (readers), while limited information on the DNA m6dA is available. The levels and the landscapes of m6A in the epitranscriptomes and epigenomes are precisely and dynamically regulated by the fine-tuned coordination of the writers and erasers in accordance with stages of the growth, development, and reproduction as naturally programmed during the lifespan. Additionally, progress has been made in appreciation of the link between aberrant m6A modification in stem cells and diseases, like cancers and neurodegenerative disorders. These achievements are inspiring scientists to further uncover the epigenetic mechanisms for stem cell development and to dissect pathogenesis of the multiple diseases conferred by development aberration of the stem cells. This review article will highlight the research advances in the role of m6A methylation modifications of DNA and RNA in the regulation of stem cell and genesis of the closely related disorders. Additionally, this article will also address the research directions in the future.

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Regulation and Directing Stem Cell Fate by Tissue Engineering Functional Microenvironments: Scaffold Physical and Chemical Cues

Stem Cells International ◽

10.1155/2019/2180925 ◽

2019 ◽

Vol 2019 ◽

pp. 1-16 ◽

Cited By ~ 8

Author(s):

Fei Xing ◽

Lang Li ◽

Changchun Zhou ◽

Cheng Long ◽

Lina Wu ◽

...

Keyword(s):

Tissue Engineering ◽

Stem Cells ◽

Stem Cell ◽

Growth Factors ◽

Cell Fate ◽

Chemical Cues ◽

Physical Factors ◽

Stem Cell Fate ◽

Physical And Chemical

It is well known that stem cells reside within tissue engineering functional microenvironments that physically localize them and direct their stem cell fate. Recent efforts in the development of more complex and engineered scaffold technologies, together with new understanding of stem cell behavior in vitro, have provided a new impetus to study regulation and directing stem cell fate. A variety of tissue engineering technologies have been developed to regulate the fate of stem cells. Traditional methods to change the fate of stem cells are adding growth factors or some signaling pathways. In recent years, many studies have revealed that the geometrical microenvironment played an essential role in regulating the fate of stem cells, and the physical factors of scaffolds including mechanical properties, pore sizes, porosity, surface stiffness, three-dimensional structures, and mechanical stimulation may affect the fate of stem cells. Chemical factors such as cell-adhesive ligands and exogenous growth factors would also regulate the fate of stem cells. Understanding how these physical and chemical cues affect the fate of stem cells is essential for building more complex and controlled scaffolds for directing stem cell fate.

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Differentiation of human pluripotent teratocarcinoma stem cells induced by bone morphogenetic protein-2

Reproduction Fertility and Development ◽

10.1071/rd98097 ◽

1998 ◽

Vol 10 (8) ◽

pp. 551 ◽

Cited By ~ 27

Author(s):

Martin F. Pera ◽

Daniella Herszfeld

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Retinoic Acid ◽

Cell Line ◽

Bone Morphogenetic Protein ◽

Morphological Changes ◽

Bone Morphogenetic Protein 2 ◽

Stem Cell Markers ◽

Potent Inducer ◽

Morphogenetic Protein

Pluripotent human teratocarcinoma stem cells cultured in vitro provide a resource for the study of early embryonic development in man, as well as a means for discovery of novel factors controlling cell differentiation and commitment. We previously reported that the human teratocarcinoma stem cell line GCT 27X-1 could be induced to differentiate into an endodermal progenitor cell by treatment with high doses of retinoic acid. A search for polypeptide inducers of differentiation in this system has identified bone morphogenetic protein-2 (BMP-2) as a potent inducer of differentiation. In cell line GCT 27X-1, treatment with BMP-2 reduces proliferation, induces morphological changes similar to obtained following treatment with retinoic acid, and causes a decrease in the expression of transcripts for the stem cell markers CD30 and Oct-4. Preliminary immunochemical studies indicate that the differentiated cells produced by BMP-2 are endodermal precursors with a pattern of marker expression similar to that found in retinoic acid treated cells. Models of endoderm differentiation in humans will be useful for identifying the molecules which mediate cell interactions in development, and in achieving directed differentiation of cells for use in transplantation.

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Tuning Adipogenic Differentiation in ADSCs by Metformin and Vitamin D: Involvement of miRNAs

International Journal of Molecular Sciences ◽

10.3390/ijms21176181 ◽

2020 ◽

Vol 21 (17) ◽

pp. 6181

Author(s):

Sara Cruciani ◽

Giuseppe Garroni ◽

Francesca Balzano ◽

Renzo Pala ◽

Emanuela Bellu ◽

...

Keyword(s):

Stem Cells ◽

Vitamin D ◽

Stem Cell ◽

Cell Fate ◽

Adipogenic Differentiation ◽

Adipose Derived Stem Cells ◽

Vitamin D Metabolism ◽

Stem Cell Fate ◽

Cellular Phenotypes

Fat tissue represents an important source of adipose-derived stem cells (ADSCs), which can differentiate towards several phenotypes under certain stimuli. Definite molecules as vitamin D are able to influence stem cell fate, acting on the expression of specific genes. In addition, miRNAs are important modulating factors in obesity and numerous diseases. We previously identified specific conditioned media able to commit stem cells towards defined cellular phenotypes. In the present paper, we aimed at evaluating the role of metformin on ADSCs differentiation. In particular, ADSCs were cultured in a specific adipogenic conditioned medium (MD), in the presence of metformin, alone or in combination with vitamin D. Our results showed that the combination of the two compounds is able to counteract the appearance of an adipogenic phenotype, indicating a feedforward regulation on vitamin D metabolism by metformin, acting on CYP27B1 and CYP3A4. We then evaluated the role of specific epigenetic modulating genes and miRNAs in controlling stem cell adipogenesis. The combination of the two molecules was able to influence stem cell fate, by modulating the adipogenic phenotype, suggesting their possible application in clinical practice in counteracting uncontrolled lipogenesis and obesity-related diseases.

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Alternative polyadenylation of Pax3 controls muscle stem cell fate and muscle function

Science ◽

10.1126/science.aax1694 ◽

2019 ◽

Vol 366 (6466) ◽

pp. 734-738 ◽

Cited By ~ 11

Author(s):

Antoine de Morree ◽

Julian D. D. Klein ◽

Qiang Gan ◽

Jean Farup ◽

Andoni Urtasun ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cell Fate ◽

Messenger Rna ◽

Adult Stem Cells ◽

Alternative Polyadenylation ◽

Quiescent State ◽

Stem Cell Fate ◽

Activation Rate

Adult stem cells are essential for tissue homeostasis. In skeletal muscle, muscle stem cells (MuSCs) reside in a quiescent state, but little is known about the mechanisms that control homeostatic turnover. Here we show that, in mice, the variation in MuSC activation rate among different muscles (for example, limb versus diaphragm muscles) is determined by the levels of the transcription factor Pax3. We further show that Pax3 levels are controlled by alternative polyadenylation of its transcript, which is regulated by the small nucleolar RNA U1. Isoforms of the Pax3 messenger RNA that differ in their 3′ untranslated regions are differentially susceptible to regulation by microRNA miR206, which results in varying levels of the Pax3 protein in vivo. These findings highlight a previously unrecognized mechanism of the homeostatic regulation of stem cell fate by multiple RNA species.

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Wnt-inhibitory factor 1 dysregulation of the bone marrow niche exhausts hematopoietic stem cells

Blood ◽

10.1182/blood-2010-09-305664 ◽

2011 ◽

Vol 118 (9) ◽

pp. 2420-2429 ◽

Cited By ~ 47

Author(s):

Christoph Schaniel ◽

Dario Sirabella ◽

Jiajing Qiu ◽

Xiaohong Niu ◽

Ihor R. Lemischka ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Wnt Signaling ◽

Cell Fate ◽

Sonic Hedgehog ◽

Hematopoietic Stem ◽

Cell Fate Decisions ◽

Cell Niche ◽

Wnt Inhibitory Factor 1 ◽

Stem Cell Pool

Abstract The role of Wnt signaling in hematopoietic stem cell fate decisions remains controversial. We elected to dysregulate Wnt signaling from the perspective of the stem cell niche by expressing the pan Wnt inhibitor, Wnt inhibitory factor 1 (Wif1), specifically in osteoblasts. Here we report that osteoblastic Wif1 overexpression disrupts stem cell quiescence, leading to a loss of self-renewal potential. Primitive stem and progenitor populations were more proliferative and elevated in bone marrow and spleen, manifesting an impaired ability to maintain a self-renewing stem cell pool. Exhaustion of the stem cell pool was apparent only in the context of systemic stress by chemotherapy or transplantation of wild-type stem cells into irradiated Wif1 hosts. Paradoxically this is mediated, at least in part, by an autocrine induction of canonical Wnt signaling in stem cells on sequestration of Wnts in the environment. Additional signaling pathways are dysregulated in this model, primarily activated Sonic Hedgehog signaling in stem cells as a result of Wif1-induced osteoblastic expression of Sonic Hedgehog. We find that dysregulation of the stem cell niche by overexpression of an individual component impacts other unanticipated regulatory pathways in a combinatorial manner, ultimately disrupting niche mediated stem cell fate decisions.

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