Stem Cells: Therapeutic Innovations under Control

By Nicole Arrighi

Stem Cells: Therapeutic Innovations under Control traces the discovery of stem cells and induced pluripotent cells. It establishes the link between knowledge about cell development and tissue engineering, and presents perspectives in regenerative medicine. Cell proliferation and tissue architecture open up unexpected applications in tissue engineering, with the development of tissues or organs. In this context emerges the need to address the issue of bioethics and regulatory considerations. Because stem cells can multiply and differentiate into cells specific to a particular tissue or organ, they represent vast potential in the health field.

• Traces the discovery of stem cells to link knowledge of cell development with tissue engineering
• Presents prospects in regenerative medicine
• Establishes the link between knowledge about cell development and tissue engineering

• Language: English
• Publisher: Elsevier Science
• Release date: Mar 27, 2018
• ISBN: 9780081025888

Nicole Arrighi

Dr Nicole Arrhighi is a lecturer at the University Nice-Sophia Antipolis. She studied at the Université de Technologie de Compiègne.

Book preview

Stem Cells

Therapeutic Innovations Under Control

Nicole Arrighi

Innovation, Benefits and Risk in Biotechnology Set

coordinated by

Nicole Arrighi and Christine Risso

Table of Contents

Cover image

Title page

Copyright

Acknowledgments

Introduction

1: Definition and Classification of Stem Cells

Abstract

1.1 Two characteristics specific to stem cells

1.2 Adult stem cells or specific stem cells of a tissue

1.3 Embryonic stem cells

1.4 Induced pluripotent stem cells

2: Stem Cells as a Necessary Experimental Platform in Medical Research

Abstract

2.1 A tool for modeling human pathologies

2.2 A pharmaceutical screening tool

2.3 A predictive toxicology tool in the pharmaceutical industry

3: Stem Cells at the Core of Cell Therapy

Abstract

3.1 Blood stem cells, pioneers of cell therapy

3.2 Skin stem cells

3.3 Stem cells at the core of clinical research

4: Stem Cells for Regenerative Medicine in Humans

Abstract

4.1 Biomaterials in tissue engineering

4.2 Nanofibers associated with stem cells organized in 3D

4.3 3D printing from stem cells

4.4 Today’s regenerative medicine

5: Bioethics: Regulatory Framework for Human Stem Cells

Abstract

5.1 The legal position relating to stem cell research

5.2 The patentability of stem cell research

5.3 Cell- and tissue-based therapy products

Glossary

Bibliography

Index

Copyright

First published 2018 in Great Britain and the United States by ISTE Press Ltd and Elsevier Ltd

Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms and licenses issued by the CLA. Enquiries concerning reproduction outside these terms should be sent to the publishers at the undermentioned address:

ISTE Press Ltd

27-37 St George’s Road

London SW19 4EU

UK

www.iste.co.uk

Elsevier Ltd

The Boulevard, Langford Lane

Kidlington, Oxford, OX5 1GB

UK

www.elsevier.com

Notices

Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

For information on all our publications visit our website at http://store.elsevier.com/

© ISTE Press Ltd 2018

The rights of Nicole Arrighi to be identified as the author of this work have been asserted by her in accordance with the Copyright, Designs and Patents Act 1988.

British Library Cataloguing-in-Publication Data

A CIP record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

ISBN 978-1-78548-254-0

Printed and bound in the UK and US

Acknowledgments

I wish to thank all those who have accompanied me in this work.

Angèle Chopard, Professor at the University of Montpellier, UMR 866 Muscular Dynamic and Metabolism team, whom I thank for her friendly energy and unwavering support.

Christian Dani, Research Director, Head of the Stem Cells and Differentiation team at the Institute of Biology Valrose (CNRS-UMR 7277 INSERM U1091), University of Nice, whom I thank for his sound advice.

Pascal Peraldi, INSERM Researcher for the Stem Cells and Differentiation team at the Institute of Biology Valrose (CNRS UMR 7277 INSERM U1091), University of Nice, whom I thank for his amicable contribution.

Introduction

Biomedical research, in its broadest sense, that is to say, widely crossing over into human sciences, can permeate, influence, guide – in a word, humanize – all great scientific advances and prepare humankind for its future.

(Simone Veil, French Health Minister, 1975)

Stem cells are the original cells of any organism. They are those of the embryo in the early stages of its development. Starting from approximately 30 stem cells contained in the embryo, the development program of the whole organism occurs. From identical embryonic cells, they progressively engage towards specialization pathways, at the origin of tissues and functional organs. Historically, the determinism of the creation of the human being, which is so complex, from a simple embryo, has been investigated by researchers exploring developmental biology. Embryonic stem cells were discovered after the stem cells found in the adult organism. The latter have been isolated in tissues such as skin or muscle, where they play a key role in their constitution and their renewal.

Since these stem cells have been maintained in proliferation in vitro, a new benefit has emerged. They can multiply to infinity and produce all of the cells of the human body. They represent a tremendous hope in the field of health. These stem cells create a technological platform that provides solutions to medicine and research. Are they able to regenerate a damaged tissue? Are they able to replace sick or aging cells? Are they a weapon against age-related disorders?

The questions are challenging and complex. Based on knowledge of cell development, these new biotechnologies call on mechanisms where the cell orchestrates the organism’s repair by specializing in all of a tissue’s functional cells. The coupling of stem cells with biomaterials offers unhoped-for prospects. This breakthrough in regenerative medicine has resulted in the invention of tissue engineering and created living medicines. These new medicines concern us all. It should be possible for all individuals to form their own opinion on the benefits and risks of these innovative therapies. The ability to estimate the safety of a treatment should be accessible to all. In order to make personal decisions, often in a hurry, an in-depth view is required, a clear and comprehensible summary of the most innovative research, which is offered in this book.

The aim of this book is to enter the world of stem cells and address the subject in its entirety. The stem cell approach is opposed to a compartmentalized vision, because they form a part of the complexity of the living. Beyond a scientific history, stem cells surpass the stakes of medicine. Handling and using stem cells has an impact on the living. What are the risks in terms of safety and toxicity for living beings? What does the law say? Is the legal framework the same in all countries? Do cellular medicines exist on the international market? From tissue regeneration to the era of augmented man, the ethical choices must be considered. While stem cells are at the core of therapeutic innovation, they bring a whole network of teams of doctors, researchers and companies into competition in a race for performance. With the acceleration of science, is this innovation really under control?

This book proposes to offer part of the response to these many questions, structured in five chapters. The starting point of this book describes the key stem cell discoveries. Based on observation, it provides pathways of scientific reasoning from discovery up to the monitoring of scientific progress in this complex subject.

First, the unique characteristics and the different types of stem cells will be defined (Chapter 1). After this classification, the use of stem cells as a new tool for studying diseases will be discussed. Decrypting the mechanism of a pathology and imagining treatment paths through the screening of pharmaceutical molecules: these are the responses provided by stem cells thanks to this experimental platform necessary to medical research (Chapter 2). Next, Chapter 3 will present the prospects of cell therapy through the transplantation of stem cells in an injured tissue or organ and, beyond the transplant, the design of tissue reconstruction, combining a whole microenvironment with stem cells, which is the starting point of regenerative medicine, explored in Chapter 4. This rapid evolution of fundamental research and translational research has raised bioethical and regulatory questions that will be developed in Chapter 5.

1

Definition and Classification of Stem Cells

Abstract

Stem cells are the original cells of the human being. With infinite multiplication potential and the ability to differentiate into any type of cell of the organism, stem cells are the foundations of tissues, organs and the entire organism. Throughout life, they regenerate and repair damaged tissues following injury or illness. Amplified from a sample taken from the patient or genetically modified, these cells grafted onto a support guarantee an optimal anchoring and a rapid proliferation. This living graft, transplanted onto the damaged tissue area, is capable of introducing cells that restore its function. These stem cells form the basis of the tissue repair processes. But what is a stem cell? Where does it come from? Where in the organism is it located? What is its role?

Keywords

Bone-marrow stem cells; Cardiac muscle stem cells; Cell lineage; Fertilization; Intestinal stem cells; Neural stem cells; Pluripotent embryonic stem cells; Skeletal muscle stem cells; Skin stem cells; Umbilical cord blood stem cells

I was captivated by the idea of understanding and controlling the pluripotent state.

(Austin Smith, Director of the Wellcome Trust Centre for Stem Cell Research, Cambridge)

Stem cells are the original cells of the human being. With infinite multiplication potential and the ability to differentiate into any type of cell of the organism, stem cells are the foundations of tissues, organs and the entire organism. Throughout life, they regenerate and repair damaged tissues following injury or illness. Amplified from a sample taken from the patient or genetically modified, these cells grafted onto a support guarantee an optimal anchoring and a rapid proliferation. This living graft, transplanted onto the damaged tissue area, is capable of introducing cells that restore its function. These stem cells form the basis of the tissue repair processes. But what is a stem cell? Where does it come from? Where in the organism is it located? What is its role?

The aim of this chapter is to define the unique properties of stem cells (SCs), locate their source and understand their development. In the human organism, several categories of SCs exist; this chapter is organized into three parts corresponding to the three categories of stem cells.

First, the stem cells present in the various tissues of the human organism will be addressed. These are called adult stem cells and are located in specific tissues or organs, part of the adult organism. Bone-marrow-, muscle-, skin- and adipose tissue-derived SCs as well as their physiological functions and the molecular markers that characterize them are thus presented. All SCs of the tissues or organs of the organism have a common origin: they come from SCs of the embryo. Each of the embryonic SCs can give rise to an entire organism. Second, in section 1.3, we will examine these embryonic SCs, situating the early stages of the embryo’s development and their role in the first weeks after fertilization. Finally, section 1.4 presents the discovery that has given a boost to regenerative medicine: the reprogramming of somatic cells into induced pluripotent cells. As if they were going back in time to the embryonic stage, these stem cells again become pluripotent and cover potentialities close to those of embryonic SCs. Sampled from the adult individual and not from the embryo, they pave the way for tissue regeneration therapies, which could have been restrained by the ethical constraints linked to embryonic SCs.

1.1 Two characteristics specific to stem cells

SCs are original cells that are considered to be the progenitors of more than 200 types of cells in the human body. They are able to divide and produce other cells that can become highly specialized. Cells are said to be SCs if they possess the following two characteristic properties: self-renewal and pluripotency. Self-renewal is the ability to multiply infinitely, by simple division. Pluripotency means that the cell is capable of producing all of the organism’s cell types. These properties can be demonstrated in vitro where the progeny of the SCs is characterized by the expression of specific genes of a cell lineage. This process is called differentiation.

Thanks to the aforementioned two properties, SCs continually reconstitute the organism’s stock of cells. They assure the renewal of the cells, which have different lifecycles. While the intestine cell is renewed after 5 days and that of the retina after 10 days, other cells live longer, such as the red blood cell, which is renewed after 120 days, or the liver cell, which lives for approximately 400 days. The subject of cancerous cells will intentionally not be discussed in this book. Although they present an infinite multiplication, they do not, however, have the capacity to generate all of the tissues of the organism.

1.1.1 An infinite multiplication capacity: self-renewal

The future for SCs – self-renewal or differentiation – is determined through the process of cell division. SCs produce undifferentiated SCs or specialize into progenitor cells. This process is regulated by symmetric and asymmetric divisions. It depends on cell-intrinsic and cell-extrinsic factors, such as microenvironmental stimuli. It is then possible for the signals from a specific microenvironment to be able to control SC dynamics. For example, SCs with a wide differentiation potential exist in bone marrow. SCs are also located in the tissues or in niches that provide a specific cellular environment indispensable for unlimited renewal.

Symmetric division gives rise to two identical daughter cells possessing the properties of the SCs. Asymmetric division produces an SC and a progenitor cell with limited self-renewal potential. The progenitors can perpetuate several cycles of cell division before finally differentiating into a specialized cell. The molecular differences between symmetric and asymmetric division would be based on a differential selection of membrane proteins (receptors) between the daughter cells. The SC continuously generates daughter cells that are invariably identical to it and, in parallel, generates other daughter cells that have different, more restricted properties.

The capacities for self-renewal and specialization are inverse. The SC is not specialized and possesses maximum self-renewal capabilities. Through the process of differentiation, it produces the progenitors and then the precursors, which is the last step toward the production of the specialized cell. This differentiated cell has lost its self-renewal capability; however, its specificity is maximum.

SCs can differentiate into several cell types, and this broad range of differentiation orientations is called SC plasticity. They have the ability to move from one type of differentiated cell to another, that is, transdifferentiation.

Figure 1.1 Self-renewal of SCs and progenitor cells. Symmetric division produces two identical cells, whereas asymmetric division leads to two different cells. For a color version of this figure, see www.iste.co.uk/arrighi/stemcells.zip

1.1.2 A specialization ability: differentiation

The organism’s original SCs are present in the fertilized egg, also known as the zygote. The zygote is a cell resulting from the fusion of two gametes. At this first stage in development, the fertilized egg possesses all differentiation capacities. The cells, which compose it, are called totipotent, from the Latin totus, meaning everything. They are fit for everything in the sense that they have the ability to become a complete individual. They can form an embryo, as well as the placenta. The egg divides into two, four and then eight cells. After 4 days, the egg resembles a blackberry and hence this stage is named morula, meaning blackberry in Latin.

After 5–6 days, the embryo reaches the stage of blastocyst, from the Greek blastos, meaning ‘bud". It takes the form of a hollow ball and consists of approximately 200 cells. The peripheral cells, or trophectoderm, will form the placenta, necessary for embryonic implantation. Inside this ball are approximately 30 cells, from which more than 200 different cell types of the organism can develop. This internal cellular mass contains SCs that are pluripotent, from the Latin pluris, which means the most, in the