DOCSLIB.ORG

This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
This Thesis Has Been Submitted in Fulfilment of the Requirements for a Postgraduate Degree (E.G This thesis has been submitted in fulfilment of the requirements for a postgraduate degree (e.g. PhD, MPhil, DClinPsychol) at the University of Edinburgh. Please note the following terms and conditions of use: This work is protected by copyright and other intellectual property rights, which are retained by the thesis author, unless otherwise stated. A copy can be downloaded for personal non-commercial research or study, without prior permission or charge. This thesis cannot be reproduced or quoted extensively from without first obtaining permission in writing from the author. The content must not be changed in any way or sold commercially in any format or medium without the formal permission of the author. When referring to this work, full bibliographic details including the author, title, awarding institution and date of the thesis must be given. Stabilisation of hepatocyte phenotype using synthetic materials Baltasar Lucendo Villarin MRes University of Edinburgh 2015 This dissertation is submitted for the degree of Doctor of Philosophy Declaration This thesis is the result of my work and includes nothing that is the outcome of work done in collaboration, except where indicated in the text. The work in this thesis has not been submitted for any other degree or professional qualification. Baltasar Lucendo Villarin i ii Abstract Primary human hepatocytes are a scare resource with limited lifespan and variable function which diminishes with time in culture. As a consequence, their use in tissue modelling and therapy is restricted. Human embryonic stem cells (hESC) could provide a stable source of human tissue due to their self-renewal properties and their ability to give rise to all the cell types of the human body. Therefore, hESC have the potential to provide an unlimited supply of hepatocytes. To date, the use of hESCs-derived somatic cells is limited due to the undefined, variable and xeno- containing microenvironment that influences the cell performance and life span, limiting scale-up and downstream application. Therefore, the development of highly defined cell based systems is required if the true potential of stem cell derived hepatocytes is to be realised. In order to replace the use of animal derived culture substrates to differentiate and maintain hESCs-derived hepatocytes, an interdisciplinary approach was employed to define synthetic materials, which maintain hepatocyte-like cell phenotype in culture. A simple polyurethane, PU134, was identified which improved hepatocyte performance and stability when compared to biological matrices. Moreover, the synthetic polymer was amenable to scale up and demonstrated batch-to-batch consistency. I subsequently used the synthetic polymer surface to probe the underlying biology, identifying key modulators of hepatocyte-like cell phenotype. This resulted in the identification of a novel genetic signature, MMP13, CTNND2 and THBS2, which was associated with stable hepatocyte performance. Importantly, those findings could be translated to two hESC lines derived at GMP. In conclusion, hepatocyte differentiation of pluripotent stem cells requires a defined microenvironment. The novel gene signature identified in this study represents an example of how to deliver stable hESCs-derived hepatocytes. iii Lay Summary Current animal and cellular hepatocyte models present limitations that make them unsuitable for clinical and toxicological applications. In the other hand, pluripotent stem cells under the correct stimuli can generate any cell type found in the human body including hepatocytes, the mayor cell type found in the liver. The ability to generate renewable sources of human hepatocytes has enormous potential to improve human health and wealth. One major obstacle to the routine deployment of stem cell-derived cells is their instability in culture due to the use of animal- derived culture substrates. To tackle this issue, I combined a synthetic polymer culture surface, polyurethane 134, previously identified as a surface that supports and promotes the generation of hepatocytes from pluripotent stem cells, with an animal-free and clinical grade hepatocyte differentiation approach to obtain stem cell-derived hepatocytes. This defined system represents a platform that permits informative and mechanism analysis of liver biology. The aim of this project is to understand how the synthetic polymer stabilise the pluripotent stem cell derived hepatocytes. From this study, I identified genes associated with stable hepatocyte function. Moreover, these findings were successfully translated to clinical grade human pluripotent stem cells. These findings hold a potential to manufacture stable clinical grade stem cell derived hepatocytes. iv Table of Contents Declaration .......................................................................................... i Abstract .............................................................................................. iii Lay summary…………………………………………………………………………………….iv List of figures and tables..................................,...................................x Abbreviations...............................................,...................................xiv Acknowledgements ......................................................................... xvii Publications ...................................................................................... xix CHAPTER ONE: GENERAL INTRODUCTION ........................................ 21 1.1 Human embryonic stem cells .................................................................. 2 1.1.1 hESC derivation ...................................................................................... 2 1.1.2 Characterisation of hESCs ...................................................................... 3 1.1.3 In vitro growth and maintenance of hESCs ............................................ 4 1.1.4 Methods for expansion of hESCs ........................................................... 5 1.1.5 The hESC microenvironment ................................................................. 6 1.2 Reprograming and programing ............................................................... 8 1.2.1 iPSCs ....................................................................................................... 8 1.2.2 Transdifferentiation ............................................................................... 9 1.3 Current sources of hepatocytes ............................................................ 11 1.4 Liver development ............................................................................... 13 1.4.1 Mammalian embryonic development ................................................. 13 1.4.2 Hepatic Endoderm Specification .......................................................... 14 1.4.3 Formation of the Hepatic Bud from Hepatic Endoderm ...................... 18 1.4.4 Hepatocyte Specification ..................................................................... 21 1.4.5 Hepatocyte Maturation ....................................................................... 22 v 1.5 Liver architecture ................................................................................. 23 1.6 Generation of in vitro hepatocyte-like cells from pluripotent stem cells or somatic cells .................................................................................................. 27 1.6.1 Differentiation via Embryoid Bodies (EBs) ........................................... 28 1.6.2 Direct differentiation of hESCs into hepatocyte-like cells (HLCs) ........ 30 1.6.3 Hepatocyte differentiation of iPSCs ..................................................... 33 1.6.4 Hepatocyte differentiation from somatic cells-transdifferentiation ... 35 1.7 Biomaterials in stem cell technology. ................................................... 36 1.7.1 Polymers in pluripotent stem cell cultures .......................................... 37 1.7.2 Polymers in stem cell differentiation ................................................... 39 1.7.3 Polymer screening approaches ............................................................ 41 1.8 The objectives of the thesis .................................................................. 42 CHAPTER 2: MATERIALS AND METHODS ........................................... 43 2.1 Materials and solutions ........................................................................ 44 2.1.1 Cell culture media ................................................................................ 44 2.1.2 Antibodies ............................................................................................ 45 2.1.3 Oligonucleotides .................................................................................. 47 2.1.4 Small-interference RNAs ...................................................................... 48 2.2 Mammalian cell culture and differentiation .......................................... 48 2.2.1 Human embryonic stem cell culture .................................................... 48 2.2.2 Embroid body formation ...................................................................... 50 2.2.3 Hepatic differentiation of hESCs .......................................................... 50 2.3 Characterisation of hESCs, hESCs-derived hepatic endoderm and hESCs- derived HLCs .................................................................................................. 52 2.3.1 Immunofluorescence ........................................................................... 52 2.3.2 Fluorescence
Load more

Recommended publications
  • Lower Genomic Stability of Induced Pluripotent Stem Cells Reflects
    Zhang et al. Cancer Commun (2018) 38:49 https://doi.org/10.1186/s40880-018-0313-0 Cancer Communications ORIGINAL ARTICLE Open Access Lower genomic stability of induced pluripotent stem cells refects increased non‑homologous end joining Minjie Zhang1,2†, Liu Wang3†, Ke An1,2†, Jun Cai1, Guochao Li1,2, Caiyun Yang1, Huixian Liu1, Fengxia Du1, Xiao Han1,2, Zilong Zhang1,2, Zitong Zhao1,2, Duanqing Pei4, Yuan Long5, Xin Xie5, Qi Zhou3 and Yingli Sun1* Abstract Background: Induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) share many common features, including similar morphology, gene expression and in vitro diferentiation profles. However, genomic stability is much lower in iPSCs than in ESCs. In the current study, we examined whether changes in DNA damage repair in iPSCs are responsible for their greater tendency towards mutagenesis. Methods: Mouse iPSCs, ESCs and embryonic fbroblasts were exposed to ionizing radiation (4 Gy) to introduce dou- ble-strand DNA breaks. At 4 h later, fdelity of DNA damage repair was assessed using whole-genome re-sequencing. We also analyzed genomic stability in mice derived from iPSCs versus ESCs. Results: In comparison to ESCs and embryonic fbroblasts, iPSCs had lower DNA damage repair capacity, more somatic mutations and short indels after irradiation. iPSCs showed greater non-homologous end joining DNA repair and less homologous recombination DNA repair. Mice derived from iPSCs had lower DNA damage repair capacity than ESC-derived mice as well as C57 control mice. Conclusions: The relatively low genomic stability of iPSCs and their high rate of tumorigenesis in vivo appear to be due, at least in part, to low fdelity of DNA damage repair.
    [Show full text]
  • I REGENERATIVE MEDICINE APPROACHES to SPINAL CORD
    REGENERATIVE MEDICINE APPROACHES TO SPINAL CORD INJURY A Dissertation Presented to The Graduate Faculty of The University of Akron In Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy Ashley Elizabeth Mohrman March 2017 i ABSTRACT Hundreds of thousands of people suffer from spinal cord injuries in the U.S.A. alone, with very few patients ever experiencing complete recovery. Complexity of the tissue and inflammatory response contribute to this lack of recovery, as the proper function of the central nervous system relies on its highly specific structural and spatial organization. The overall goal of this dissertation project is to study the central nervous system in the healthy and injured state so as to devise appropriate strategies to recover tissue homeostasis, and ultimately function, from an injured state. A specific spinal cord injury model, syringomyelia, was studied; this condition presents as a fluid filled cyst within the spinal cord. Molecular evaluation at three and six weeks post-injury revealed a large inflammatory response including leukocyte invasion, losses in neuronal transmission and signaling, and upregulation in important osmoregulators. These included osmotic stress regulating metabolites betaine and taurine, as well as the betaine/GABA transporter (BGT-1), potassium chloride transporter (KCC4), and water transporter aquaporin 1 (AQP1). To study cellular behavior in native tissue, adult neural stem cells from the subventricular niche were differentiated in vitro. These cells were tested under various culture conditions for cell phenotype preferences. A mostly pure (>80%) population of neural stem cells could be specified using soft, hydrogel substrates with a laminin coating and interferon-γ supplementation.
    [Show full text]
  • Application of Fibrin-Based Hydrogels for Nerve Protection And
    Yu et al. Journal of Biological Engineering (2020) 14:22 https://doi.org/10.1186/s13036-020-00244-3 REVIEW Open Access Application of fibrin-based hydrogels for nerve protection and regeneration after spinal cord injury Ziyuan Yu, Hongru Li, Peng Xia, Weijian Kong, Yuxin Chang, Chuan Fu, Kai Wang, Xiaoyu Yang* and Zhiping Qi* Abstract Traffic accidents, falls, and many other events may cause traumatic spinal cord injuries (SCIs), resulting in nerve cells and extracellular matrix loss in the spinal cord, along with blood loss, inflammation, oxidative stress (OS), and others. The continuous development of neural tissue engineering has attracted increasing attention on the application of fibrin hydrogels in repairing SCIs. Except for excellent biocompatibility, flexibility, and plasticity, fibrin, a component of extracellular matrix (ECM), can be equipped with cells, ECM protein, and various growth factors to promote damage repair. This review will focus on the advantages and disadvantages of fibrin hydrogels from different sources, as well as the various modifications for internal topographical guidance during the polymerization. From the perspective of further improvement of cell function before and after the delivery of stem cell, cytokine, and drug, this review will also evaluate the application of fibrin hydrogels as a carrier to the therapy of nerve repair and regeneration, to mirror the recent development tendency and challenge. Keywords: Fibrin hydrogels, Spinal cord injury, Topographical guidance, Stem cells delivery, Cytokines delivery, Drug delivery Introduction secondary death of remaining nerves or to enhance the The spinal cord is an integral part of the central nervous compensation of spared circuits function [4–7].
    [Show full text]
  • What Are IPS Cells? Stem Cell & Regenerative Medicine Center University of Wisconsin-Madison
    What are IPS cells? Stem Cell & Regenerative Medicine Center University of Wisconsin-Madison n induced pluripotent stem cell, or IPS cell, How do we know induced pluripotent stem is a stem cell that has been created from an cells can match embryonic stem cells? So adult cell such as a skin, liver, stomach or far, induced pluripotent stem cells appear to Aother mature cell through the introduction of genes exhibit the same key features of embryonic that reprogram the cell and transform it into a cell stem cells: the ability to differentiate from a that has all the characteristics of an embryonic stem blank-slate state to any of the 220 types of cell. The term pluripotent connotes the ability of a cells in the human body, and the ability to cell to give rise to multiple cell types, including all reproduce indefinitely in culture. Because in- three embryonic lineages forming the body’s or- duced stem cells are relatively new, however, gans, nervous system, skin, muscle and skeleton. scientists must compare the cells to those obtained from embryos to assess their charac- What are the advantages of induced pluripotent teristics in detail and ensure that there are no stem cells? significant differences. Bioethics: Induced stem cells have the obvious edge Do induced pluripotent stem cells mean of not having to be derived from human embryos, we no longer need embryonic stem cells? a major ethical consideration. The ability to re- No. It remains to be seen whether repro- program an adult cell to behave like an embryonic grammed cells differ in significant ways from stem cell may also enable scientists to sidestep embryonic stem cells.
    [Show full text]
  • Stem Cells: the Secret to Change | Science News for Kids
    Stem cells: The secret to change | Science News for Kids http://www.sciencenewsforkids.org/2013/04/stem-cells-the-secret-to-change/ SNK E-Blast Sign-up Privacy Policy Contact Us AA BB OO UU TT SS NN KK CC OO MM PP EE TT EE Who We Are Broadcom MASTERS For Educators Our Sponsors Intel ISEF SSP News & Events Intel STS EXPLORE: ATOMS & FORCES EARTH & SKY HUMANS & HEALTH LIFE TECH & MATH EXTRA SEARCH FOR: HUMANS & HEALTH : BODY & HEALTH Stem cells: The secret to change Unusual, versatile cells hold the key to regrowing lost tissues By Alison Pearce Stevens / April 10, 2013 Related Links Deadly new virus emerges The AIDS virus that vanished Bad for breathing Sleeping in space Going Deeper P. B arry. “Stem cells, show your face.” Science News. August 24, 2008. Neurons created from induced stem cells in Iqbal Ahmad’s lab glow red with fluorescent dye. The neuroscientist at the University of Nebraska Medical Center is researching whether the nerve cells could one day help restore sight to patients S. Ornes. “The 2012 Nobel Prizes.” Science with glaucoma. Once injected in a patient, the nerve cells would work by inserting themselves between the retina and optic News for Kids. Oct. 19, 2012. nerve, restoring signals to the brain. Credit: Courtesy of Iqbal Ahmad Inside your body, red blood cells are constantly on the move. They deliver oxygen to every tissue in every E. Sohn. “From stem cell to any cell.” Science part of your body. These blood cells also cart away waste. So their work is crucial to your survival.
    [Show full text]
  • Emerging Roles of Myc in Stem Cell Biology and Novel Tumor Therapies Go J
    Yoshida Journal of Experimental & Clinical Cancer Research (2018) 37:173 https://doi.org/10.1186/s13046-018-0835-y REVIEW Open Access Emerging roles of Myc in stem cell biology and novel tumor therapies Go J. Yoshida Abstract The pathophysiological roles and the therapeutic potentials of Myc family are reviewed in this article. The physiological functions and molecular machineries in stem cells, including embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, are clearly described. The c-Myc/Max complex inhibits the ectopic differentiation of both types of artificial stem cells. Whereas c-Myc plays a fundamental role as a “double-edged sword” promoting both iPS cells generation and malignant transformation, L-Myc contributes to the nuclear reprogramming with the significant down-regulation of differentiation-associated genetic expression. Furthermore, given the therapeutic resistance of neuroendocrine tumors such as small-cell lung cancer and neuroblastoma, the roles of N-Myc in difficult-to-treat tumors are discussed. N-Myc-driven neuroendocrine tumors tend to highly express NEUROD1, thereby leading to the enhanced metastatic potential. Importantly enough, accumulating evidence strongly suggests that c-Myc can be a promising therapeutic target molecule among Myc family in terms of the biological characteristics of cancer stem-like cells (CSCs). The presence of CSCs leads to the intra-tumoral heterogeneity, which is mainly responsible for the therapeutic resistance. Mechanistically, it has been shown that Myc-induced epigenetic reprogramming enhances the CSC phenotypes. In this review article, the author describes two major therapeutic strategies of CSCs by targeting c-Myc; Firstly, Myc-dependent metabolic reprogramming is closely related to CD44 variant-dependent redox stress regulation in CSCs.
    [Show full text]
  • Stem Cells in Cancer Therapy: Opportunities and Challenges
    www.impactjournals.com/oncotarget/ Oncotarget, 2017, Vol. 8, (No. 43), pp: 75756-75766 Review Stem cells in cancer therapy: opportunities and challenges Cheng-Liang Zhang1, Ting Huang1, Bi-Li Wu2, Wen-Xi He1 and Dong Liu1 1Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China 2Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China Correspondence to: Dong Liu, email: [email protected] Keywords: stem cell, targeted cancer therapy, tumor-tropic property, cell carrier Received: June 22, 2017 Accepted: August 17, 2017 Published: September 08, 2017 Copyright: Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Metastatic cancer cells generally cannot be eradicated using traditional surgical or chemoradiotherapeutic strategies, and disease recurrence is extremely common following treatment. On the other hand, therapies employing stem cells are showing increasing promise in the treatment of cancer. Stem cells can function as novel delivery platforms by homing to and targeting both primary and metastatic tumor foci. Stem cells engineered to stably express various cytotoxic agents decrease tumor volumes and extend survival in preclinical animal models. They have also been employed as virus and nanoparticle carriers to enhance primary therapeutic efficacies and relieve treatment side effects. Additionally, stem cells can be applied in regenerative medicine, immunotherapy, cancer stem cell-targeted therapy, and anticancer drug screening applications.
    [Show full text]
  • Genomic Instability in Induced Stem Cells
    Cell Death and Differentiation (2011) 18, 745–753 & 2011 Macmillan Publishers Limited All rights reserved 1350-9047/11 www.nature.com/cdd Genomic instability in induced stem cells CE Pasi1,8, A Dereli-O¨ z2,8, S Negrini2,8, M Friedli3, G Fragola1,4, A Lombardo5, G Van Houwe2, L Naldini5, S Casola4, G Testa1, D Trono3, PG Pelicci*,1,6 and TD Halazonetis*,2,7 The ability to reprogram adult cells into stem cells has raised hopes for novel therapies for many human diseases. Typical stem cell reprogramming protocols involve expression of a small number of genes in differentiated somatic cells with the c-Myc and Klf4 proto-oncogenes typically included in this mix. We have previously shown that expression of oncogenes leads to DNA replication stress and genomic instability, explaining the high frequency of p53 mutations in human cancers. Consequently, we wondered whether stem cell reprogramming also leads to genomic instability. To test this hypothesis, we examined stem cells induced by a variety of protocols. The first protocol, developed specifically for this study, reprogrammed primary mouse mammary cells into mammary stem cells by expressing c-Myc. Two other previously established protocols reprogrammed mouse embryo fibroblasts into induced pluripotent stem cells by expressing either three genes, Oct4, Sox2 and Klf4, or four genes, OSK plus c-Myc. Comparative genomic hybridization analysis of stem cells derived by these protocols revealed the presence of genomic deletions and amplifications, whose signature was suggestive of oncogene-induced DNA replication stress. The genomic aberrations were to a significant degree dependent on c-Myc expression and their presence could explain why p53 inactivation facilitates stem cell reprogramming.
    [Show full text]
  • Understanding the Roadmaps to Induced Pluripotency
    Citation: Cell Death and Disease (2014) 5, e1232; doi:10.1038/cddis.2014.205 OPEN & 2014 Macmillan Publishers Limited All rights reserved 2041-4889/14 www.nature.com/cddis Review Understanding the roadmaps to induced pluripotency K Liu1,2,4, Y Song1,4,HYu1,3,4 and T Zhao*,1 Somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) by ectopic expression of transcription factors Oct4, Sox2, Klf4 and cMyc. Recent advancements have shown that small-molecule compounds can induce pluripotency, indicating that cell fate can be regulated by direct manipulation of intrinsic cell signaling pathways, thereby innovating our current understanding of reprogramming. The fact that lineage specifiers can induce pluripotency suggests that the pluripotent state is a fine balance between competing differentiation forces. Dissection of pluripotent roadmaps indicates that reprogramming is a process of reverse development, involving a series of complicated and distinct reprogramming stages. Evidence from mouse iPSC transplantation studies demonstrated that some certain but not all cells derived from iPSCs are immunogenic. These studies provide new ways to minimize reprogramming-induced abnormalities and maximize reprogramming efficiency to facilitate clinical development and use of iPSCs. Cell Death and Disease (2014) 5, e1232; doi:10.1038/cddis.2014.205; published online 15 May 2014 Subject Category: Immunity Facts How do the complicated signal transduction networks inside a cell control its fate? Reprogramming is not only a simple process of reverse development but also a very complicated procedure with The concept of totipotent differentiated vertebrate cells was different reprogramming stages. first proposed by the German embryologist Spemann in 1938, Binding of both facilitators and inhibitors by reprogramming who reported that the nucleus from an embryo retained the factors simultaneously at early stage directly contributes to ability to develop into a salamander after undergoing four low reprogramming efficiency.
    [Show full text]
  • The Role of the Transcription Factor SOX2 in Tumorigenesis and Development of the Stomach
    Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften der Fakultät für Biologie der Ludwig-Maximilians- Universität München The role of the transcription factor SOX2 in tumorigenesis and development of the stomach Vorgelegt von Katharina Antonia Hütz München 2013 2 „Wenn Du ein Schiff bauen willst, dann trommle nicht Männer zusammen um Holz zu beschaffen, Aufgaben zu vergeben und die Arbeit einzuteilen, sondern lehre die Männer die Sehnsucht nach dem weiten, endlosen Meer.“ Antoine de Saint-Exupery 3 4 Erklärung Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29. Januar 1998 (in der Fassung der sechsten Änderungssatzung vom 16. August 2010) von Prof. Thomas Cremer von der Fakultät der Biologie vertreten. Eidesstattliche Versicherung Diese Dissertation wurde selbständig, ohne unerlaubte Hilfe erarbeitet. München, ……………………………………………………. Katharina Hütz Dissertation eingereicht am 06. Juni 2013 1. Gutachter: Prof. Thomas Cremer 2. Gutachter: Prof. Elisabeth Weiss Mündliche Prüfung am 21. Oktober 2013 5 6 Meinen Eltern und meinen Schwestern 7 8 Table of Contents Table of Contents ................................................................................................................. 9 List of Abbreviations .......................................................................................................... 13 1. Introduction ................................................................................................................ 17 1.1. The stomach .....................................................................................................
    [Show full text]
  • Stem Cell Therapy: Recent Success and Continuing Progress in Treating Diabetes Elton Mathias1*, Roveena Goveas2 and Manish Rajak1
    ISSN: 2469-570X Mathias et al. Int J Stem Cell Res Ther 2018, 5:053 DOI: 10.23937/2469-570X/1410053 Volume 5 | Issue 1 International Journal of Open Access Stem Cell Research & Therapy REVIEW ARTICLE Stem Cell Therapy: Recent Success and Continuing Progress in Treating Diabetes Elton Mathias1*, Roveena Goveas2 and Manish Rajak1 1 Check for Innvocept Solutions, Mumbai, India updates 2Department of Internal Medicine, Mountainside Medical Center, Montclair, USA *Corresponding author: Elton Mathias, Medical Professional, Innvocept Solutions, Mumbai, India, Tel: +1-(732)-804- 5257, E-mail: [email protected] at any age, but most often occurs in children and young Abstract adults. The etiology of DM type 1 is not fully uncovered, Diabetes mellitus (DM), a cluster of metabolic diseases, re- however in most cases, the body’s immune system at- sulting in high blood glucose levels, is prevalent in today’s world. The global costs of diabetes and its consequences tacks and destroys insulin producing beta-cells. Family are rising and are expected substantially increase by 2030, history is known to play a role, in about 10% to 15% of especially in middle- and lower-income countries. Evi- people with DM type 1. Type 2 diabetes, also known as dence-based therapies, specifically targeting the reduction adult-onset DM, which usually develops after the age of high blood glucose levels, and minimizing diabetic com- of 40 but can appear earlier in obese patients. With plications, are currently the choice of treatment. Stem cell therapy offers a promising vision to treat DM. Although chal- DM type 2, the pancreas produces insulin, but the body lenges are still posed with this line of therapy, studies have cannot use it effectively.
    [Show full text]
  • Modeling Stem Cell Induction Processes
    Modeling Stem Cell Induction Processes The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Grácio, Filipe, Joaquim Cabral, and Bruce Tidor. Modeling Stem Cell Induction Processes. Edited by Rajasingh Johnson. PLoS ONE 8, no. 5 (May 8, 2013): e60240. As Published http://dx.doi.org/10.1371/journal.pone.0060240 Publisher Public Library of Science Version Final published version Citable link http://hdl.handle.net/1721.1/79416 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/2.5/ Modeling Stem Cell Induction Processes Filipe Gra´cio1,2, Joaquim Cabral1, Bruce Tidor2,3,4* 1 Institute for Biotechnology and Bioengineering (IBB), Centre for Biological and Chemical Engineering, Instituto Superior Te´cnico, Lisboa, Portugal, 2 Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 3 Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America, 4 Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America Abstract Technology for converting human cells to pluripotent stem cell using induction processes has the potential to revolutionize regenerative medicine. However, the production of these so called iPS cells is still quite inefficient and may be dominated by stochastic effects. In this work we build mass-action models of the core regulatory elements controlling stem cell induction and maintenance. The models include not only the network of transcription factors NANOG, OCT4, SOX2, but also important epigenetic regulatory features of DNA methylation and histone modification.
    [Show full text]