Physiology of Regeneration · realtime PCR (Heatmap builder) Pluripotency Epiblast Germ-line...
Transcript of Physiology of Regeneration · realtime PCR (Heatmap builder) Pluripotency Epiblast Germ-line...
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Physiology of Regeneration
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Topics:
• Stem cell biology
• Sources of stem cells for regenerative medicine
– embryonic and nonembryonic
• Pluripotent stem cells
• Very Small Embryonic Like Stem Cells (VSELs)
isolated from the adult tissues
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Right concept – Wrong design……
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DREAMS
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People always dreamed to achieve
longevity, but….
-Ambrosia is a food
of gods and not of
ordinary people,
- Holly Grail was
never found by
Knights of Templar,
and…
?
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Lucas Cranach (The Elder) (1546)
The Fountain of Youth….
- a legendary spring that restores the youth of anyone who
drinks of its waters
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Olive Tree
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Urodels - Salamander
blastema
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Why we do not regenerate like
salamander?
• Regeneration – risk of tumorogenesis?
• Different philosophy to adjust to the
environment ?
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• Longevity = Regeneration = Stem Cell Renewal
• Senescence = Decrease in Regeneration =
Decrease in number/function of Stem Cells?
Would Stem Cells become our Ambrosia?
I want
Ambrosia !!!!
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We are regenerating ourselves
continuously
• Intestine epithelium – 2 days
• Epidermis – 14 days
• Erythrocytes – 150 days
• Leucocytes – 4-7 days
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1. Turtle 188 years
2. Human 122 years
3. Sturgeon ~ 100 years
4. Wale fish ~ 80 years
5. Elephant 77 years
Longevity records:
Jeanne Louise Calment
Tui Malila
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Clinical applications of stem cells
• Currently:
• Hematopoietic Stem Cells
• Epidermal Stem Cells
• Mesenchymal Stroma Cells
• New potential applications:
• Heart Infarct
• Stroke
• Parkinson's disease
• Spinal cord injuries
• Diabetes
• Myopathies
• Liver damage
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Clinical applications of stem cells
• Currently:
• Hematopoietic Stem Cells
• Epidermal Stem Cells
• Mesenchymal Stroma Cells
• New potential applications:
• Heart Infarct
• Stroke
• Parkinson's disease
• Spinal cord injuries
• Diabetes
• Myopathies
• Liver damage
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Clinical applications of stem cells
• Currently:
• Hematopoietic Stem Cells
• Epidermal Stem Cells
• Mesenchymal Stroma Cells
• New potential applications:
• Heart Infarct
• Stroke
• Parkinson's disease
• Spinal cord injuries
• Diabetes
• Myopathies
• Liver damage
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Komórki macierzyste – “panaceum
na wszystko” ?
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Properties of Stem Cell
• Self-renewal
• Quiescence
• High resistance to radio-chemotherapy and
cytostatic drugs
• Characteristic morphology (e.g., large nucleus,
euchromatin)
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Zygote
More than 200 different cell
types (totally~1014 cells)
Fertilization
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Commitment
Fertilized
egg cell
(Zygote) Embryonic
Stem Cells
Tissue Committed
Stem Cells
blood
muscles
neural
epidermis
liver
other
Ectodermal SC
Mesodermal SC
Endodermal SC
Totipotent
Pluripotent
Multipotent
Unipotent
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Hierarchy of stem cells
Totipotent stem
cells
They give onset to both the body of an embryo and
tissues of placenta. Under normal conditions
totipotent cells are fertlized oocyte ( zygote) and initial
blastomers. Under artificial conditions totipotency is
retained by zygote equivalent so-called clonote created as
a result of nuclear transfer of nucleus of somatic cell to
the oocyte.
Pluripotent stem
cells
They give onset to cells of all three germ layers.
Pluripotent cells are cells of internal mass of blastocyst
and cells in epiblast.
Monopotent stem
cells or tissue
specific stem cells
They include so-called tissue specific cells which give
onset to one line of cells. Examples include stem cells of
intestinal epithelium, hemopoietic stem cells, epidermal
stem cells, neural stem cells, hepatic stem cells and stem
cells of skeletal muscles.
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Embryogenesis
Zygote Morula Blastula (Blastocyst) Gastrula
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Tissue contribution of three germ layers
Ectoderm Brain, sympathetic ganglions, peripheral
nerves, eye, epidermis, skin appendices,
pigment cells
Mesoderm Hemato/lymphopoietic cells,
endothelium, skeletal muscles, heart,
adipocytes, connective tissues (bone,
tendon, cartilage), smooth muscles,
tubule cells of the kidney
Endoderm liver, pancreas, lung, gut, thyroid gland
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SYMETRIC ASYMETRIC
STEM CELL DIVISION
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Organ/tissue stem cell niches
• Bone Marrow
• Skeletal muscles
• Myocardium
• Brain
• Liver
• Intestine
• Epidermis
• Kidney
Hormones
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Bone Marrow
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Epidermis Intestinal epithelium
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Sites of adult neurogenesis (rodent studies) compared with appropriate human brain regions. Neurogenesis has
been confirmed in two regions of the adult brain: the subventricular zone (SVZ) of the anterior lateral ventricles (the
site of origin for olfactory bulb neurons) and the dentate gyrus of the hippocampus (a brain region involved in
learning and memory). In the SVZ, progenitor cells migrate to the olfactory bulb, where they differentiate into
neurons. In the dentate gyrus, cells divide along the subgranular zone (also see the figure in the sidebar, below) and
migrate into the granule cell layer before terminally differentiating into granule cells.
Brain
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Liver
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ETHICS
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• Due to scientific advances, at the beginning of the third millennium, human beings have reached out for technologies available, till now, only to the supreme beings.
- the development of physics has enabled us to explore
nuclear energy,
- the development of biology and genetics has explained the mystery of the creation of new organisms and their regeneration thus leading humanity into the fascinating world of stem cells
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Innowacyjne metody wykorzystania komórek macierzystych w medycynie
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Zygote
200 different types of stem cells
Oocyte - fertilization
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?
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?
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Clonote
2. Therapeutic
Cloning
Oocyte Somatic Cell
+
Oocyte
Sperm
PLURIPPOTENT STEM CELL
Zygote
1. Fertilization Blastocyst
Isolation form
Embryos
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Therapeutic Cloning
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Clonote
2. Therapeutic
Cloning
Oocyte Somatic Cell
+
Oocyte
Sperm
PLURIPPOTENT STEM CELL
Zygote
1. Fertilization Blastocyst
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Cloning Mammoth?
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Clonote
2. Therapeutic
Cloning
Oocyte Somatic Cell
+
Oocyte
Sperm
PLURIPPOTENT STEM CELL
Zygote
1. Fertilization Blastocyst
?
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Reproductive cloning???
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Fertilization Cloning
Clonote Clonote Zygote
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Adult Stem cells
Pluripotent Stem Cells
Isolation from Adult
Tisuses Gene Transduction
Somatic Cell (e.g., fibroblast)
Oct-4, Nanog, c-myc, Klf-4
Adult Stem Cell Induced Pluripotent Stem
Cell (iPS)
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Various potential sources of pluripotent stem cells (PSC)
PSC isolated from
embryos obtained
by fertilization and
stored in embryo
banks
PSC isolated from
embryos obtained
by formation of
clonote (therapeutic
cloning)
PSC obtained as a
result of
transformation of
somatic cells
(induced PSC)
PSC isolated from
adult tissues
Risk of developing
teratomas + + + -
Histo -
incompatibility
problem
+ - - -
Required donor of
ovum + + - -
Ethical
reservations
yes yes/no* no no
* This problem is differently considered by various major religions of the world. A number of religions
potentially accept therapeutic cloning (for example Islam, Buddhism, Judaism) but unquestionable majority
of them reject reproductive cloning.
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Various potential sources of pluripotent stem cells (PSC)
PSC isolated from
embryos obtained
by fertilization and
stored in embryo
banks
PSC isolated from
embryos obtained
by formation of
clonote (therapeutic
cloning)
PSC obtained as a
result of
transformation of
somatic cells
(induced PSC)
PSC isolated from
adult tissues
Risk of developing
teratomas + + + -
Histo -
incompatibility
problem
+ - - -
Required donor of
ovum + + - -
Ethical
reservations
yes yes/no* no no
* This problem is differently considered by various major religions of the world. A number of religions
potentially accept therapeutic cloning (for example Islam, Buddhism, Judaism) but unquestionable majority
of them reject reproductive cloning.
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Teratoma
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Somatotrophic factors, stem cells,
regeneration, aging and cancer
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?
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- The Rosetta Stone is an ancient Egyptian granodiorite stele inscribed with a decree issued at
Memphis in 196 BCE on behalf of King Ptolemy V.
- The decree appears in three scripts: the upper text is Ancient Egyptian hieroglyphs, the middle
portion Demotic script, and the lowest Ancient Greek.
- Because it presents essentially the same text in all three scripts (with some minor differences
between them), it provided the key to the modern understanding of Egyptian hieroglyphs
?
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- The Rosetta Stone is an ancient Egyptian granodiorite stele inscribed with a decree issued at
Memphis in 196 BCE on behalf of King Ptolemy V.
- The decree appears in three scripts: the upper text is Ancient Egyptian hieroglyphs, the middle
portion Demotic script, and the lowest Ancient Greek.
- Because it presents essentially the same text in all three scripts (with some minor differences
between them), it provided the key to the modern understanding of Egyptian hieroglyphs
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Concept of trans-dedifferentiation (plasticity) of HSC
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Concept of trans-dedifferentiation (plasticity) of HSC
?
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PARACRINE EFFECTS OF STEM CELLS
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Adult Stem Cell Therapies
Ratajczak M.Z. et al. Leukemia 2012, 26, 1166 -- 1173.
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Adult Stem Cell Therapies – Paracrine Effects
Ratajczak M.Z. et al. Leukemia 2012, 26, 1166 -- 1173.
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Adult Stem Cell Therapies – Heterogeneity of Stem Cells
Ratajczak M.Z. et al. Leukemia 2012, 26, 1166 -- 1173.
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Part I
Of Pluripotent Stem
Cells in Adult
Tissues…
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Sca-1+lin-CD45+
Sca-1+lin-CD45-
Kucia et al. Leukemia 2006,20:857-869
Very Small Embryonic/Epiblast Like (VSEL) Stem Cell Hematopoietic Stem Cell (HSC)
0 200 400 600 800 1000 FL2-A
M1
VSEL are diploid
SS
EA
-1
Oc
t4
Na
no
g
7-AAD
VSEL exclude 7-ADD
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TEM of murine Sca-1+lin- CD45- cells (VSELs)
Kucia et al. Leukemia 2006,20:857-869
A
B
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Scenario 1 Scenario 2
PSC
TCSCs
PSC
TCSCs + quiescent
“locked in” PSCs
Embryo
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Scenario 1 Scenario 2
PSC
TCSCs
PSC
TCSCs + quiescent
“locked in” PSCs
Embryo
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VSELs are present in different murine tissues (A) and their
number decreases with age (B)
Zuba-Surma et al. Cytometry 2008, 73, 1116-1127.
24
Co
nte
nt
of
VS
ELs [
%]
Age of mice [months]
2 4 7 10 12 18 36
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Ratajczak et al. Exp. Gerontology 2008, 43, 1009-1017.
A B
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Heat-Map Analysis
for Ct Value from
realtime PCR
(Heatmap builder)
Pluripotency
Epiblast
Germ-line
Specification
Germ-line
Development
DNA
methylation
C/T antigen
Imprinted
genes
Cell Cycle
VSEL HSC MNC ESC-D3
Shin et al. Leukemia 2010, 24, 1450–1461
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1 mm 1 mm 1 mm
1 mm 1 mm 1 mm
UCB - VSELs
mPB - VSELs
TEM of human CD133+lin- CD45- cells (VSELs)
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• In vitro PSC criteria
- Undifferentiated morphology, euchromatin, high nuclear/cytoplasm ratio
- Express PSCs markers (e.g., Oct-4, Nanog, SSEA) and bivalent domains, female PSCs reactivate X chromosome
- Differentiate into cells from all three germ layers (meso-, ecto- and endoderm) – multilineage differentiation
• In vivo PSC criteria
- Complementation of blastocyst development
- Teratoma formation
Pluripotent Stem Cell (PSC) - Criteria
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• In vitro PSC criteria
- Undifferentiated morphology, euchromatin, high nuclear/cytoplasm ratio
- Express PSCs markers (e.g., Oct-4, Nanog, SSEA) and bivalent domains, female PSCs reactivate X chromosome
- Differentiate into cells from all three germ layers (meso-, ecto- and endoderm) – multilineage differentiation
• In vivo PSC criteria
- Complementation of blastocyst development
- Teratoma formation
Pluripotent Stem Cell (PSC) - Criteria
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• In vitro PSC criteria
- Undifferentiated morphology, euchromatin, high nuclear/cytoplasm ratio
- Express PSCs markers (e.g., Oct-4, Nanog, SSEA) and bivalent domains, female PSCs reactivate X chromosome
- Differentiate into cells from all three germ layers (meso-, ecto- and endoderm) – multilineage differentiation
• In vivo PSC criteria
- Complementation of blastocyst development
- Teratoma formation
Pluripotent Stem Cell (PSC) - Criteria
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Part II
Of Germline and
Imprinted Genes….
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+
Zygote
Morula
ICM
Epiblast
? ?
PGC
Trophoectoderm Trophoectoderm
Mesoderm
Ectoderm
Endoderm
Mesoderm
Ectoderm
Endoderm
Germ Cells
Oocyte Sperm
Ratajczak et al. Leukemia 2007, 21, 860-867.
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1. Inflammation, tissue injury
2. Epigenetic changes
3. Reestablishment of the
somatic imprint
SDF-1 gradient
CXCR4+ epiblast derived cells/PGC (VSEL)
Legend:
Embryo
extra-embryonic
ectoderm
EPIBLAST
(primitive ectoderm)
PGC
precursors
Bone Marrow Fetal Liver
Muscles
Myocardium
Genital Ridges
Adrenal Glands
Nervous System
Activation
Quiescence
1. Ectopic niche
2. Inhibitory factors
3. Erasure of the somatic
imprint
VS
EL
sta
tus
Germ line as origin and “skeleton/scafold” of
stem cell system in adult body
Ratajczak et al. J Autoimmunity 2008:30;151-162.
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Germ Cells
+
Zygote
Morula
ICM
Epiblast
? ?
PGC
Trophoectoderm Trophoectoderm
Mesoderm
Ectoderm
Endoderm
Mesoderm
Ectoderm
Endoderm
Oocyte Sperm
Erasure of
somatic
imprint ?
Erasure of
somatic
imprint ?
Ratajczak et al. Leukemia 2007, 21, 860-867.
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Somatic imprinting – regulates expression of some developmentally important genes
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Somatic imprinting – regulates expression of some developmentally important genes
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Primordial germ cells
Somatic imprinting – regulates expression of some developmentally important genes
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Somatic imprinting – regulates expression of some developmentally important genes
VSEL?
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Igf2-H19
Rasgrf1
VSEL HSC MSC ESC-D3
7.6 % 43.8 % 66.1 % 52.7 %
10.4 % 52.5 % 40.0 % 64.6 %
VSEL HSC MSC ESC-D3
Epigenetic changes in imprinted genes
Shin et al. Leukemia 2009, 23, 2042-2051.
78.6 %
VSEL HSC MSC ESC-D3
88.8 % 36.7 % 44.7 %
Igf2R
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VSEL HSC MSC ESC
Oct-4
Igf2-H19 N N
Rasgrf1 N N N
Igf2R N N
KCNQ1 N N
Peg1/Mest N N N
SNRPN N N N N
Legend - : hypermethylation, : hypomethylation, N : normal status
Methylation status of crucial somatic imprinted genes
VSEL: Increase in mRNA for proliferation repressing genes - H19, p57Kip2 , Igf2R
Decrease in mRNA for proliferation promoting genes - IGF2, Rasgrf1. Igf1R
Shin et al. Leukemia 2009, 23, 2042-2051.
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VSEL HSC MSC ESC
Oct-4
Igf2-H19 N N
Rasgrf1 N N N
Igf2R N N
KCNQ1 N N
Peg1/Mest N N N
SNRPN N N N N
Legend - : hypermethylation, : hypomethylation, N : normal status
Methylation status of crucial somatic imprinted genes
Shin et al. Leukemia 2009, 23, 2042-2051.
VSEL: Increase in mRNA for proliferation repressing genes - H19, p57Kip2 , Igf2R
Decrease in mRNA for proliferation promoting genes - IGF2, Rasgrf1. Igf1R
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CELL PROLIFERATION METABOLIC FUNCTIONS
I NITIATION OF EMBRYOGENESIS
PROLIFERATION OF PLURIPOTENT STEM CELLS
INSULIN-INSULIN LIKE GROWTH FACTORS SIGNALING
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M
P
H19 Igf2
DMR1
H19 Igf2
M
P
CTCF
H19 Igf2
DMR1
H19 Igf2
Igf2-H19 – imprinted
“master” locus
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H19 Igf2
DMR1
H19 Igf2
M
P
CTCF
Proper Somatic Imprint
Paternally Imprinted Locus Igf2-H19 –
master regulator of VSELs quiescence
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H19 Igf2
DMR1
H19 Igf2
M
P
CTCF
Jin-Yang locus
Paternally Imprinted Locus Igf2-H19 –
master regulator of VSELs quiescence
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H19 Igf2
DMR1
H19 Igf2
CTCF
CTCF
M
P
Erasure of Imprint
Paternally Imprinted Locus Igf2-H19 –
master regulator of VSELs quiescence
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H19 Igf2
DMR1
H19 Igf2
CTCF
CTCF
M
M
H19 Igf2
DMR1
H19 Igf2
M
M
CTCF
Development of viable bimaternal mouse individual from a reconstructed oocyte containing two haploid sets
of maternal genome, was made possible by the appropriate expression of Igf2 and H19 genes.
“Kaguya” a bimaternal mouse grew
up a normal adult with reproductive
competence
+
Kono et al. Nature 2004, 71, 1560-1567.
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Part III
VSELs –
Somatotrophic
Signaling, Aging and
Cancerogenesis….
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VSELs and Aging
Zuba-Surma et al. Cytometry 2008, 73, 1116-1127.
24
Co
nte
nt
of
VS
ELs [
%]
Age of mice [months]
2 4 7 10 12 18 36
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Ratajczak et al. Exp. Gerontology 2008, 43, 1009-1017.
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VSELs and Aging
Zuba-Surma et al. Cytometry 2008, 73, 1116-1127.
24
Co
nte
nt
of
VS
ELs [
%]
Age of mice [months]
2 4 7 10 12 18 36
0.00
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
Ratajczak et al. Exp. Gerontology 2008, 43, 1009-1017.
Extension of life
span?
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GH/Insulin/IGF-1 axis in Aging
Calorie
Restriction
Growth Hormone
Insulin
Insulin-like growth
factor-1
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Calorie
Restriction
Growth Hormone
Insulin
Insulin-like growth
factor-1
EXTENSION OF LIFESPAN
LOWER RISK OF CANCER
GH/Insulin/IGF-1 axis in Aging
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GH/Insulin/IGF-1 axis
High
Calorie Diet
Growth Hormone Insulin-like growth
factor-1 Insulin
Calorie
Restriction
Growth Hormone
Insulin
Insulin-like growth
factor-1
EXTENSION OF LIFESPAN
LOWER RISK OF CANCER
GH/Insulin/IGF-1 axis in
Aging
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High
Calorie Diet
Growth Hormone Insulin-like growth
factor-1 Insulin
Calorie
Restriction
Growth Hormone
Insulin
Insulin-like growth
factor-1
EXTENSION OF LIFESPAN
LOWER RISK OF CANCER
DECREASE OF LIFESPAN
HIGHER RISK OF CANCER
GH/Insulin/IGF-1 axis in Aging
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Insulin/Insulin like growth factor molecular pathways are
involved in regulation of lifespan
Down-regulation of glucose-dependent signaling by mutations in the
RAS2, CYR1/PKA or SCH9 genes extend life-span up to 300%
Down-regulation of DAF-2, AGE-1 and AKT-1/AKT-2 proteins extend
survival up to 300%
Mutations that decrease the activity of the insulin/IGF-1-like pathway
cause dwarfism but nearly double longevity
Mice homozygous for mutation in GH-R, GH, Prop-1 or Pit-1 genes
are dwarfs but live 25 to 65% longer, Long living mice are also RasGRF1 mutants.
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Short Living Mice – (higher risk of cancer)
- bGH transgenic mice
- Igf-2 transgenic mice
Long Living Mice (lower risk of cancer)
- Laron dwarfs
- Ames dwarfs
- GH -/- mice
- PAPP-A -/-
- RasGRF1-/- mice
GH/Insulin/IGF-1 axis in Aging
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Increase in number of VSELs (left panel) and HSCs (right
panel) in 2 month old and 2 year old Laron dwarf mice (GHR-/-)
as compared to their normal littermates (GHR+/-).
2 months old 2 years old
VS
EL
ra
tio
No
. o
f S
ca-1
+li
n- C
D45
- cell
s
per
10
6 B
MM
NC
/bo
dy w
eig
ht
2 months old 2 years old
HS
C r
ati
o
No
. o
f S
ca-1
+li
n- C
D45
+ c
ell
s
per
10
6 B
MM
NC
/bo
dy w
eig
ht
GHR+/- GHR-/- GHR+/- GHR-/- GHR+/- GHR-/- GHR+/- GHR-/-
*
* *
*
Kucia M. et al. Age 2012 (in press)
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VS
EL
ra
tio
No
. o
f S
ca
-1+li
n- C
D4
5- c
ell
s
pe
r 1
06 B
MM
NC
/bo
dy w
eig
ht
HS
C r
ati
o
No
. o
f S
ca
-1+li
n- C
D4
5+ c
ell
s
pe
r 1
06 B
MM
NC
/bo
dy w
eig
ht
normal bGH normal bGH normal bGH normal bGH
6 months 1 year 6 months 1 year
Reduced number of VSELs and HSCs in 6 months and 12
months old high circulating IGF-1 level bovine Growth
Hormone (bGH) Transgenic Mice
Kucia M. et al. Age 2012 (in press)
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Kucia M. et al. Leukemia 2011, 25, 1370–1374.
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Aging…..
I have plenty
of VSELs !!!
Lucky you !!!
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Beckwith-Wiedemann Syndrome (fetal overgrowth + pediatric sarcomas)
High level of Igf-2 due to LOI
H19 Igf2
DMR1
H19 Igf2
M
P
CTCF
Normal Somatic Imprint Loss of Imprint (LOI)
H19 Igf2
DMR1
H19 Igf2
M
P
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H19 Igf2
DMR1
H19 Igf2
M
P
Loss of Imprint
Beckwith-Wiedemann Syndrome (fetal overgrowth + pediatric sarcomas)
High level of Igf-2 due to LOI
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Embryonal rest theory of cancer development
1829 – J. Recamier; 1854 – R. Remak; 1858 – R. Virchow
Proposed that cancer arises from embryo-like cells.
1874 – F. Durante; 1875 – J. Cohnheim – Suggested that adult tissues contain
embryonic remnants that normally lie dormant, but can be activated to
become cancerous.
1910 - Wright - Proposed germinal cell origin of Willm’s tumor (nephroblastoma)
1911 – J. Beard – Tumors arise from displaced trophoblast or activated germ cells
Julius Cohnheim Rudolf Virchow John Beard
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• Presence of “classical” germ line tumors
Seminomas, ovarian tumors, yolk sac tumor, mediastinal-, brain-germ cell tumors, teratomas, teratocarcinomas,
• Expression of Cancer Testis (C/T) Antigens in cancer cells
C/T antigens (~40 identified) are encoded by genes that are normally expressed only in the human germ line, but C/T antigens are also expressed in various tumor types (e.g., gastric-, lung-, liver-, bladder-carcinomas, melanomas, medulloblastomas, pediatric sarcomas, germinal tumors).
• Expression of chorionic gonadotropin (hCG) and/or carcinoembryonic antigen (CEA)
Several types of cancer contain either the beta subunit of hCG or its fragments and/or CEA.
• Expression of Oct-4 by several tumors
Oct-4 is a marker of germ line pluripotent stem cells an is also expressed in various tumor types (e.g., gastric-, lung-, bladder-, oral mucosa-carcinomas, germinal tumors).
Data supporting theory of cancer formation in germ cell
compartment
VSEL HS
C
MNC
0
50
100
150
200
250
Fold
diffe
renc
e (m
RNA)
MAGE-A2
VSEL HS
C
MNC
0
100
200
300
400
500
Fold
diffe
renc
e (m
RNA)
MAGE-A10
VSEL HS
C
MNC
0
50
100
150
200
Fold
diffe
renc
e (m
RNA)
MAGE-B3
VSEL HS
C
MNC
0
10
20
30
40
50
60
Fold
diffe
renc
e (m
RNA)
Ssbx1
VSEL –
express
several C/T
Antigens
Ratajczak et al. Am J Pathology 2009, 174, 1985-1992.
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Germ line/epiblast-derived Oct-4+ VSEL as tumor initiating cells?
Tumor types
Potential Mechanisms
Teratomas, Teratocarcinomas Persistent somatic imprint in Oct-4+
cells (epiblast-derived?), additional
mutations
Germinomas, Seminomas, Teratomas,
Dermoid cyst, Hydatidiform mole,
Cells left along PGC migratory
route, persistent somatic imprint,
additional mutations?
Pediatric Sarcomas (rhabdomyosarcoma,
neuroblastoma, Ewing sarcoma, Willms
tumor-nephroblastoma)
Mutated Oct-4+ cells in various
peripheral tissue locations?
Other malignancies (e.g., Helicobacter
pylori – related stomach cancer, smoke -
related lung cancer)
Circulating Oct-4+ cells
incorporated at the wrong time to
the wrong place, additional
mutations? Fusion – chromosomal
instability?
Ratajczak et al. Leukemia 2007, 21, 860-867.
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Laron Dwarfs – Liver GH receptor deficiency –
Low level of circulating IGF-1
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Laron Dwarfs – Liver GH receptor deficiency –
Low level of circulating IGF-1
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Problems still to be addressed
- Human counterparts of VSELs are not characterized yet extensively at molecular level.
- Efficient ex vivo expansion of VSELs is still a problem.
- Does number of VSELs correlates also with longevity in humans?
- Does calorie restriction and physical activity positively regulate number of VSELs in adult tissues?
- The involvement of VSELs in development of malignancies still needs a direct evidence
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year 1925 year 1930
Pablo Picasso – “Study of the women head”
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• If you have a horse run with it
• If you have a bird fly with it
• If you have a dream follow it……