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Full summary trends in stem cell therapy
Full summary for the course trends in stem cell therapy (NWI-BM073) given in 2023 - Radboud University, Nijmegen
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Trends in Stem Cell Biology: EthicsEthical Theories – 06-09-2023
Introduction
Ethical subjectivism is the idea that moral opinions are based on our feelings and nothing more. On
this view, there is no such thing as “objective” right or wrong. Ethical theories explain what makes an
action right or wrong. The difference between ethical theories and particular ethical judgements can
be compared to the difference between scientific theories and observations. Ethics aren’t equal to
morals, nor law.
The different kinds of ethical theories are consequentialism, deontology, virtue ethics,
contractarianism, natural law and relativism.
Consequentialism
Consequentialism states that the rightness/wrongness of an action is determined by its
consequences. It can be subdivided into utilitarianism and ethical egoism.
In utilitarianism, the right action is the one that promotes the greatest happiness of the greatest
number (maximizes social utility). In ethical egoism, the right action is the one that promotes the
greatest happiness of the agent (maximizes the agent’s utility).
Deontology
Deontology states that the rightness/wrongness of an action is determined by inherent features of
the action itself, or by an inherently valid rule. If an action is of the wrong kind, it is forbidden, no
matter how good its consequences are. It rejects both utilitarianism and ethical egoism: the end
doesn’t justify the means. What makes an action right, is the fact that God commands it. An example
is Kantianism.
In Kantianism, the right actions must be universalizable and treat rational agents as ends, not mere
means. The universalizability means that it must be possible to will the principle of your action for
everybody without inconsistency. Lying violates universalizability because it presupposes and exploits
a general practice of telling the truth. One should not treat rational agents (others or yourself) as
mere objects to be used or exploited: personhood is the basis of ethical value and can’t be
subordinated to other values. One mustn’t sacrifice the few, even to benefit the many.
Virtue Ethics
Virtue ethics states that the rightness/wrongness of an action is determined by the character traits it
expresses; it emphasizes what kind of person you should be. Virtue-ethicists tend to side with
deontologists against consequentialists, as they both focus on what you should do, rather than the
result/outcome.
,Trends in Stem Cell Biology: Lecture 1
Pluripotency – 20-09-2023
Stem cells are biological cells that can differentiate into other types of cells and can divide to produce
more of the same type of stem cells (self-renewal). In mammals, there are two broad types of stem
cells: embryonic stem cells that are isolated from the inner cell mass of blastocysts and adult stem
cells. Embryonic stem cells can form the whole organism, meaning that they are pluripotent. Adult
stem cells can only divide into certain types of cell (e.g. kidney stem cells can only form kidney cells).
Different Forms of Cell Potency During Development in Vivo
During embryonic development, the cells lose potency. The ICM stage already contains two defined,
irreversible cell populations. The inner cell mass cells are unable to form the placenta anymore.
During gastrulation, the 2nd lineage decision is made: the cells differentiate into ectoderm, endoderm
or mesoderm. During further differentiation, about 200 cell types emerge.
Trophoblast and inner cell mass are totipotent. Embryonic stem cells are pluripotent, meaning that
they are capable of differentiation into all three germ layers
(ecto-, endo- and mesoderm), but not the placenta. Adult
stem cells can either be multipotent (progenitor cells, e.g.
haematopoietic stem cells), oligopotent (e.g. myeloid stem
cells, not lymphoid lineage) or unipotent (differentiate into
one cell only).
Reprogramming and trans-differentiation have been
developed in vitro, but are likely not widespread in vivo.
The canalisation of development is not dependent on
genetic factors, but is dependent on epigenetic factors
instead. Cells lose potency during in vivo development.
Different Pluripotent Cells in Vivo
The three types of pluripotent mouse cells are
embryonic stem cells (ESC), epiblast-derived
stem cells (EpiSC) and embryonic germ cells
(EGCs).
The different types of in vitro pluripotent cells are embryonic stem cells (ESCs), epiblast stem cells
(EpiSCs; primed ES cells), embryonal carcinoma cells (ECs), embryonic germ cells (EGCs), induced
pluripotent stem cells (iPSCs). Pluripotency is transient in the embryo. Embryonic stem cells are a
culture phenomenon.
Testing for pluripotency for newly derived cell lines from mice are multilineage differentiation in
vitro/vivo (germline colonization), extensive proliferation in vitro under well-defined culture
conditions or through the use of known marker genes/proteins (Oct4, Nanog, Sox2, SSEA, etc.). In
, practice, absolute proof of pluripotency is the ability to contribute to all somatic lineages/produce
germ line (chimerism) or the ability to form teratomas (germ cell tumour).
Testing for pluripotency for newly derived cell lines from humans can be done through multilineage
differentiation in vitro, in a process called germline colonization (not in vivo). Pluripotency is also
characterized by a normal, stable karyotype and an extensive proliferation in vitro under well-defined
culture conditions. They can also be tested with known marker genes/proteins (Oct4, Nanog, Sox2,
SSEA, etc.). In practice, absolute proof of pluripotency in human cells is the ability to form teratomas
with differentiated cells of all three germ layers (contribution to all somatic lineages/produce germ
line does not give absolute proof of pluripotency).
In conclusion, embryonic stem cells, like some other in vitro cultured cells, are pluripotent.
Application of Embryonic Stem (ES) Cells
Embryonic stem cells are pluripotent and are capable of self-renewal. They can be used for
embryonic development models (e.g. regenerative medicine, generation of KO mouse, disease
models and cytotoxicity tests). However, there are ethical concerns (e.g. can we use human ESCs?
Are human embryonic stem cells human beings with full moral status).
Replacement of lost cells might be useful in cases of
• Stroke (heart attack) -> loss of muscle cells
• Duchenne muscular dystrophy -> muscle degeneration (eventual death)
• Parkinson’s disease -> loss of dopamine-generating cells in the substantia nigra, a region of
the midbrain
• Alzheimer
The dangers to stem cell therapies are graft rejection (doesn’t happen when the cells are from the
patient itself; e.g. from cord blood), graft-versus-host reactions or teratocarcinoma. ES cells are very
useful for regenerative medicine and to study embryonic development.
Molecular Mechanisms to Maintain Pluripotency
As mentioned before, embryonic stem cells are pluripotent and are capable of (clonal) self-renewal.
Pluripotency is transient in the embryo, ESCs are a culture phenomenon and they are primed to
differentiate due to autocrine FGF4. The different ways to inhibit differentiation in vitro are the
addition of feeders + serum, the addition of Lif + serum or the addition of 2i (+ LIF).
The pluripotency network acts to self-induce its own expression (and of other pluripotency genes),
by binding in the promoter and to repress
genes that induce differentiation.
Oct4/Nanog/Sox2 also mediate enhancers.
TF ESC overexpression ESC loss of function Embryo null
Oct4 Differentiation Differentiation to ICM becomes
trophoblast trophectoderm
Sox2 May reduce differentiation Differentiation to Early post implantation
trophoblast; rescued by Oct4 lethal
Nanog Autonomous self-renewal Prone to differentiate, but Loss of epiblast and
can self-renew secondarily of hypoblast
Stat3 Hormone-activatable No self-renewal in LIF, but Post gastrulation lethal
fusion substitutes for LIF maintained in 2i
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