The Act of Controlling Adult Stem Cell Dynamics: Insights from Animal Models
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Epigenetic Metabolites License Stem Cell States
CHAPTER SIX Epigenetic metabolites license stem cell states Logeshwaran Somasundarama,b,†, Shiri Levya,b,†, Abdiasis M. Husseina,b, Devon D. Ehnesa,b, Julie Mathieub,c, Hannele Ruohola-Bakera,b,∗ aDepartment of Biochemistry, University of Washington, Seattle, WA, United States bInstitute for Stem Cell and Regenerative Medicine, University of Washington, Seattle, WA, United States cDepartment of Comparative Medicine, University of Washington, Seattle, WA, United States ∗ Corresponding author: e-mail address: [email protected] Contents 1. Introduction 210 2. Stem cell energetics 210 3. Metabolism of quiescent stem cells 212 3.1 Adult stem cells 212 3.2 Pluripotent stem cell quiescence, diapause 216 4. Metabolism of active stem cells 217 4.1 Metabolism after fertilization 217 4.2 Metabolism of pre-implantation and post-implantation pluripotent stem cells 218 4.3 Metabolism of actively cycling adult stem cells: MSC as case-study 220 5. HIF, the master regulator of metabolism 222 6. Epigenetic signatures and epigenetic metabolites 224 6.1 Epigenetic signatures of naïve and primed pluripotent stem cells 224 6.2 Epigenetic signatures of adult stem cells 227 6.3 Epigenetic metabolites 228 7. Conclusion 229 Acknowledgments 230 References 230 Further reading 240 Abstract It has become clear during recent years that stem cells undergo metabolic remodeling during their activation process. While these metabolic switches take place in pluripotency as well as adult stem cell populations, the rules that govern the switch are not clear. † Equal contribution. # Current Topics in Developmental Biology, Volume 138 2020 Elsevier Inc. 209 ISSN 0070-2153 All rights reserved. https://doi.org/10.1016/bs.ctdb.2020.02.003 210 Logeshwaran Somasundaram et al. -
(12) Patent Application Publication (10) Pub. No.: US 2015/0023954 A1 Wu Et Al
US 2015 0023954A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0023954 A1 Wu et al. (43) Pub. Date: Jan. 22, 2015 (54) POTENTIATING ANTIBODY-INDUCED GOIN33/574 (2006.01) COMPLEMENT-MEDIATED CYTOTOXCITY A613 L/4745 (2006.01) VAPI3K INHIBITION A613 L/4375 (2006.01) (52) U.S. Cl. (71) Applicant: MEMORIAL SLOAN-KETTERING CPC ....... A6IK39/39558 (2013.01); A61 K3I/4745 CANCER CENTER, New York, NY (2013.01); A61 K39/00II (2013.01); A61 K (US) 39/385 (2013.01); A61K31/4375 (2013.01); A6IK3I/5377 (2013.01); A61K.39/39 (72) Inventors: Xiaohong Wu, Forest Hills, NY (US); (2013.01); GOIN33/57484 (2013.01); CI2O Wolfgang W. Scholz, San Diego, CA I/6886 (2013.01); A61 K 2039/505 (2013.01); (US); Govind Ragupathi, New York, C12O 2600/16 (2013.01); C12O 2600/106 NY (US); Philip O. Livingston, (2013.01); A61K 2039/545 (2013.01) Bluffton, SC (US) USPC .................. 424/133.1; 424/277.1; 424/193.1; 424f1 74.1436/5O1435/7.1 : 506/9:435/7.92: (21) Appl. No.: 14/387,153 s s 435/6.12. 436/94 (22) PCT Filed: Mar. 14, 2013 (57) ABSTRACT (86). PCT No.: PCT/US 13/31278 Methodologies and technologies for potentiating antibody S371 (c)(1), based cancer treatments by increasing complement-mediated (2) Date: Sep. 22, 2014 cell cytotoxicity are disclosed. Further provided are method O O ologies and technologies for overcoming ineffective treat Related U.S. Application Data ments correlated with and/or caused by sub-lytic levels of (60) Provisional application No. -
Regulation of Adult Neurogenesis in Mammalian Brain
International Journal of Molecular Sciences Review Regulation of Adult Neurogenesis in Mammalian Brain 1,2, 3, 3,4 Maria Victoria Niklison-Chirou y, Massimiliano Agostini y, Ivano Amelio and Gerry Melino 3,* 1 Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath BA2 7AY, UK; [email protected] 2 Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK 3 Department of Experimental Medicine, TOR, University of Rome “Tor Vergata”, 00133 Rome, Italy; [email protected] (M.A.); [email protected] (I.A.) 4 School of Life Sciences, University of Nottingham, Nottingham NG7 2HU, UK * Correspondence: [email protected] These authors contributed equally to this work. y Received: 18 May 2020; Accepted: 7 July 2020; Published: 9 July 2020 Abstract: Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. -
Rapid and Efficient Generation of Oligodendrocytes from Human
Rapid and efficient generation of oligodendrocytes PNAS PLUS from human induced pluripotent stem cells using transcription factors Marc Ehrlicha,b, Sabah Mozafaric,d,e,f, Michael Glatzab, Laura Starosta,b, Sergiy Velychkob, Anna-Lena Hallmanna,b, Qiao-Ling Cuig, Axel Schambachh, Kee-Pyo Kimb, Corinne Bachelinc,d,e,f, Antoine Marteync,d,e,f, Gunnar Hargusa,b, Radia Marie Johnsoni, Jack Antelg, Jared Sterneckertj, Holm Zaehresb,k, Hans R. Schölerb,l, Anne Baron-Van Evercoorenc,d,e,f, and Tanja Kuhlmanna,1 aInstitute of Neuropathology, University Hospital Münster, 48149 Muenster, Germany; bDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, 48149 Muenster, Germany; cINSERM, U1127, F-75013 Paris, France; dCNRS, UMR 7225, F-75013 Paris, France; eSorbonne Universités, Université Pierre et Marie Curie Paris 06, UM-75, F-75005 Paris, France; fInstitut du Cerveau et de la Moelle epinière-Groupe Hospitalier Pitié-Salpêtrière, F-75013 Paris, France; gMontreal Neurological Institute, McGill University, Montreal, QC, Canada H3A 2B4; hInstitute of Experimental Hematology, Hannover Medical School, 30625 Hannover, Germany; iDepartment of Physiology, McGill University, Montreal, QC, Canada H3A 2B4; jDFG Research Center for Regenerative Therapies, Technische Universität Dresden, 01307 Dresden, Germany; kMedical Faculty, Department of Anatomy and Molecular Embryology, Ruhr-University Bochum, 44801 Bochum, Germany; and lMedicial Faculty, Westphalian Wilhelms-University of Muenster, 48149 Muenster, Germany Edited by Brigid L. M. Hogan, Duke University Medical Center, Durham, NC, and approved February 1, 2017 (received for review August 30, 2016) Rapid and efficient protocols to generate oligodendrocytes (OL) more, these protocols require long culture periods (70–150 d) to + from human induced pluripotent stem cells (iPSC) are currently obtain O4 OL and show limited efficiency (9–12). -
Translational Applications of Adult Stem Cell-Derived Organoids Jarno Drost1,2,* and Hans Clevers1,2,3,‡
© 2017. Published by The Company of Biologists Ltd | Development (2017) 144, 968-975 doi:10.1242/dev.140566 PRIMER Translational applications of adult stem cell-derived organoids Jarno Drost1,2,* and Hans Clevers1,2,3,‡ ABSTRACT of organotypic organoids from single Lgr5-positive ISCs (Sato Adult stem cells from a variety of organs can be expanded long- et al., 2009). These organoids contained all cell types of the ‘ ’ term in vitro as three-dimensional organotypic structures termed intestinal epithelium and were structured into proliferative crypt ‘ ’ organoids. These adult stem cell-derived organoids retain their organ and differentiated villus compartments, thereby retaining the identity and remain genetically stable over long periods of time. The architecture of the native intestine (Sato et al., 2009). In addition ability to grow organoids from patient-derived healthy and diseased to Wnt/R-spondin, epidermal growth factor (EGF) (Dignass and tissue allows for the study of organ development, tissue homeostasis Sturm, 2001), noggin (BMP inhibitor) (Haramis et al., 2004) and an and disease. In this Review, we discuss the generation of adult artificial laminin-rich extracellular matrix (provided by Matrigel) stem cell-derived organoid cultures and their applications in in vitro complemented the cocktail for successful in vitro propagation of disease modeling, personalized cancer therapy and regenerative mouse ISC-derived organoids (Sato et al., 2009). At the same time, medicine. Ootani et al. reported another Wnt-driven in vitro culture of ISCs (Ootani et al., 2009). In contrast to Sato et al., this culture was not KEY WORDS: Adult stem cells, Organoids, Disease modelling, based on defined growth factors. -
Cancer from the Perspective of Stem Cells and Misappropriated Tissue Regeneration Mechanisms
Leukemia (2018) 32:2519–2526 https://doi.org/10.1038/s41375-018-0294-7 REVIEW ARTICLE Corrected: Correction Stem cell biology Cancer from the perspective of stem cells and misappropriated tissue regeneration mechanisms 1,2 1 1 1,2 1 Mariusz Z. Ratajczak ● Kamila Bujko ● Aaron Mack ● Magda Kucia ● Janina Ratajczak Received: 8 September 2018 / Accepted: 17 September 2018 / Published online: 30 October 2018 © The Author(s) 2018. This article is published with open access Abstract Tumorigenesis can be considered as pathologically misappropriated tissue regeneration. In this review we will address some unresolved issues that support this concept. First, we will address the issue of the identity of cancer-initiating cells and the presence of cancer stem cells in growing tumors. We will also ask are there rare and distinct populations of cancer stem cells in established tumor cell lines, or are all of the cells cancer stem cells? Second, the most important clinical problem with cancer is its metastasis, and here a challenging question arises: by employing radio-chemotherapy for tumor treatment, do we unintentionally create a prometastatic microenvironment in collateral organs? Specifically, many factors upregulated in response to radio-chemotherapy-induced injury may attract highly migratory cancer cells that survived initial treatment. 1234567890();,: 1234567890();,: Third, what is the contribution of normal circulating stem cells to the growing malignancy? Do circulating normal stem cells recognize a tumor as a hypoxia-damaged tissue that needs -
SAV1 Promotes Hippo Kinase Activation Through Antagonizing the PP2A Phosphatase STRIPAK
RESEARCH ARTICLE SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK Sung Jun Bae1†, Lisheng Ni1†, Adam Osinski1, Diana R Tomchick2, Chad A Brautigam2,3, Xuelian Luo1,2* 1Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States; 2Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States; 3Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, United States Abstract The Hippo pathway controls tissue growth and homeostasis through a central MST- LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A *For correspondence: phosphatase complex. [email protected] DOI: https://doi.org/10.7554/eLife.30278.001 †These authors contributed equally to this work Competing interests: The Introduction authors declare that no The balance between cell division and death maintains tissue homeostasis of multicellular organisms. -
Adult Spinal Cord Stem Cells Generate Neurons After Transplantation in the Adult Dentate Gyrus
The Journal of Neuroscience, December 1, 2000, 20(23):8727–8735 Adult Spinal Cord Stem Cells Generate Neurons after Transplantation in the Adult Dentate Gyrus Lamya S. Shihabuddin, Philip J. Horner, Jasodhara Ray, and Fred H. Gage The Salk Institute, Laboratory of Genetics, La Jolla, California 92037 The adult rat spinal cord contains cells that can proliferate and population of cells into the adult rat spinal cord resulted in their differentiate into astrocytes and oligodendroglia in situ. Using differentiation into glial cells only. However, after heterotopic clonal and subclonal analyses we demonstrate that, in contrast transplantation into the hippocampus, transplanted cells that to progenitors isolated from the adult mouse spinal cord with a integrated in the granular cell layer differentiated into cells char- combination of growth factors, progenitors isolated from the acteristic of this region, whereas engraftment into other hip- adult rat spinal cord using basic fibroblast growth factor alone pocampal regions resulted in the differentiation of cells with display stem cell properties as defined by their multipotentiality astroglial and oligodendroglial phenotypes. The data indicate and self-renewal. Clonal cultures derived from single founder that clonally expanded, multipotent adult progenitor cells from a cells generate neurons, astrocytes, and oligodendrocytes, con- non-neurogenic region are not lineage-restricted to their devel- firming the multipotent nature of the parent cell. Subcloning opmental origin but can generate region-specific neurons in vivo analysis showed that after serial passaging, recloning, and ex- when exposed to the appropriate environmental cues. pansion, these cells retained multipotentiality, indicating that they Key words: spinal cord; stem cells; FGF; transplantation; neu- are self-renewing. -
Stem Cell Therapy and Gene Transfer for Regeneration
Gene Therapy (2000) 7, 451–457 2000 Macmillan Publishers Ltd All rights reserved 0969-7128/00 $15.00 www.nature.com/gt MILLENNIUM REVIEW Stem cell therapy and gene transfer for regeneration T Asahara, C Kalka and JM Isner Cardiovascular Research and Medicine, St Elizabeth’s Medical Center, Tufts University School of Medicine, Boston, MA, USA The committed stem and progenitor cells have been recently In this review, we discuss the promising gene therapy appli- isolated from various adult tissues, including hematopoietic cation of adult stem and progenitor cells in terms of mod- stem cell, neural stem cell, mesenchymal stem cell and ifying stem cell potency, altering organ property, accelerating endothelial progenitor cell. These adult stem cells have sev- regeneration and forming expressional organization. Gene eral advantages as compared with embryonic stem cells as Therapy (2000) 7, 451–457. their practical therapeutic application for tissue regeneration. Keywords: stem cell; gene therapy; regeneration; progenitor cell; differentiation Introduction poietic stem cells to blood cells. The determined stem cells differentiate into ‘committed progenitor cells’, which The availability of embryonic stem (ES) cell lines in mam- retain a limited capacity to replicate and phenotypic fate. malian species has greatly advanced the field of biologi- In the past decade, researchers have defined such com- cal research by enhancing our ability to manipulate the mitted stem or progenitor cells from various tissues, genome and by providing model systems to examine including bone marrow, peripheral blood, brain, liver cellular differentiation. ES cells, which are derived from and reproductive organs, in both adult animals and the inner mass of blastocysts or primordial germ cells, humans (Figure 1). -
Progenitor Cell Therapy for the Treatment of Damaged Myocardium
Progenitor Cell Therapy for the Treatment of Damaged Protocol Myocardium due to Ischemia (20218) Medical Benefit Effective Date: 01/01/11 Next Review Date: 07/22 Preauthorization No Review Dates: 09/10, 07/11, 07/12, 07/13, 07/14, 07/15, 07/16, 07/17, 07/18, 07/19, 07/20, 07/21 This protocol considers this test or procedure investigational. If the physician feels this service is medically necessary, preauthorization is recommended. The following protocol contains medical necessity criteria that apply for this service. The criteria are also applicable to services provided in the local Medicare Advantage operating area for those members, unless separate Medicare Advantage criteria are indicated. If the criteria are not met, reimbursement will be denied and the patient cannot be billed. Please note that payment for covered services is subject to eligibility and the limitations noted in the patient’s contract at the time the services are rendered. RELATED PROTOCOLS Orthopedic Applications of Stem Cell Therapy (Including Allograft and Bone Substitute Products Used With Autologous Bone Marrow) Stem Cell Therapy for Peripheral Arterial Disease Populations Interventions Comparators Outcomes Individuals: Interventions of interest Comparators of interest Relevant outcomes include: • With acute cardiac are: are: • Disease-specific survival ischemia • Progenitor cell therapy • Standard therapy • Morbid events • Functional outcomes • Quality of life • Hospitalizations Individuals: Interventions of interest Comparators of interest Relevant outcomes -
Differential Contributions of Haematopoietic Stem Cells to Foetal and Adult Haematopoiesis: Insights from Functional Analysis of Transcriptional Regulators
Oncogene (2007) 26, 6750–6765 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Differential contributions of haematopoietic stem cells to foetal and adult haematopoiesis: insights from functional analysis of transcriptional regulators C Pina and T Enver MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK An increasing number of molecules have been identified ment and appropriate differentiation down the various as candidate regulators of stem cell fates through their lineages. involvement in leukaemia or via post-genomic gene dis- In the adult organism, HSC give rise to differentiated covery approaches.A full understanding of the function progeny following a series of relatively well-defined steps of these molecules requires (1) detailed knowledge of during the course of which cells lose proliferative the gene networks in which they participate and (2) an potential and multilineage differentiation capacity and appreciation of how these networks vary as cells progress progressively acquire characteristics of terminally differ- through the haematopoietic cell hierarchy.An additional entiated mature cells (reviewed in Kondo et al., 2003). layer of complexity is added by the occurrence of different As depicted in Figure 1, the more primitive cells in the haematopoietic cell hierarchies at different stages of haematopoietic differentiation hierarchy are long-term ontogeny.Beyond these issues of cell context dependence, repopulating HSC (LT-HSC), -
Acute Myeloid Leukemia - Biology 2 with Pmscv-NUP98-NSD1-Neo Or Pmscv-FLT3-ITD-GFP Retroviral Vectors Or Both
Milan, Italy, June 12 – 15, 2014 Methods: Lineage marker-negative murine bone marrow cells were transduced Acute myeloid leukemia - Biology 2 with pMSCV-NUP98-NSD1-neo or pMSCV-FLT3-ITD-GFP retroviral vectors or both. Transduced cells were analyzed for their clonogenic potential by serial plating in growth-factor containing methylcellulose followed by expansion and P142 injection into sublethally irradiated syngeneic recipients. Results: Expression of NUP98-NSD1 provided aberrant self-renewal poten - Abstract withdrawn tial to bone marrow progenitor cells. Co-expression of FLT3-ITD increased proliferation but impaired self-renewal in vitro . Transplantation of cells expressing NUP98-NSD1 and FLT3-ITD into mice resulted in transplantable P143 AML after a short latency. The leukaemic blasts expressed myeloid markers + + + lo lo THE CAMP RESPONSE ELEMENT BINDING PROTEIN (CREB) OVEREX - (Mac-1 /Gr-1 /Fc γRII/III /c-kit /CD34 ). Splinkerette-PCR revealed similar PRESSION INDUCES MYELOID TRANSFORMATION IN ZEBRAFISH patterns of potential retroviral integration sites of in vitro immortalized bone C Tregnago 1,* V Bisio 1, E Manara 2, S Aveic 1, C Borga 1, S Bresolin 1, G Germano 2, marrow cells before and after expansion in vivo . Mice that received cells G Basso 1, M Pigazzi 2 expressing solely NUP98-NSD1 did not develop AML but showed signs of a 1Dipartimento di salute della donna e del bambino, Università degli Studi di myeloid hyperplasia after long latency, characterized by expansion of Mac- Padova, 2Dipartimento di salute della donna e del bambino, IRP, Padova, Italy 1+/Gr-1 + cells in the bone marrow and active extramedullary haematopoiesis in the spleen.