scholarly journals mTORC1 activates PASK-Wdr5 signaling to epigenetically connect the nutrient status with myogenesis

2017 ◽  
Author(s):  
Chintan K. Kikani ◽  
Xiaoying Wu ◽  
Sarah Fogarty ◽  
Seong Anthony Woo Kang ◽  
Noah Dephoure ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Nutrient Status ◽  
Stem Cell Differentiation ◽  
Self Renewal ◽  
Muscle Stem Cell ◽  
Downstream Target ◽  
Cell Functions ◽  
Dietary Nutrients

SummaryIn the tissue microenvironment, stem cell functions are modulated by extrinsic signaling cues such as peptide hormones and dietary nutrients. These signaling cues maintain the balance between self-renewal and differentiation of its resident stem cells. The mechanistic Target of Rapamycin Complex 1 (mTORC1) is implicated to play an important role in regulating this balance, although its downstream effectors in stem cells have been elusive. We have recently shown that the PASK protein kinase phosphorylates Wdr5 to stimulate muscle stem cell differentiation by epigenetically activating the Myogenin promoter. Here, we show that the PASK-Wdr5 signaling pathway is a nutrient-sensitive downstream target of mTORC1 in muscle stem cells. We show that phosphorylation of PASK, and in turn of Wdr5, by mTORC1 is required for the activation of Myogenin transcription, exit from the self-renewal and induction of the myogenesis program. Thus, mTOR connects the diverse extrinsic signaling cues to a central epigenetic process to regulate the muscle stem cell fate between self-renewal and differentiation.

scholarly journals PASsing on Signals: PAS Kinase (PASK)-mTOR Signaling Conveys Nutrient Sufficiency Signals to Epigenetic (COMPASS) Complexes to Activate Stem Cell Differentiation Program (P15-009-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Chintan Kikani ◽  
Michael Xiao ◽  
Xiaoying Wu ◽  
Jared Rutter
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Cell Fate ◽  
Early Stage ◽  
Stem Cell Differentiation ◽  
Mtor Signaling ◽  
Kinase Assay ◽  
Cell Functions ◽  
Nutrient Signaling

Abstract Objectives To determine how nutrient signaling impacts stem cell functions Methods PASK phosphorylation: We measured in situ phosphorylation of PASK by metabolic 32P labeling of stem cells expressing WT or mutant versions of PASK. PASK Activation: PASK activation was measured using in vitro kinase assay using radio-labeled ATP. Myogenesis: Myogenesis was measured by immunohistological, and immunofluorescent analysis of differentiating muscle stem cells. Antibodies used were: Myogenin (F5D-Developmental Hybridoma), MF20 (Myosin heavy chain), Pax7 and MyoD. Results Stem cell fate in the tissue niche is intimately connected with intracellular metabolic state and the extracellular hormonal stimulations. We have identified PAS domain containing Kinase (PASK) as a stem cell enriched protein kinase that is required for establishment of the differentiation program in many stem cell paradigms. For this function, PASK phosphorylates Wdr5, a member of the COMPASS family of histone methyltransferases, to activate the epigenetic processes required for the stem cell differentiation (eLife, 2016). Here we show that a master nutrient sensor, mTOR complex 1 (mTORC1) activates PASK via multi-site phosphorylation during stem cell differentiation. This phosphorylation of PASK by mTORC1 is required for epigenetic activation of the Myogenin transcription, exit from the self-renewal and induction of the myogenesis program. Our data suggest that mTORC1-PASK signaling generates MyoG + committed myoblasts (epigenetically - an early stage of myogenesis), whereas mTORC1-S6K1 signaling is required for myoblast fusion (translationally - later stage of myogenesis). Conclusions Our discoveries show that nutrient signaling can partition stem cell fates during different stages of the myogenesis program downstream of mTOR signaling via activation of two distinct protein kinases. Funding Sources NIH R01 (Chintan Kikani), HHMI (Jared Rutter) Supporting Tables, Images and/or Graphs

Metabolic Regulation and Related Molecular Mechanisms in Various Stem Cell Functions

2020 ◽  
Vol 15 (6) ◽  
pp. 531-546 ◽  
Author(s):  
Hwa-Yong Lee ◽  
In-Sun Hong
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Oxidative Phosphorylation ◽  
Metabolic Pathways ◽  
Critical Role ◽  
The Self ◽  
Specific Cell ◽  
Differentiation Potential ◽  
Self Renewal ◽  
Cell Functions

Recent studies on the mechanisms that link metabolic changes with stem cell fate have deepened our understanding of how specific metabolic pathways can regulate various stem cell functions during the development of an organism. Although it was originally thought to be merely a consequence of the specific cell state, metabolism is currently known to play a critical role in regulating the self-renewal capacity, differentiation potential, and quiescence of stem cells. Many studies in recent years have revealed that metabolic pathways regulate various stem cell behaviors (e.g., selfrenewal, migration, and differentiation) by modulating energy production through glycolysis or oxidative phosphorylation and by regulating the generation of metabolites, which can modulate multiple signaling pathways. Therefore, a more comprehensive understanding of stem cell metabolism could allow us to establish optimal culture conditions and differentiation methods that would increase stem cell expansion and function for cell-based therapies. However, little is known about how metabolic pathways regulate various stem cell functions. In this context, we review the current advances in metabolic research that have revealed functional roles for mitochondrial oxidative phosphorylation, anaerobic glycolysis, and oxidative stress during the self-renewal, differentiation and aging of various adult stem cell types. These approaches could provide novel strategies for the development of metabolic or pharmacological therapies to promote the regenerative potential of stem cells and subsequently promote their therapeutic utility.

scholarly journals Skeletal muscle stem cell self-renewal and differentiation kinetics revealed by EdU lineage tracing during regeneration

2019 ◽  
Author(s):  
Bradley Pawlikowski ◽  
Nicole Dalla Betta ◽  
Tiffany Antwine ◽  
Bradley B. Olwin
Keyword(s):  
Skeletal Muscle ◽  
Stem Cells ◽  
Stem Cell ◽  
Young Adult ◽  
Muscle Injury ◽  
Lineage Tracing ◽  
Stem Cell Population ◽  
Post Injury ◽  
Self Renewal ◽  
Muscle Stem Cell

SummarySkeletal muscle maintenance and repair is dependent on the resident adult muscle stem cell (MuSC). During injury, and in diseased muscle, stem cells are engaged to replace or repair damaged muscle, which requires the stem cells to exit quiescence and expand, followed by differentiation to regenerate myofibers and self-renewal to replenish the stem cell population. Following an injury, little is known regarding the timing of MuSC (skeletal muscle stem cell) self-renewal, myoblast expansion or myoblast differentiation. To determine the timing and kinetics of these cell fate decisions, we employed DNA-based lineage tracing to label newly replicated cells and followed cell fates during skeletal muscle regeneration. MuSCs activate and expand as myoblasts rapidly following injury, where the majority differentiate into myonuclei, establishing the centrally located myonuclear pool. Re-establishing the majority MuSC pool by self-renewal occurs after 5 days post-muscle injury, accompanied by low levels of myonuclear accretion that generate only peripheral myonuclei. In aged mice, possessing ∼1/2 the number of MuSCs present in young adult mice, the timing of post injury MuSC self-renewal is delayed, and although MuSCs expansion as myoblasts in aged muscle is impaired, the number of MuSC unexpectedly recovers to young adult levels during regeneration. Following an induced muscle injury, we found that myonuclei are generated within the first four days post injury derived from myoblasts expanding from activated MuSCs. Only later during regeneration, from 5 d to 14 d post injury, is the MuSC pool replenished by self-renewal, accompanied by generation of peripheral myonuclei.

scholarly journals Cell cycle exit and stem cell differentiation are coupled through regulation of mitochondrial activity in the Drosophila testis

2021 ◽  
Author(s):  
Diego Sainz de la Maza ◽  
Silvana Hof-Michel ◽  
Lee Phillimore ◽  
Christian Bökel ◽  
Marc Amoyel
Keyword(s):  
Cell Cycle ◽  
Stem Cells ◽  
Stem Cell ◽  
Cell Cycle Progression ◽  
Stem Cell Differentiation ◽  
Mitochondrial Activity ◽  
Self Renewal ◽  
Cycle Progression ◽  
Cell Identity ◽  
Drosophila Testis

AbstractStem cells maintain tissue homeostasis by proliferating to replace cells lost to damage or natural turnover. Whereas stem and progenitor cells proliferate, fully differentiated cells exit the cell cycle. How cell identity and cell cycle state are coordinated during this process is still poorly understood. The Drosophila testis niche supports germline stem cells and somatic cyst stem cells (CySCs), which are the only proliferating somatic cells in the testis. CySCs give rise to post-mitotic cyst cells and therefore provide a tractable model to ask how stem cell identity is linked to proliferation. We show that the G1/S cyclin, Cyclin E, is required for CySC self-renewal; however, its canonical transcriptional regulator, a complex of the E2f1 and Dp transcription factors is dispensable for self-renewal and cell cycle progression. Nevertheless, we demonstrate that E2f1/Dp activity must be silenced to allow CySCs to differentiate. We show that E2f1/Dp activity inhibits the expression of genes important for mitochondrial activity. Furthermore, promoting mitochondrial activity or biogenesis is sufficient to rescue the differentiation of CySCs with ectopic E2f1/Dp activity but not their exit from the cell cycle. Our findings together indicate that E2f1/Dp coordinates cell cycle progression with stem cell identity by regulating the metabolic state of CySCs.

Roles of Ring1A/B on Stem Cell Potential of MOZ and Other Acute Myeloid Leukemias,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3998-3998
Author(s):  
Haruko Shima ◽  
Mika Shino ◽  
Kazutsune Yamagata ◽  
Yukiko Aikawa ◽  
Haruhiko Koseki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Differentiation ◽  
Conflicts Of Interest ◽  
Expression Profiles ◽  
Leukemia Stem Cells ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Functions ◽  
Acute Myeloid

Abstract Abstract 3998 Leukemia and other cancers possess self-renewing stem cells that help maintain cancer. Chromosomal translocations are often involved in the development of human acute myeloid leukemia (AML). The monocytic leukemia zinc finger (MOZ) gene is one of the targets of such translocations. While MOZ is essential for the self-renewal of hematopoietic stem cells, the leukemia associated MOZ-fusion proteins enable the transformation of non–self-renewing myeloid progenitors into leukemia stem cells. Ring1A and Ring1B are catalytic subunits of the polycomb-group repressive complex 1 (PRC1) complex containing Bmi1, and PRC1 complex plays an important role in the regulation of stem cell self-renewal. Using Ring1A-null and Ring1B-conditional deficient mice, we showed that Ring1A/B are required for continuous colony forming ability that is enabled by MOZ-TIF2 and other AML-associated fusions such as MLL-AF10, AML1-ETO, and PML-RARα. Furthermore, MOZ-TIF2- and MLL-AF10-induced AML development in mice were prevented by Ring 1A/B deficiency. To clarify the mechanism of stemness regulation in AML stem cells by PRC1 complex, we compared gene expression profiles of Ring1A/B deleted and non-deleted MOZ-TIF2-induced AML cells. As expected, Ink4a/Arf, a known major target of PRC1 complex involved in stem cell functions, was derepressed by deletion of Ring1A/B. Although deletion of Ink4a/Arf in Ring1A/B deficient AML cells partially restored colony formation ability, it was not substantial to initiate leukemia in recipient mice. Among several target genes which were derepressed by deletion of Ring1A/B, we focused on “Stemness inhibitory factor (SIF)”, known to be required for cell differentiation and morphogenesis in some specific organs. Enforced expression of SIF in MOZ-TIF2-induced AML cells stimulated differentiation of AML progenitors into macrophages. On the other hand, knock-down of SIF blocked cell differentiation block and restored the immortalizing ability of MOZ-TIF2-induced AML progenitors, despite of the absence of Ring1A/B. Collectively, our data demonstrate that Ring 1A/B play crucial roles in the maintenance of AML stem cells through repression of SIF, which strongly promote differentiation of leukemia stem cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Control of plant cell fate transitions by transcriptional and hormonal signals

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Christophe Gaillochet ◽  
Thomas Stiehl ◽  
Christian Wenzl ◽  
Juan-José Ripoll ◽  
Lindsay J Bailey-Steinitz ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Temporal Dynamics ◽  
Developmental Trajectories ◽  
Stem Cell Differentiation ◽  
Integrated Approach ◽  
Shoot Meristem ◽  
Environmental Signals ◽  
Auxin Signalling

Plant meristems carry pools of continuously active stem cells, whose activity is controlled by developmental and environmental signals. After stem cell division, daughter cells that exit the stem cell domain acquire transit amplifying cell identity before they are incorporated into organs and differentiate. In this study, we used an integrated approach to elucidate the role of HECATE (HEC) genes in regulating developmental trajectories of shoot stem cells in Arabidopsis thaliana. Our work reveals that HEC function stabilizes cell fate in distinct zones of the shoot meristem thereby controlling the spatio-temporal dynamics of stem cell differentiation. Importantly, this activity is concomitant with the local modulation of cellular responses to cytokinin and auxin, two key phytohormones regulating cell behaviour. Mechanistically, we show that HEC factors transcriptionally control and physically interact with MONOPTEROS (MP), a key regulator of auxin signalling, and modulate the autocatalytic stabilization of auxin signalling output.

scholarly journals Controlling Self-Renewal and Differentiation of Stem Cells via Mechanical Cues

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Michele M. Nava ◽  
Manuela T. Raimondi ◽  
Riccardo Pietrabissa
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Cell Response ◽  
Recent Literature ◽  
Focal Adhesions ◽  
Substrate Stiffness ◽  
Self Renewal ◽  
Mechanical Factors

The control of stem cell responsein vitro, including self-renewal and lineage commitment, has been proved to be directed by mechanical cues, even in the absence of biochemical stimuli. Through integrin-mediated focal adhesions, cells are able to anchor onto the underlying substrate, sense the surrounding microenvironment, and react to its properties. Substrate-cell and cell-cell interactions activate specific mechanotransduction pathways that regulate stem cell fate. Mechanical factors, including substrate stiffness, surface nanotopography, microgeometry, and extracellular forces can all have significant influence on regulating stem cell activities. In this paper, we review all the most recent literature on the effect of purely mechanical cues on stem cell response, and we introduce the concept of “force isotropy” relevant to cytoskeletal forces and relevant to extracellular loads acting on cells, to provide an interpretation of how the effects of insoluble biophysical signals can be used to direct stem cells fatein vitro.

scholarly journals Drosophila neuroblasts as a new model for the study of stem cell self-renewal and tumour formation

2014 ◽  
Vol 34 (4) ◽  
Author(s):  
Song Li ◽  
Hongyan Wang ◽  
Casper Groth
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Daughter Cell ◽  
Asymmetric Cell Division ◽  
Cell Fate Specification ◽  
Larval Brain ◽  
Self Renewal ◽  
Intrinsic Factors ◽  
Tumour Formation

Drosophila larval brain stem cells (neuroblasts) have emerged as an important model for the study of stem cell asymmetric division and the mechanisms underlying the transformation of neural stem cells into tumour-forming cancer stem cells. Each Drosophila neuroblast divides asymmetrically to produce a larger daughter cell that retains neuroblast identity, and a smaller daughter cell that is committed to undergo differentiation. Neuroblast self-renewal and differentiation are tightly controlled by a set of intrinsic factors that regulate ACD (asymmetric cell division). Any disruption of these two processes may deleteriously affect the delicate balance between neuroblast self-renewal and progenitor cell fate specification and differentiation, causing neuroblast overgrowth and ultimately lead to tumour formation in the fly. In this review, we discuss the mechanisms underlying Drosophila neural stem cell self-renewal and differentiation. Furthermore, we highlight emerging evidence in support of the notion that defects in ACD in mammalian systems, which may play significant roles in the series of pathogenic events leading to the development of brain cancers.

scholarly journals Epidermal stem cells self-renew upon neighboring differentiation

2017 ◽  
Author(s):  
Kailin R. Mesa ◽  
Kyogo Kawaguchi ◽  
David G. Gonzalez ◽  
Katie Cockburn ◽  
Jonathan Boucher ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Nearest Neighbor ◽  
Population Level ◽  
Cell Fates ◽  
Self Renewal ◽  
Stem Cell Fate ◽  
Asymmetric Divisions ◽  
Functional Blocking

Many adult tissues are dynamically sustained by the rapid turnover of stem cells. Yet, how cell fates such as self-renewal and differentiation are orchestrated to achieve long-term homeostasis remains elusive. Studies utilizing clonal tracing experiments in multiple tissues have argued that while stem cell fate is balanced at the population level, individual cell fate - to divide or differentiate – is determined intrinsically by each cell seemingly at random ( 1 2 3 4 5). These studies leave open the question of how cell fates are regulated to achieve fate balance across the tissue. Stem cell fate choices could be made autonomously by each cell throughout the tissue or be the result of cell coordination ( 6 7). Here we developed a novel live tracking strategy that allowed recording of every division and differentiation event within a region of epidermis for a week. These measurements reveal that stem cell fates are not autonomous. Rather, direct neighbors undergo coupled opposite fate decisions. We further found a clear ordering of events, with self-renewal triggered by neighbor differentiation, but not vice-versa. Typically, around 1-2 days after cell delamination, a neighboring cell entered S/G2 phase and divided. Functional blocking of this local feedback showed that differentiation continues to occur in the absence of cell division, resulting in a rapid depletion of the epidermal stem cell pool. We thus demonstrate that the epidermis is maintained by nearest neighbor coordination of cell fates, rather than by asymmetric divisions or fine-tuned cell-autonomous stochastic fate choices. These findings establish differentiation-dependent division as a core feature of homeostatic control, and define the relevant time and length scales over which homeostasis is enforced in epithelial tissues.

scholarly journals Heterochromatin protein 1 promotes self-renewal and triggers regenerative proliferation in adult stem cells

2013 ◽  
Vol 201 (3) ◽  
pp. 409-425 ◽  
Author(s):  
An Zeng ◽  
Yong-Qin Li ◽  
Chen Wang ◽  
Xiao-Shuai Han ◽  
Ge Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Heterochromatin Protein 1 ◽  
Self Renewal ◽  
Blastema Formation ◽  
Cell Fate Decisions ◽  
Chromatin Regulators

Adult stem cells (ASCs) capable of self-renewal and differentiation confer the potential of tissues to regenerate damaged parts. Epigenetic regulation is essential for driving cell fate decisions by rapidly and reversibly modulating gene expression programs. However, it remains unclear how epigenetic factors elicit ASC-driven regeneration. In this paper, we report that an RNA interference screen against 205 chromatin regulators identified 12 proteins essential for ASC function and regeneration in planarians. Surprisingly, the HP1-like protein SMED–HP1-1 (HP1-1) specifically marked self-renewing, pluripotent ASCs, and HP1-1 depletion abrogated self-renewal and promoted differentiation. Upon injury, HP1-1 expression increased and elicited increased ASC expression of Mcm5 through functional association with the FACT (facilitates chromatin transcription) complex, which consequently triggered proliferation of ASCs and initiated blastema formation. Our observations uncover an epigenetic network underlying ASC regulation in planarians and reveal that an HP1 protein is a key chromatin factor controlling stem cell function. These results provide important insights into how epigenetic mechanisms orchestrate stem cell responses during tissue regeneration.

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