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Author: Fanju Meng Publisher: ISBN: Category : Languages : en Pages : 137
Book Description
Proper maintenance of tissue homeostasis is essential for the organism's architecture and function. In many tissues, homeostasis is maintained by resident stem cells that precisely adapt their proliferation and differentiation to tissue demands, especially in response to stress and injury. However, the underlying mechanisms are largely unclear. Importantly, mis-regulation of either stem cell proliferation or differentiation is associated with tissue degeneration and tumor formation. Therefore, understanding the basic mechanisms by which stem cell activities are precisely controlled is a critical step towards understanding the physiological causes of many diseases. The Drosophila midgut epithelium is actively maintained by intestinal stem cells (ISCs) and has proven to be a valuable model to study regulation of stem cell activities both at homeostasis and in response to stress. Here I focus on two Sox family transcription factors, Sox21a and Sox100B, and investigate their expression patterns and functions in the adult Drosophila intestine. In the first part of this dissertation, I present data showing that Sox21a acts as a critical regulator of adult ISC proliferation. I found that ISC-specific Sox21a expression is required for basal and stress-induced ISC proliferation. Interestingly, Sox21a expression is increased upon stress exposure to promote ISC proliferation. Furthermore, I showed that Sox21a induction integrates signal inputs from multiple stress signaling pathways to regulate injury-induced ISC proliferation. The mechanism by which ISC/EB-specific Sox21a expression pattern is generated is not clear. I screened the Sox21a locus and found that the 1st intron of Sox21a is sufficient to generate this pattern and thus I generated an in vivo reporter. In the second part of my dissertation, I present data showing that Sox100B is required for Sox21a reporter expression, as well as endogenous Sox21a expression, indicating that Sox21a is a target gene of Sox100B. I found that Sox100B is required for proper ISC differentiation, highlighting a role of this Sox regulatory network in the process of ISC differentiation. Altogether, my work uncovered a Sox transcriptional network which interacts with stress-sensing signaling pathways, precisely regulating ISC proliferation and differentiation at homeostasis and in response to stress to maintain tissue homeostasis. My findings may inform studies of other stem cell populations,including in humans.
Author: Fanju Meng Publisher: ISBN: Category : Languages : en Pages : 137
Book Description
Proper maintenance of tissue homeostasis is essential for the organism's architecture and function. In many tissues, homeostasis is maintained by resident stem cells that precisely adapt their proliferation and differentiation to tissue demands, especially in response to stress and injury. However, the underlying mechanisms are largely unclear. Importantly, mis-regulation of either stem cell proliferation or differentiation is associated with tissue degeneration and tumor formation. Therefore, understanding the basic mechanisms by which stem cell activities are precisely controlled is a critical step towards understanding the physiological causes of many diseases. The Drosophila midgut epithelium is actively maintained by intestinal stem cells (ISCs) and has proven to be a valuable model to study regulation of stem cell activities both at homeostasis and in response to stress. Here I focus on two Sox family transcription factors, Sox21a and Sox100B, and investigate their expression patterns and functions in the adult Drosophila intestine. In the first part of this dissertation, I present data showing that Sox21a acts as a critical regulator of adult ISC proliferation. I found that ISC-specific Sox21a expression is required for basal and stress-induced ISC proliferation. Interestingly, Sox21a expression is increased upon stress exposure to promote ISC proliferation. Furthermore, I showed that Sox21a induction integrates signal inputs from multiple stress signaling pathways to regulate injury-induced ISC proliferation. The mechanism by which ISC/EB-specific Sox21a expression pattern is generated is not clear. I screened the Sox21a locus and found that the 1st intron of Sox21a is sufficient to generate this pattern and thus I generated an in vivo reporter. In the second part of my dissertation, I present data showing that Sox100B is required for Sox21a reporter expression, as well as endogenous Sox21a expression, indicating that Sox21a is a target gene of Sox100B. I found that Sox100B is required for proper ISC differentiation, highlighting a role of this Sox regulatory network in the process of ISC differentiation. Altogether, my work uncovered a Sox transcriptional network which interacts with stress-sensing signaling pathways, precisely regulating ISC proliferation and differentiation at homeostasis and in response to stress to maintain tissue homeostasis. My findings may inform studies of other stem cell populations,including in humans.
Author: Ishara Surangi Ariyapala Publisher: ISBN: Category : Adult stem cells Languages : en Pages : 0
Book Description
The adult Drosophila intestinal epithelium hosts a heterogenous cell population including a pool of actively proliferating stem cells known as intestinal stem cells (ISCs), intermediate daughter cell type enteroblasts (EBs) and two differentiated cell types, enterocytes (ECs) and enteroendocrine cells (ee). Being able to adapt to rapid environmental changes through tightly controlled programs of cell proliferation and differentiation, the adult intestine serves as an excellent model system to study stem cell mediated tissue homeostasis. The underlying molecular mechanisms that mediate stem cell proliferation, differentiation and maintenance are poorly understood, in part because of a lack of available tools to spatially manipulate gene expression in this tissue. Previous work from our lab has shown that RNA Binding Protein (RBP) mediated post transcriptional gene regulatory mechanisms in the cytoplasm are key to maintain stem cell functions and behaviors. My work aimed to investigate nuclear RBP mediated post transcriptional gene regulatory mechanisms in intestinal progenitors (ISCs and EBs) and generate genetic tools to manipulate gene expression based on intestinal cell type and regional identities.
Author: Reina Aoki Publisher: ISBN: Category : Languages : en Pages : 156
Book Description
The intestinal epithelium is one of the most rapidly self-renewing tissues in the body and thus the ideal tissue for studying somatic progenitor and stem cell biology. The intestinal epithelium is composed of a single layer of cells that contains four major differentiated cell types as well as intestinal stem cells (ISCs) and progenitor cells that replenish differentiated cells throughout life. However, the molecular mechanisms that govern the self-renewal and differentiation of ISCs are only partially understood. Previously, one of the terminally differentiated epithelial cell types, the Paneth cells, were proposed to be the ISC "niche." However, subsequent studies have found ablation of Paneth cells in mice showed no effect on either stem cell maintenance or proliferation. I have analyzed the poorly understood mesenchymal contribution to epithelial stem cell maintenance and homeostasis by generating Foxl1-hDTR transgenic mice, in which the human diphtheria toxin receptor (hDTR ) is placed under the control of the Foxl1 promoter. Foxl1 is exclusively expressed in the subepithelial mesenchyme of the adult gastrointestinal tract. Ablation of Foxl1+ mesenchymal cells resulted in severe weight loss and disruption of epithelial architecture and a dramatic reduction in proliferation of both epithelial stem and transit-amplifying progenitor cells. I found that these effects are caused by the loss of activated Wnt/[beta]-catenin signaling signaling in the epithelium. Taken together, I have identified a novel mesenchymal ISC niche that supports both proliferation and maintenance of stem cells possibly through providing important Wnt ligands.
Author: Wen-Chih Lee Publisher: ISBN: Category : Electronic dissertations Languages : en Pages : 175
Book Description
Organisms are constantly challenged by injury and senescence. To replenish lost cells, adult tissue must contain a cellular reserve to maintain homeostasis. For example, adult stem cells exhibit two unique properties, self-renewal and potency, that make them well suited for this role. Tight regulatory control of stem cell properties is critical to maintain homeostatic balance; misregulation often leads to tumors or diseases. Recently, homeostasis of the intestinal epithelium has been shown to depend on a population of molecular defined intestinal stem cells (ISCs) in both Drosophila and mammals. However, the regulatory mechanisms controlling ISC behaviors remain poorly defined. We took advantage of the molecular genetic approaches available in Drosophila melanogaster to investigate how ISC properties are regulated by both intrinsic and extrinsic factors. In the course of the thesis, we identified two conserved signaling pathways that regulate ISC properties intrinsically. First, we demonstrated that WNT/APC signaling is an important regulator of ISC proliferation and relatively dispensable for potency. Parallel studies in mammals also show that loss of APC (APClof) in the ISC lineage leads to hyperplasia, supporting a model whereAPClofISCs can function as a cell-of-origin for intestinal tumors. In follow-up studies, we have taken a genetic approach to identify modifiers that control the expansion of tumorigenicAPCloflineages. We have now identified Insulin signaling as a modifier that is necessary and sufficient for the expansion of tumorigenicAPCloflineages. Future studies will define the precise cellular and molecular mechanisms underlying this phenomenon. A second key finding of our studies is that JAK/STAT signaling pathway coordinates ISC proliferation and regulates the competency for daughter cell differentiation. In summary, ISC properties are regulated by conserved WNT/APC and JAK/STAT signaling similar to what has been shown in other stem cell lineages. The intestinal tract is a primary site of nutrient absorption. We hypothesized that dietary nutrients can extrinsically regulate ISC properties. However, the precise requirement of individual macronutrients or micronutrients could not be investigated because a chemically defined food (CDF) consisting entirely of purified compounds was not available. We developed a new CDF media that permits CDFs with different nutrient compositions at iso-caloric density to be generated. Using this CDF recipe, we defined the individual macronutrient requirements for development, reproduction and longevity of Drosophila. Ongoing experiments are focused on determining the role of macronutrients in regulating ISC properties. We also seek to determine if nutrients are differentially required for normal and tumorigenic ISC lineages. Findings from this nutritional study may identify new therapeutic targets for regenerative medicine or cancer therapy.
Author: Publisher: Academic Press ISBN: 0128128917 Category : Science Languages : en Pages : 260
Book Description
Stem Cell Proliferation and Differentiation, Volume 138, the latest release in the Current Topics in Developmental Biology series, highlights new advances in the field, with this new volume presenting interesting chapters. Each chapter is written by an international board of authors. - Provides the authority and expertise of leading contributors from an international board of authors - Presents the latest release in the Current Topics in Developmental Biology series - Includes the latest information on stem cell proliferation and differentiation
Author: Christopher Lee Koehler Publisher: ISBN: Category : Languages : en Pages : 175
Book Description
Aging is a degenerative process characterized by the accumulation of cellular damage that results in altered tissue homeostasis, organ function, and, ultimately, death. Tissues with the potential for regeneration (muscle) or that undergo cellular turnover (intestine, blood, skin) rely on populations of adult stem or progenitor cells to divide and replace damaged cells to maintain tissue homeostasis. One hallmark of aging is reduced stem cell function, which can lead to decreased tissue homeostasis. The exact mechanisms for aging are still unclear, but recent evidence suggests an important role for adult stem cells in organismal aging. Current reports indicate that alterations in adult stem cell function via changes in stem cell metabolism can have widespread effects on tissue homeostasis and aging. Thanks to its relatively short lifespan and amenability to genetic manipulations, the model organism Drosophila melanogaster provides a convenient system to study the interaction between somatic stem cell metabolism and aging. A recently discovered population of intestinal stem cells in Drosophila bears many similarities to the stem cells of the mammalian small intestine. Genetic tractability, a simple cell lineage, and conserved pathways that regulate stem cell behavior combine to make the Drosophila midgut epithelium a powerful model system for the study of stem cell regulation and tissue homeostasis. Here, we show that increased mitochondrial biogenesis or enhanced electron transport chain function in the intestinal stem cells results in increased tissue homeostasis, a delay in age-related midgut phenotypes, and increased lifespan. This prompted us to study the roles of mitochondrial dynamics (fission, fusion, movement, and turnover) on intestinal stem cell function. We demonstrate that loss of either of two, mitophagy-related genes, pink1 or parkin, in Drosophila ISCs leads to: severe alterations in mitochondrial structure, nearly complete inhibition of stem cell proliferation during aging or stress, and the appearance of senescence-associated markers within the ISCs.
Author: Christine E. Hochmuth Publisher: ISBN: Category : Languages : en Pages : 118
Book Description
"Organisms are faced with the challenge of maintaining tissue homeostasis despite various environmental and intracellular assaults that damage cells. Programmed cell death can eliminate cells that are no longer contributing to the proper function of a tissue. However, apoptosis without concomitant cell replacement over time would result in the loss of tissue and is not ideal for the overall health of the organism. Therefore, regenerative processes are critical in delaying the loss of tissue homeostasis that is characteristic of aging animals. In the adult metazoan, this goal is accomplished by pluripotent stem cells. How the regenerative capacity of stem cells changes in aging animals is the subject of intense investigation. The recent discovery of intestinal stem cells (ISCs) in the posterior midgut of Drosophila melanogaster has introduced this organism as a genetically amenable model for such studies. Antioxidant defenses and cytoprotective processes are believed to be critical for the maintenance of stem cell function. Here I present work which characterizes the role of a stress-responsive signaling pathway, NF-E2-related factor 2 [Nrf2(CncC in Drosophila)], in stem cell maintenance and regeneration of the intestinal epithelium of Drosophila. Using genetic and cellular biology approaches, I found Nrf2 to be a key regulator of ISC quiescence and also established cellular redox state, in general, as important for the control of ISC proliferation. Additional work presented in this dissertation will explore mechanisms of CncC regulation in ISCs in response to stress and a potential interaction between the CncC and Jun-N-terminal kinase (JNK) pathways. Furthermore, ISC proliferation will be investigated to determine the dynamics of stem cell quiescence in the adult intestinal epithelium. Together, these data demonstrate the importance of cellular redox state in the control of cellular processes and reveal a novel mechanism of stem cell and stem cell progenitor regulation by Nrf2"--Page iv.
Author: Jaclyn Geok Yueen Lim Publisher: ISBN: Category : Languages : en Pages :
Book Description
Adult stem cells are undifferentiated cells that are capable of both self-renewal and differentiation into a variety of specialized cells. Adult stem cell lineages have been identified in several organs including skin, blood, breast, intestine, bladder, skeletal muscle, prostate, and the testes. The changes in homeostatic conditions in these organs caused by tissue turnover or injury rely heavily on the pool of adult stem cells for cell replenishment. Therefore, the activity of adult stem cells must be tightly controlled, and many of these regulations are orchestrated by the stem cell niche, the local microenvironment in which stem cells reside. The fast generation cycle and the genetic tractability of fruit flies make the Drosophila testis stem cell niche an ideal system for the study of adult stem cell regulation. The Drosophila testis maintains two types of stem cells: germline stem cells (GSCs) which give rise to sperm, and cyst stem cells (CySCs) which differentiate into cyst cells that encapsulate germ cells. The somatic cyst cell lineage has been implicated to be required at several stages of spermatogenesis and play pivotal roles in germline proliferation, survival, and differentiation. This dissertation focuses on understanding the role of the cyst cell lineage in GSC maintenance and investigating the mechanisms by which cyst cells direct early germ cell differentiation. Previously, it has been proposed that CySCs are the source of instructive self-renewal cues for GSCs. In contrast to this model, I showed that early germ cells with GSC characteristics can be maintained in the absence of CySCs and cyst cells. These germ cells failed to enter the transit-amplifying program, which is regarded as the first step of differentiation in many adult stem cell lineages. My observations suggest that cyst cells provide a pro-differentiation environment for GSCs, and that this mechanism(s) may be repressed in CySCs which indirectly allow for GSC self-renewal. Encapsulation of germ cells by cyst cells is one of the differentiation-promoting mechanisms imposed by the soma on the germline, and I have uncovered that this process requires activation of the EGFR-Ras-MEK-MAPK pathway in differentiated cyst cells. Furthermore, I also showed that repression of EGFR activation in CySCs is important in maintaining the population of GSCs and CySCs at the niche, as premature activation of the pathway resulted in displacement of GSCs from the hub by somatic cells. Preliminary studies revealed a STAT target gene, Socs36E as a negative regulator of the EGFR pathway in CySCs to prevent out-competition of GSCs by somatic cells. To understand how the somatic cyst cells germline differentiation, I performed two genetic screens: an RNAi screen of genes that caused premature germ cell differentiation when misexpressed in the soma, and a misexpression screen of genes predicted to be cell-surface and secreted proteins. Three promising candidates were identified through these screens: two ribosomal subunits, Rpl13A and RpS10a; and a septate junction component, Neurexin IV. The two ribosomal proteins may be involved in the soma to promote germ cell encapsulation. Neurexin IV however, operates non-cell autonomously in cyst cells to regulate germ cell differentiation into spermatocytes. Together, the results of this dissertation emphasize the importance and complexity of the interaction between adult stem cells and their microenvironment in maintaining tissue homeostasis.
Author: Publisher: Academic Press ISBN: 9780128134818 Category : Science Languages : en Pages : 150
Book Description
Advances in Stem Cells and Their Niches addresses stem cells during development, homeostasis, and disease/injury of the respective organs, presenting new developments in the field, including new data on disease and clinical applications. Video content illustrates such areas as protocols, transplantation techniques, and work with mice. Explores not only reviews of research, but also shares methods, protocols, and transplantation techniques Contains video content to illustrate such areas as protocols, transplantation techniques, and work with mice Each volume concentrates on one organ, making this a unique publication
Author: Fanju Meng
Author: Fanju Meng
Author: Ishara Surangi Ariyapala
Author: Reina Aoki
Author: Wen-Chih Lee
Author: 
Author: Christopher Lee Koehler
Author: Christine E. Hochmuth
Author: Jaclyn Geok Yueen Lim
Author: Eurico Morais-de-Sá
Author: