Advanced Human Disease Model Technologies
Lecture 1 – Introduction
The goal of aging research is to extend human healthspan. Left panel shows average human
lifespan (black line) and the rate of disease onset (red line). Delaying age-dependent diseases
(dashed red line) would improve healthy aging (dashed green line). Right panel depicts disease
free time (healthspan) and the problem of co-morbidities at the end of life for the average
human population and centenarians. Eliminating one disease will only slightly increase
healthspan because of other age-dependent diseases.
1. Ageing: hallmarks
Study ageing:
- In vitro > mimic ageing cells
- Population studies
- Cellular models vs animal models (yeast, worms, flies, mice, mole rat, monkey, whale)
First stroke activates anti-apoptotic proteins, reducing the effect of the second stroke.
Mice and rats do not get Alzheimer’s > induce Alzheimer’s with genes (5% familial vs 95%
sporadic)
2. Lung diseases
3. Brain diseases
Disease Freq US Genetic Patho-physio Neurochem
Parkinson’s 500k Low Nigrostriatal DA
Alzheimer’s 5.4m Moderate Diffuse cortex ACh?
Huntington’s 30k High Striatum ?
ALS 25k low Motor neurons Glut?
,Familial AD can be studied well on animal models
Mice: huge neuronal loss, as happens in humans
D. melanogaster: brain, behaviour, and plaques/tangles are very different in. However, the
APP effect can be studied good.
C elegans: brain anatomy, behaviour, tangles/plaque are not similar.
Stem cells:
Cells are the basic functional unit of the human body. Cells have different functions,
specialize/differentiate. Many diseases are caused by breakdown in cells. Cells are alive but
damaged (cancer, heart failure), or cells die and are lost (Parkinson’s).
Stem cells are cells that divide and provide to make more stem cells or become specialized.
They are promising because raw material can replace damaged cells/organs, they are tools to
understand the disease, and they are tools to test and develop new drugs.
Sourced of stem cells:
- Adult/tissue/foetal cord blood/amniotic (skin stem cells, heart/brain tissue,
Mesenchymal stem cells/bone, cartilage)
- Embryonic (fertilization in vitro)
- Reprogrammed (iPSC)
Every second, 15 million blood cells die, and are replaced in the human body.
,Stem cells are special types of cells that can develop or differentiate into more specialized cells
with specific functions. In many tissues, stem cells serve to replenish/replace damaged cells
that no longer function adequately. The two unique characteristics that define stem cells are
their ability to self-renew or replicate while maintaining the undifferentiated ‘stem’ state, and
their potency or capability to differentiate into specialized cell types.
4 levels of stem cell potency:
1. Totipotency: a cell has the ability to produce all of the differentiated cells in an organism
2. Pluripotency: a cell has the ability to differentiate into cells of any of the three germ
layers (endoderm, ectoderm, mesoderm)
3. Multipotency: a cell can differentiate into multiple cell types of the same lineage
4. Unipotentcy: cells can differentiate into only one cell type
BELANGRIJK^
, Classification of stem cells:
1. Embryonic stem cells: pluripotent, able to form all adult cell types, obtained from the
inner cell mass (ICM) of a 5-6 day old human blastocyst
2. Adult stem cells / somatic stem cells (ASCs): multipotent, located in small quantities in
specific ‘stem cell niches’ found in many organs in the adult human body. Generate
specialized cells for their location, mostly to maintain cell numbers or replenish dying
cells
3. Induced pluripotent stem cells (iPSCs): obtained by reprogramming differentiated adult
cells by the ectopic expression of four embryonic genes – OCT4, SOX2, KLF4, and C-
MYC. First generated from mouse fibroblasts in 2006 in Shinya Yamanaka’s lab, where
the reprogramming factors were delivered via retroviral infection.
Immune reactions can come up with transplantation (rejection), higher chance in ESC and
lower chance in ASC.
Generating iPSCs: iPSCs have
- High self-renewal rate
- Can be used universally to generate many adult cell types
- Can differentiate in vitro into derivatives of all three germ layers, form embryoid bodies,
and form teratomas
iPSCs also possess similar similar morphologies, growth properties, and express stem cell
markers similar to ESCs.
Somatic cell conversion:
- Conversion via iPSC formation > reprogramming
- Direct conversion from one somatic cell type to another > transdifferentiation
Stem cells are very young, however you want to study aged cells. Somehow, the cells should
be treated to be ‘aged’, however this is difficult.
iPSCs have increasingly become the ideal experimental system for research in regenerative
medicine over the last decade. ESC are hard to extract, and therefore less suitable.
Lecture 1 – Introduction
The goal of aging research is to extend human healthspan. Left panel shows average human
lifespan (black line) and the rate of disease onset (red line). Delaying age-dependent diseases
(dashed red line) would improve healthy aging (dashed green line). Right panel depicts disease
free time (healthspan) and the problem of co-morbidities at the end of life for the average
human population and centenarians. Eliminating one disease will only slightly increase
healthspan because of other age-dependent diseases.
1. Ageing: hallmarks
Study ageing:
- In vitro > mimic ageing cells
- Population studies
- Cellular models vs animal models (yeast, worms, flies, mice, mole rat, monkey, whale)
First stroke activates anti-apoptotic proteins, reducing the effect of the second stroke.
Mice and rats do not get Alzheimer’s > induce Alzheimer’s with genes (5% familial vs 95%
sporadic)
2. Lung diseases
3. Brain diseases
Disease Freq US Genetic Patho-physio Neurochem
Parkinson’s 500k Low Nigrostriatal DA
Alzheimer’s 5.4m Moderate Diffuse cortex ACh?
Huntington’s 30k High Striatum ?
ALS 25k low Motor neurons Glut?
,Familial AD can be studied well on animal models
Mice: huge neuronal loss, as happens in humans
D. melanogaster: brain, behaviour, and plaques/tangles are very different in. However, the
APP effect can be studied good.
C elegans: brain anatomy, behaviour, tangles/plaque are not similar.
Stem cells:
Cells are the basic functional unit of the human body. Cells have different functions,
specialize/differentiate. Many diseases are caused by breakdown in cells. Cells are alive but
damaged (cancer, heart failure), or cells die and are lost (Parkinson’s).
Stem cells are cells that divide and provide to make more stem cells or become specialized.
They are promising because raw material can replace damaged cells/organs, they are tools to
understand the disease, and they are tools to test and develop new drugs.
Sourced of stem cells:
- Adult/tissue/foetal cord blood/amniotic (skin stem cells, heart/brain tissue,
Mesenchymal stem cells/bone, cartilage)
- Embryonic (fertilization in vitro)
- Reprogrammed (iPSC)
Every second, 15 million blood cells die, and are replaced in the human body.
,Stem cells are special types of cells that can develop or differentiate into more specialized cells
with specific functions. In many tissues, stem cells serve to replenish/replace damaged cells
that no longer function adequately. The two unique characteristics that define stem cells are
their ability to self-renew or replicate while maintaining the undifferentiated ‘stem’ state, and
their potency or capability to differentiate into specialized cell types.
4 levels of stem cell potency:
1. Totipotency: a cell has the ability to produce all of the differentiated cells in an organism
2. Pluripotency: a cell has the ability to differentiate into cells of any of the three germ
layers (endoderm, ectoderm, mesoderm)
3. Multipotency: a cell can differentiate into multiple cell types of the same lineage
4. Unipotentcy: cells can differentiate into only one cell type
BELANGRIJK^
, Classification of stem cells:
1. Embryonic stem cells: pluripotent, able to form all adult cell types, obtained from the
inner cell mass (ICM) of a 5-6 day old human blastocyst
2. Adult stem cells / somatic stem cells (ASCs): multipotent, located in small quantities in
specific ‘stem cell niches’ found in many organs in the adult human body. Generate
specialized cells for their location, mostly to maintain cell numbers or replenish dying
cells
3. Induced pluripotent stem cells (iPSCs): obtained by reprogramming differentiated adult
cells by the ectopic expression of four embryonic genes – OCT4, SOX2, KLF4, and C-
MYC. First generated from mouse fibroblasts in 2006 in Shinya Yamanaka’s lab, where
the reprogramming factors were delivered via retroviral infection.
Immune reactions can come up with transplantation (rejection), higher chance in ESC and
lower chance in ASC.
Generating iPSCs: iPSCs have
- High self-renewal rate
- Can be used universally to generate many adult cell types
- Can differentiate in vitro into derivatives of all three germ layers, form embryoid bodies,
and form teratomas
iPSCs also possess similar similar morphologies, growth properties, and express stem cell
markers similar to ESCs.
Somatic cell conversion:
- Conversion via iPSC formation > reprogramming
- Direct conversion from one somatic cell type to another > transdifferentiation
Stem cells are very young, however you want to study aged cells. Somehow, the cells should
be treated to be ‘aged’, however this is difficult.
iPSCs have increasingly become the ideal experimental system for research in regenerative
medicine over the last decade. ESC are hard to extract, and therefore less suitable.
