Chapter 8 Stem cells and differentiation
Stem cells and differentiation
What is a stem cell?
• Ability to divide (self replicate) for indefinite periods → self renewal
• Ability to differentiate to many different cell types upon different signals →
pluripotency
Differentiation: the process whereby stem cells become specialized to
perform a particular function
During cell division a stem cell can asymmetrically divided to become
stem cell or more differentiated cell
All cells contain full complement of genes (46 chromosomes) except red
blood cells and germ cells.
But all the cells differ in expression of genes (mRNA and protein)
The fate of the cell is determined by lineage-specific transcription factors and
epigenetic mechanisms
Epigenetic mechanisms regulation self-renewal and differentiation
Epigenetic mechanisms – these modifications affect transcriptional regulation – they
are reversible and thus not very stable
• Transcription factors
• DNA methylation; relative stable modification
• Histone modification
• Chromatin openness
Reversibility:
• Stem cells (open chromatin structure) →
differentiated cells (close chromatin structure) by
differentiation
• Differentiated cells (close chromatin structure) →
stem cells (open chromatin structure) by
reprogramming (transformation)
Different kind of stem cells and how to make them
1. Totipotent stem cells: can create everything needed to make a baby
(extraembryonic membranes and tissues, embryo itself and all postembryonic
tissues and organs) (blastomere (zygote))
2. Pluripotent stem cells: capability of developing cells of all germ layers
(endoderm, ectoderm and mesoderm) (inner cell mass (blastocyst))
3. Multipotent stem cells: give rise to cells that have a function dependent of the
embryonic germ layer they derived from (adult stem cells)
4. Unipotent stem cells: can only make more of itself
, 2 types of stem cells:
1. Embryonic stem cells – they are pluripotent – indefinite self-
renewal
Embryonic stem cells of the inner cell mass are able to
differentiate to generate primitive ectoderm which
differentiate during gastrulation into endoderm, ectoderm and
mesoderm
2. Adult stem cells – they are multipotent – limited self-renewal
They are present in every tissue and involved in regeneration
of these tissues.
Examples: hematopoietic stem cells (in the bone marrow), hair follicle stem
cells, breast stem cells and intestinal stem cells
These can be used for stem cell therapy – replace the damaged
tissue. Already proven useful: bone marrow transplantation, skin
injury, stroke, heart attack, neurodegenerative diseases and
diabetes
How to get pluripotent stem cells (embryonic stem cells) used for
therapy?
• Use embryonic stem (ES) cells; derived from inner cell
mass – but people don’t want to use them because it is a
human
• From induced pluripotent stem (iPS) cells you get pluripotent
stem cells; add reprogramming factors (Yamanaka factors)
(Oct3/4, Sox2, Klf4 and c-Myc) to mature differentiated cell to
reprogram it to induced pluripotent stem cells. From iPS they
differentiated into various cells of the body
• From nuclear transfer embryonic stem (NT-ES) cells you get
pluripotent stem cells; needed a cytoplasmic donor with enucleated cell
(enuclated oocyte) and a nuclear donor (somatic donor cell). The egg
cell and the DNA are brought together. And is injected in a third animal
which carry the blastocyst which is formed. From this inner cell mass is
taken and this is pluripotent stem cells
Cancer cells with self-renewal capacity: cancer stem cells
More self-renewal than differentiation: cancer
Balance between self-renewal and differentiation: tissue
homeostasis
More differentiation than self-renewal: tissue aging/degeneration
How can cancer cells have more self-renewal?
1. Aberrant expression of (mutated) genes induce stem cell features
2. The initial/founder hit (driver mutation) is in a stem cell. Tumor has inherited
the stem cell state/features of the cell of origin
3. Microenvironment imposes stem cells features onto the cancer cells
Stem cells and differentiation
What is a stem cell?
• Ability to divide (self replicate) for indefinite periods → self renewal
• Ability to differentiate to many different cell types upon different signals →
pluripotency
Differentiation: the process whereby stem cells become specialized to
perform a particular function
During cell division a stem cell can asymmetrically divided to become
stem cell or more differentiated cell
All cells contain full complement of genes (46 chromosomes) except red
blood cells and germ cells.
But all the cells differ in expression of genes (mRNA and protein)
The fate of the cell is determined by lineage-specific transcription factors and
epigenetic mechanisms
Epigenetic mechanisms regulation self-renewal and differentiation
Epigenetic mechanisms – these modifications affect transcriptional regulation – they
are reversible and thus not very stable
• Transcription factors
• DNA methylation; relative stable modification
• Histone modification
• Chromatin openness
Reversibility:
• Stem cells (open chromatin structure) →
differentiated cells (close chromatin structure) by
differentiation
• Differentiated cells (close chromatin structure) →
stem cells (open chromatin structure) by
reprogramming (transformation)
Different kind of stem cells and how to make them
1. Totipotent stem cells: can create everything needed to make a baby
(extraembryonic membranes and tissues, embryo itself and all postembryonic
tissues and organs) (blastomere (zygote))
2. Pluripotent stem cells: capability of developing cells of all germ layers
(endoderm, ectoderm and mesoderm) (inner cell mass (blastocyst))
3. Multipotent stem cells: give rise to cells that have a function dependent of the
embryonic germ layer they derived from (adult stem cells)
4. Unipotent stem cells: can only make more of itself
, 2 types of stem cells:
1. Embryonic stem cells – they are pluripotent – indefinite self-
renewal
Embryonic stem cells of the inner cell mass are able to
differentiate to generate primitive ectoderm which
differentiate during gastrulation into endoderm, ectoderm and
mesoderm
2. Adult stem cells – they are multipotent – limited self-renewal
They are present in every tissue and involved in regeneration
of these tissues.
Examples: hematopoietic stem cells (in the bone marrow), hair follicle stem
cells, breast stem cells and intestinal stem cells
These can be used for stem cell therapy – replace the damaged
tissue. Already proven useful: bone marrow transplantation, skin
injury, stroke, heart attack, neurodegenerative diseases and
diabetes
How to get pluripotent stem cells (embryonic stem cells) used for
therapy?
• Use embryonic stem (ES) cells; derived from inner cell
mass – but people don’t want to use them because it is a
human
• From induced pluripotent stem (iPS) cells you get pluripotent
stem cells; add reprogramming factors (Yamanaka factors)
(Oct3/4, Sox2, Klf4 and c-Myc) to mature differentiated cell to
reprogram it to induced pluripotent stem cells. From iPS they
differentiated into various cells of the body
• From nuclear transfer embryonic stem (NT-ES) cells you get
pluripotent stem cells; needed a cytoplasmic donor with enucleated cell
(enuclated oocyte) and a nuclear donor (somatic donor cell). The egg
cell and the DNA are brought together. And is injected in a third animal
which carry the blastocyst which is formed. From this inner cell mass is
taken and this is pluripotent stem cells
Cancer cells with self-renewal capacity: cancer stem cells
More self-renewal than differentiation: cancer
Balance between self-renewal and differentiation: tissue
homeostasis
More differentiation than self-renewal: tissue aging/degeneration
How can cancer cells have more self-renewal?
1. Aberrant expression of (mutated) genes induce stem cell features
2. The initial/founder hit (driver mutation) is in a stem cell. Tumor has inherited
the stem cell state/features of the cell of origin
3. Microenvironment imposes stem cells features onto the cancer cells
