stem cell: a cell capable of 1) tissue plasticity - make different cell types 2) infinite self...
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Stem cell: a cell capable of 1) tissue plasticity - make different cell types 2) infinite self renewal through asymmetric division
skin
muscle
nerve
stem cellstem cell
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Properties of STEM cellsProperties of STEM cells
Plasticity
Self renewal
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STEM CELLS
1. Source
2. Cloning
3. Plasticity
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CLASSIC EXAMPLES of STEM CELLS
• Embryonic stem cells (ESC)
• Bone marrow derived stem cells
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Blastocyst
•Fluid-filled cavity termed
blastocoele
ICM
Trophoblast• Blastocyst implants in
uterine wall
• Two regions identifiable
- outer trophoblast
- inner cell mass (ICM)
ICM = embryonic stem cells
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Origin of vertebrate stem cells
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USES of EMBRYONIC STEM CELLS
1. Source of different types of human cells
for Transplantation: for Cell Therapy or Tissue Engineering (organs). Merit and ethics are controversial
2. Cloning:
3. Somatic nuclear transfer (therapeutic cloning):
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USES of EMBRYONIC STEM CELLS
1. Source of different types of human cells for transplantation: for Cell Therapy or Tissue Engineering. Merit and ethics are controversial
2. Cloning: to make ‘genetically identical’ new individuals Achieved for animals – unlikely for humans.
3. Somatic nuclear transfer (therapeutic cloning):
to generate autologous cells for transplantation Avoids problems of immune rejection of non-self
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CLONING
1962 John Gurdon in the UK took (diploid) nucleus from tissue of adult frog and implanted this into an unfertilised egg that had the nucleus removed. The special influence of the maternal cytoplasm caused the ‘differentiated’ adult nucleus to give rise to a complete new frogFIRST EXAMPLE OF ADULT CLONING. Shows mature nucleus has capacity to revert to ‘equivalent’ ESC.
1996 Over 30 years later Dolly the sheep was cloned in Scotland. Then cattle, pigs, cats pets – humans??
ISSUES• Ethics (especially for humans)• Genes vs environment• Status/quality of ‘aged’ DNA• Role of maternal cytoplasmic factors and mtDNA
Movies like Boys from Brazil and Jurassic park
Variation on this is THERAPEUTIC CLONING (NOT make a new adult) . Perhaps a better name to avoid ethical issues is somatic nuclear transfer.
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USES of EMBRYONIC STEM CELLS
1. Source of different types of human cells for transplantation: for Cell Therapy or Tissue Engineering. Merit and ethics are controversial
2. Cloning: to make ‘genetically identical’ new individuals Achieved for animals – unlikely for humans.
3. Somatic nuclear transfer (therapeutic cloning):
to generate autologous cells for transplantation Avoids problems of immune rejection of non-self
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ADULT STEM CELLS
Bone marrow derived stem cell
classic source
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Haematopoiesis
Stem Cell (HSC)
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adult
embryo
ES cells
EG cells
Somatic Stem cells
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Multiple paths to new cell identities
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Fluorescent Activated Cell Sorting (FACS)
to isolate stem cells
based on many cell surface markers Sca1, CD34 etc
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Blastocyst
Embryo/Fetal
Post-Natal Tissues
• Bone marrow (HSC)• Blood vessels (ESC)• Interstitial connective tissue (MSC)• Other tissues
Germ cellsFetal tissues
ES cells
Umbilical cord blood (UCB)Supporting tissues (MSC)
Umbilical Cord
UBC
ES Cells
Stem cells can be derived from tissues throughout development
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STEM CELLS
1. Source
2. Cloning
3.Plasticity
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Myogenic Stem Cells
Satellite cellTerry Partridge
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myotubesmyofibre(only part is shown)
myoblasts
1 satellite cell3 myonucleus
2 multipotential/stem cell
Sources of myoblasts within skeletal muscle
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Plasticity
Resident C/T cellsResident C/T cells skeletal cardiac pluripotent STEM cells (multi)
progenitor cells VascularVascular
endothelial smooth muscle ()
pericytes ?
MyofibroblastsMyofibroblasts ()
Ectopic cells Ectopic cells (chickens)(chickens) Thymus Thymus (myoid cells) NeuralNeural ((multimulti)) ()
DermisDermis Circulating bone-marrow Circulating bone-marrow **((multimulti)) **
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Issues of immune rejection
of foreign.
2. Separation of
HOST specific stem
cell type
3. Correction or replacement
of DONOR
bone marrowstem cells
Healthy Healthy donordonor bone-marrow bone-marrow derived stem cells to repopulate derived stem cells to repopulate
diseased diseased host tissueshost tissues
Issues of immune rejection of foreign cells can be reduced by using closely matched donor and host cells.
Inject healthy donor stem cells derived from another person. These circulating donor stem cells may repopulate any damaged host tissue e.g heart
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Bone-marrow stem cell
(1) Muscle precursor cell with limited proliferation
1
2
Conversion
Conversion
Asymmetric Cell division
AA
BB
Possibilities to explain presence of bone-marrow derived (donor) nucleus (cell) within a (host) cell or tissue. Illustrated for muscle
(2) Ideal scenario = Muscle Stem cellwith capacity to formmany (cardio)myoblasts
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+
1
2
3
Bone-marrow stem cell
Conversion
Conversion
Fusion
(1) Muscle precursor cell with limited proliferation
(2) Muscle Stem cell
Asymetric Cell division
(3) Fusion of 2 cells
capacity to form many (cardio)myoblasts
Hybrid stem-muscle cell with 2 or more nuclei
AA
BB
Stem Stem cellcell
XX
CC
The stem cell has NOT become a muscle cell
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Autograft of genetically corrected stem cells: delivered through the circulation
1. Remove patient’s bone-marrow
2. Separation of specific type of host stem cell
3. Correction or replacement of defective gene in host stem cell
4. Infusion of host’s corrected stem cells to replace or supplement defective host cells
Use of own cells avoids immune problemsand rejection
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Two studies show that few of the bone-marrow derived nuclei located within muscle cells actually express muscle-specific genes:
indicating fusion without lineage conversion
• Beth McNally (normal male) bone marrow (b/m) reconstitution of female sarcoglycan (SG) deficient host mice: The rare male b/m-derived nuclei within some myofibres and heart muscle cells, showed NO expression of SGLapidos KA et al (2004)
• Anton Wernig male/GFP b/m reconstitution of female mdx (dystrophin deficient) mice: ~80% of male b/m myonuclei showed NO expression of skeletal muscle specific genesWernig G et al (2005) 3 labels: Y-probe, GFP, dystrophin
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1, 2: SERIAL SECTIONS
Donor nucleus (Y-FISH) without dystrophin expression
1
WERNIG G et al (2005)
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Current interest in blood vessel derived circulating
STEM CELLS: mesangioblasts.Sampaolesi M…. Cossu J (2006). Mesoangioblast stem cells ameliorate
muscle function in dystrophic dogs. Nature Nov 15.
Major problems in data interpretation due to lack of fundamental controlsDogs injected with immunosuppressants alone (without stem cells) were not included. Yet….
Cyclosporine alone reduces severity of muscular dystrophyPrecise source of stem cells? Poor correlation between increased dystrophin immunostaining (derived from the circulating stem cells) and
improved muscle function. Potential issues with digital imaging and image enhancementConfounded by high biological variation
Causes major confusion and distress for families of boys with DMD who are seeking a cure/treatment
Davies K, Grounds MD (2006) Treating muscular dystrophy with stem cells? Cell. Dec 29.
Grounds MD, Davies K (2007) The allure of stem cell therapy for muscular dystrophy. Neuromuscular Disorders March.
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KEY issues for researchKEY issues for research
•INDUCERS to recruit/convert stem cells into specific lineages: critical effects of environment (Plasticity)
•EXPANSION of cell numbers(proliferation and stem cell renewal)
•Stem cell isolation/identification
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Properties of STEM cellsProperties of STEM cells
Plasticity
Self renewal