Essential Current Concepts in Stem Cell Biology

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Editor
Beate Brand-Saberi
Department of Anatomy & Molecular Embryology, Ruhr-University
Bochum, Bochum, Nordrhein-Westfalen, Germany

ISSN 2509-6125 e-ISSN 2509-6133

Learning Materials in Biosciences
ISBN 978-3-030-33922-7 e-ISBN 978-3-030-33923-4
https://doi.org/10.1007/978-3-030-33923-4

© Springer Nature Switzerland AG 2020

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Preface
Over the past two decades, stem cell research has exploded:
Publications have multiplied exponentially.
The path of ground-breaking findings and innovative molecular
approaches was paved with Nobel prizes. Mentioning only a few, the
derivation of embryonic stem cells by Sir Martin Evans (Nobel Prize
together with Professors Carpecchi and Smithies in 2007) is an
outstanding example for a mutual fertilization of interdisciplinary
approaches, in this case derived from developmental biology and
pathology. The traditional concept of a one-way track regarding the
developmental potencies during embryonic development of cells was
challenged in the late 1960s by Sir John Gurdon’s nuclear transfer
experiments and eventually revolutionized by Yamanaka’s pluripotency
induction with defined factors (Nobel Prize Professor John Gurdon and
Professor Shinya Yamanaka in 2012).
Clearly, stem cell biology belongs to the most innovative and
competitive research fields. What is more, it has combined different
disciplines in a unique way: Molecular and morphological basic
sciences have met with clinical approaches, material sciences and
philosophy. Reality has overtaken our imagination once more so rapidly
that most of us almost forgot about implementing structured modern
approaches to teach stem cell biology.
To date, there are still only very few textbooks addressing stem cell
biology and none of them is as comprehensive as the present one. This
book has been written by scientists who have been involved in teaching
the students of the international master program –Molecular and
Developmental Stem Cell Biology – which was launched at Ruhr
University Bochum in 2011 and has been running with great success
since then. I am very grateful to all the contributors to this textbook for
their great efforts and dedication to their roles as academic teachers in
spite of their competitive research projects. Our authors from Tongji
University were involved in the ISAP (Internationale Studien- und
Ausbildungspartnerschaften) exchange program supported by the
DAAD between 2012 and 2016. It was not easy for all contributors to
spare the time for writing down their valuable experience and
recommendations in textbook chapters. So thank you again to all of
them!
This book will be helpul to all those who strive to get into this
important transdisciplinary research topic, be it master students, PhD
students, MD students, postdocs or clinicians. However, as you will see,
there is still some work for you to do: The book is not only intended for
learning facts, but also for contemplating the white patches in the
mosaic of our growing knowledge. Importantly, the chapters included
here reveal that stem cell biology is rapidly expanding towards
translational medical approaches, but they also address the challenges
to be overcome for future progress. iPSCs, MSC, organoids, regeneration
using scaffolds, extracellular vesicles, disease modelling and in depth
knowledge of the multiple interacting cell types composing the tissues
in our bodies are fascinating still developing aspects of stem cell
biology written by experts in the field to be included into this volume. I
personally hope that the book will contribute to an unbiassed
interdisciplinary (and international) academic dialogue in this field. As
stem cell research is often being perceived either with inappropriate
hype, hope or simplistic damnation in public, a chapter on bioethics has
been included as an integral part of learning about stem cells.
My thanks are due to my colleague PD Dr. Holm Zaehres for his kind
advice, support and encouragement during the assembly of the
chapters and final stages of this book. I would also like to express my
gratitude to Dr. Amrei Strehl of the Springer Nature team and to Bibhuti
Sharma of the publishing team for their constructive support and
extraordinary patience. Finally and importantly, I wish to thank my
family for their understanding and support.
Beate Brand-Saberi
Bochum, Germany
August 2019
Abbreviations
ATMP Advanced Therapy Medicinal Products
BM MSC Bone marrow mesenchymal/multipotent stromal cells
CB MSC Cord blood mesenchymal/multipotent stromal cells
CB Cord blood
CB-SC Cord blood stromal cells
CD Cluster of differentiation
C-MET MET or MNNG HOS Transforming gene
CPD Cumulative population doubling
DCBT Double cord blood transplantation
DLK-1 Delta-like 1 homologue
DMEM Dulbecco’s Modified Eagle Medium
ECFC Endothelial cord forming cell
EPC Endothelial progenitor cell
ESC Embryonic Stem Cells
FACS Fluorescence-activated cell sorting
FCS Fetal calf serum
FGF Fibroblast growth factor
FLT3LG Fms-related tyrosine kinase 3 ligand
GMP Good manufacturing practice
GvHD Graft-versus-host-disease
HOX Homeobox
HPP-CFC High Proliferative Potential-Colony Forming Cell
HSC Hematopoietic stem cells
IL-6 Interleukin 6
iPSC Induced pluripotent stem cells
LTC-IC Long Term Culture-Initiating cell
MNC Mononuclear cells
MSC Mesenchymal/multipotent stromal cells
NC Nucleated cells
NOD/SCID non-obese diabetic/severe combined immunodeficiency
OC Osteocalcin
OCT4A Octamer binding transcription factor 4
OSX (SP7) Osterix
Runx2 Runt domain –containing transcription factor 2
SCF Stem cell factor
SCID Severe combined immunodeficiency
SDF-1 Stromal cell-derived factor 1
SRC SCID- repopulating cells
TPO Thrombopoietin
UC MSC Umbilical cord mesenchymal stromal cells
USSC Unrestricted somatic stromal cells
Contents
1 Hematopoietic Stem Cells
Hannes Klump
2 Mesenchymal Stem Cells
Christian Horst Tonk, Markus Witzler, Margit Schulze and
Edda Tobiasch
3 Cord Blood Stem Cells
Gesine Kogler
4 Neural Stem Cells and Their Niche
Jacqueline Reinhard, Lars Roll, Ursula Theocharidis and
Andreas Faissner
5 Skeletal Muscle Stem Cells
Beate Brand-Saberi and Eric Bekoe Offei
6 Heart Muscle Tissue Engineering
Michelle Coffee, Santoshi Biswanath, Emiliano Bolesani and
Robert Zweigerdt
7 Induced Pluripotent Stem Cells
Holm Zaehres
8 Epigenetics of Somatic Cell Reprogramming
Yixuan Wang, Jianfeng Zhou and Shaorong Gao
9 Human Pluripotent Stem Cells and Neural Regeneration
Xiaoqing Zhang
10 Dopaminergic Neuron-Related Stem Cells
Chengzhong Wang and Yu-Qiang Ding
11 Liver Disease Modelling
Nina Graffmann, Lucas-Sebastian Spitzhorn, Audrey Ncube,
Wasco Wruck and James Adjaye
12 Organoids in Developmental Biology Research and Application
Tobias Cantz
13 Extracellular Vesicles
André Gö rgens and Bernd Giebel
14 Ethics in Stem Cell Applications
Michael Fuchs
Contributors
James Adjaye
Institute for Stem Cell Research and Regenerative Medicine, Heinrich
Heine University Dü sseldorf, Medical Faculty, Dü sseldorf, Germany
[email protected]

Santoshi Biswanath
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery
(HTTG) Leibniz Research Laboratories for Biotechnology and Artificial
Organs (LEBAO), Hannover Medical School (MHH), Hannover, Germany
[email protected]

Emiliano Bolesani
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery
(HTTG)Leibniz Research Laboratories for Biotechnology and Artificial
Organs (LEBAO), Hannover Medical School (MHH), Hannover, Germany
[email protected]

Beate Brand-Saberi
Department of Anatomy and Molecular Embryology, Institute of
Anatomy, Ruhr-University Bochum, Bochum, Germany
[email protected]

Tobias Cantz
Research Group Translational Hepatology and Stem Cell Biology,
Department of Gastroenterology, Hepatology and Endocrinology,
Hannover Medical School, Hannover, Germany
[email protected]

Michelle Coffee
Department of Cardiac, Thoracic, Transplantation and Vascular Surgery
(HTTG)Leibniz Research Laboratories for Biotechnology and Artificial
Organs (LEBAO), Hannover Medical School (MHH), Hannover, Germany
[email protected]

Yu-Qiang Ding
Key Laboratory of Arrhythmias, Ministry of Education of China, East
HospitalDepartment of Anatomy and Neurobiology Tongji University
School of Medicine, Shanghai, China
Institutes of Brain Sciences, State Key Laboratory of Medical
Neurobiology, and Department of Laboratory Animal Science, Fudan
University, Shanghai, China
[email protected]

Andreas Faissner
Department of Cell Morphology and Molecular Neurobiology, Faculty of
Biology and Biotechnology, Ruhr-University Bochum, Bochum,
Germany
[email protected]

Michael Fuchs
Department of Practical Philosophy and Ethics, Catholic Private
University Linz, Linz, Austria
[email protected]

Shaorong Gao
Tongji University, School of Life Sciences and Technology, Shanghai,
China
[email protected]

Bernd Giebel
Institute for Transfusion Medicine, University Hospital Essen,
University of Duisburg-Essen, Essen, Germany
[email protected]

André Görgens
Institute for Transfusion Medicine, University Hospital Essen,
University of Duisburg-Essen, Essen, Germany
Clinical Research Center, Department of Laboratory Medicine,
Karolinska Institutet, Stockholm, Sweden
[email protected]

Nina Graffmann
Institute for Stem Cell Research and Regenerative Medicine, Heinrich
Heine University Dü sseldorf, Medical Faculty, Dü sseldorf, Germany

Hannes Klump
Institute for Transfusion Medicine University Hospital Essen,
Virchowstrasse, Essen, Germany
[email protected]

Gesine Kogler
Heinrich-Heine-University, Medical Faculty Institute for
Transplantation Diagnostics and Cell Therapeutics, Dü sseldorf,
Germany
University Medical Clinic, Dü sseldorf, Germany
[email protected]

Audrey Ncube
Institute for Stem Cell Research and Regenerative Medicine, Heinrich
Heine University Dü sseldorf, Medical Faculty, Dü sseldorf, Germany

Eric Bekoe Offei

Department of Anatomy and Molecular Embryology, Institute of
Anatomy, Ruhr University Bochum, Bochum, Germany
School of Veterinary Medicine University of Ghana, Accra, Ghana

Jacqueline Reinhard
Department of Cell Morphology and Molecular Neurobiology, Faculty of
Biology and Biotechnology, Ruhr-University Bochum, Bochum,
Germany

Lars Roll
Department of Cell Morphology and Molecular Neurobiology, Faculty of
Biology and Biotechnology, Ruhr-University Bochum, Bochum,
Germany

Margit Schulze
Hochschule Bonn-Rhein-Sieg, Tissue Engineering, Sankt Augustin,
Germany
Lucas-Sebastian Spitzhorn
Institute for Stem Cell Research and Regenerative Medicine, Heinrich
Heine University Dü sseldorf, Medical Faculty, Dü sseldorf, Germany

Ursula Theocharidis
Department of Cell Morphology and Molecular Neurobiology, Faculty of
Biology and Biotechnology, Ruhr-University Bochum, Bochum,
Germany

Edda Tobiasch
Hochschule Bonn-Rhein-Sieg, Tissue Engineering, Sankt Augustin,
Germany
[email protected]

Christian Horst Tonk

Hochschule Bonn-Rhein-Sieg, Tissue Engineering, Sankt Augustin,
Germany

Chengzhong Wang
Mitokinin Incorporation, San Francisco, CA, USA
[email protected]

Yixuan Wang
Tongji University, School of Life Sciences and Technology, Shanghai,
China

Markus Witzler
Hochschule Bonn-Rhein-Sieg, Tissue Engineering, Sankt Augustin,
Germany

Wasco Wruck
Institute for Stem Cell Research and Regenerative Medicine, Heinrich
Heine University Dü sseldorf, Medical Faculty, Dü sseldorf, Germany

Holm Zaehres
Department of Anatomy and Molecular Embryology, Institute of
Anatomy Ruhr University Bochum, Bochum, Germany
Department of Cell and Developmental Biology, Max Planck Institute for
Molecular Biomedicine, Mü nster, Germany
[email protected]

Xiaoqing Zhang
Tongji University School of Medicine Tongji University, Shanghai, China
[email protected]

Jianfeng Zhou
Tongji University, School of Life Sciences and Technology, Shanghai,
China

Robert Zweigerdt
Department of Cardiac, Thoracic Transplantation and Vascular Surgery
(HTTG) Leibniz Research Laboratories for Biotechnology and Artificial
Organs (LEBAO) Hannover Medical School (MHH), Hannover, Germany
[email protected]
© Springer Nature Switzerland AG 2020
B. Brand-Saberi (ed.), Essential Current Concepts in Stem Cell Biology, Learning Materials in
Biosciences
https://doi.org/10.1007/978-3-030-33923-4_1

1. Hematopoietic Stem Cells

Hannes Klump1

(1) Institute for Transfusion Medicine, University Hospital Essen,

Virchowstrasse, Essen, Germany

Hannes Klump
Email: [email protected]

1.1 The Discovery of Hematopoietic Stem Cells

1.2 How to Detect Multipotent Hematopoietic Stem Cells
1.3 Prospective Isolation of HSCs
1.4 Development of HSCs in the Embryo
1.5 Clinical Use of HSCs
1.6 Gene Therapy of HSCs
1.7 Derivation of Patient-Specific, Tailored HSCs Derived from
Pluripotent Stem Cells
References

What You Will Learn in This Chapter

Multipotent, hematopoietic stem cells (HSCs) as central
organizers of blood cell production are the longest and probably
best-known stem cell entity. In this chapter you will first receive
a brief introduction into the genesis of the stem cell theory of
hematopoiesis. You will learn which in vitro and in vivo assays
can be performed to detect HSCs as well as their gradually
differentiating descendants, and what their individual
informative value is. After a short focus on when and where they
 develop during ontogenesis and some of the molecular cues
involved in their generation, we will get back to adult
hematopoietic stem and progenitor cells and discuss their use
for organ replacement therapy in the clinical setting. Because
gene therapy of patients was first implemented in the
hematopoietic system, you will learn about the current status of
this rapidly evolving field. In the last paragraph, the future
prospect of regenerative medicine based on de novo generated,
patient-tailored, autologous HSCs derived from induced,
pluripotent stem cells will be briefly discussed.

1.1 The Discovery of Hematopoietic Stem Cells

First evidence for their existence arose as a consequence from the
experience with persons in whom a complete failure of blood formation
was observed after exposure to lethal doses of ionizing radiation when
the atomic bombs at the end of World War II were dropped (Keller
1946). In animal experiments, two research groups found that
intravenously transfused bone marrow or spleen cells from a healthy
animal were able to rescue lethally irradiated animals by restoring
blood formation for a life-time (Jacobson et al. 1951; Lorenz et al.
1951). A series of ground breaking experiments performed by James
Till, Ernest McCulloch and coworkers showed that hematopoiesis is
organized by cell clones which exist in the bone marrow, which can
expand (i.e. make more of themselves) and are capable to generate
myeloid, erythroid as well as lymphoid colonies in spleens after
transplantation, so-called colony forming units-spleen (CFU-S) (◘ Fig.
1.1) (Till and McCulloch 1961; Becker et al. 1963; Wu et al. 1968) (Free
access to some of the historical references can be found at the
University of Toronto Website: ► https://​tspace.​library.​utoronto.​ca/​
handle/​1807/​2326). After transplantation, spleen colonies were
observed between day 7 and day 12. However, the later colonies
showed a different cellular composition than those observed earlier:
the early colonies mainly contained myeloerythroid cells derived from a
transplanted cell with limited potency, a lineage-restricted,
myeloerythroid progenitor, whereas the later colonies also contained
lymphoid cells. Years later, using highly purified cell fractions, it was