Download hemopoietic stem cells

MB 207 Molecular Cell Biology
The lives and deaths of cells in
tissues
The lives & Deaths of Cells in Tissues
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Epidermis and its renewal by stem cells
Sensory epithelia
Blood vessels and epithelial cells
Renewal by pluripotent stem cells: Blood cell
formation
Genesis, modulation and regeneration of skeletal
muscle
Fibroblasts and their transformations: the connective
tissue cell family
Stem cell engineering
Mammalian skin
Epidermal cells form a multilayered waterproof barrier
What is stem cells?
• One of the body's master cells, with the
ability to grow into any one of the body's more
than 200 cell types
• Unspecialized (undifferentiated) cells
• Contribute to the body's ability to renew and
repair its tissues.
• Renew themselves as well as create new
cells of whatever tissue they belong to (and
other tissues).
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The properties of a stem cells are:
a) Not terminally differentiated
b) can divide without limit (or at least for the life
time of the animal)
c) When it divides, each progeny has a choice
– either remain a stem cell or cells that
differentiate.
Stem cell biology
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In the normal adult body, different classes of stem cells are responsible
for the renewal of different types of tissue.
Some tissues are incapable of repair by the genesis of new cells
because no competent stem cells are present.
Recent discoveries have opened up new possibilities for manipulating
stem-cell behaviour artificially for repairing of un-repairable tissues.
Example:
i) Epidermal stem cells taken from undamaged skin of a
badly burnt patient can be rapidly grown in large numbers
in culture and grafted back to reconstruct an epidermis
to cover the burns.
ii) Neural stem cells persist in a few regions of the adult
mammalian brain and when grafted into a developing or
damaged brain can generate new neurons and glia appropriate
to the site of grafting.
→ Stem-cell biology offer hope of remedy for many serious
diseases (eg. Parkinson disease).
Stem cell biology –
Adult and Embryonic stem cells
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Embryonic stem cells (ES cells)
- from embryos (human or animal)
- cells able to differentiate into many cell types in the body
- can be induce to differentiate into different cell types in culture, when
supplemented with certain growth/differentiation factors.
Adult stem cells
- from some adult tissues (eg. bone marrow)
- in a suitable environment, are able to generate a wider range of
differentiated cell types than normally.
Stem cell division
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Each daughter produced can either remain a stem cell or go on to
become terminally differentiated.
Two ways in which stem cells produce daughters with different fate:
i) based on environmental asymmetry
- daughters of the stem cell are initially similar
- are directed into different pathways according to
the environmental influences that act on them
- number of stem cells can be increased or reduced
to fit the niche available for them
ii) based on divisional asymmetry
- the stem cell has an internal asymmetry
- cell divides in such a way that its two daughters
readily contained different determinants.
Two ways for a stem cell to produce daughters with different fates
Stem cell division
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Stem cells in many tissues divide at a low rate.
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Cell division give rise to transit amplifying daughters cells.
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Transit cells are committed to differentiation - undergoes additional more
rapid cell divisions to complete differentiation.
Transit Amplifying Cells
In the example shown here, each
stem cell division gives rise in this
way to 8 terminally differentiated
progeny
Role of Stem Cells
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Stem cells division required when there is a need to replace
differentiated cells (cannot divide) in a great variety of tissues.
Many types of stem cells, specialized for the genesis/generation of
different classes of terminally differentiated cells
Eg. Epidermal stem cells for epidermis
Intestinal stem cells for intestinal epithelium
Hemopoietic stem cells for blood etc…
Many factors determining whether stem cells divide or stay quiescent,
progeny stay stem cells or differentiate
= controlled by interactions with a variety of signals
from surroundings or neighboring cells
What is Tissue Regeneration?
aims to develop living cell based biological approaches to aid the
repair and regeneration of damaged and diseased tissues.
incorporates and links the areas of tissue engineering and regenerative
medicine.
to develop living tissues, such as blood vessels, bone, cartilage, tendons,
nerves in the laboratory, to implant into patients to recover physiological
functions; to use synthetic and natural biomaterials to provide structure and
form for laboratory assembled tissues and to use natural biological signals to
direct tissue repair and to engage patient responses in completing the repair
process.
is interdisciplinary research which combines the skills of biologists with
material, engineering and physical scientists and with clinical and surgical
expertise.
Tissue regeneration: Skin
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The skin viewed as a large organ composed of 2 main tissues: the
epidermis and the underlying connective tissue (consist of dermis &
hypodermis).
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Each tissue is composed of a variety of cell types.
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The dermis and hypodermis are richly supplied with blood vessels
and nerves (nerve fibers extend into the epidermis).
Regeneration of Skin
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Consist of tough connective tissue (the dermis & hypodermis) overlaid by a
multilayered waterproof epithelium (the epidermis).
Epidermis –continually renewed from stem cells (turnover time ~1 month in
human).
Epidermal stem cells are clustered near the tips of the dermal papillae,
attached to basal lamina.
Fate of these stem cells are controlled by interactions with basal lamina and
variety of signals from neighboring cells – regulate rate of basal cell
proliferation in time of need.
Stem cell divide infrequently, giving rise (through a sideways movement) to
transit amplifying cells.
The transit amplifying cells undergo several rapid divisions in the basal
layer and then stop dividing, begin to differentiate and slip out of the basal
layer.
They progressively differentiate to form keratinocytes, switching from
expression of one set of keratins to another until their nuclei degenerate,
giving rise to an outer layer of dead keratinized cells that are continually shed
from the surface.
Glands in the epidermis (mammary glands) have their own stem cells and
their distinct patterns of cell turnover. - eg. Circulating hormones stimulate
cells to proliferate and differentiate.
The distribution of stem cells in human epidermis, and the
pattern of epidermal cell production.
Localization of different cells in skin regeneration:
 Stem cells was identified by staining for b1-integrin.
 Dividing cells were identified by labeling with BrdU (a thymidine
analog that is incorporated into cells in S-phase of the cell
division cycle).
 Differentiating cells by staining for keratin-10 (a marker of
keratinocyte differentiation).
Regeneration of Sensory receptor, Intestine and Liver
Sensory receptor cells
 eg. Epidermal cells and nerve cells = derived from the epithelium.
 Olfactory receptor cells in the nose are full-fledge neurons.
 They have a lifetime of 1-2 month and are continually replaced by new cells
from stem cells in the olfactory epthelium.
Intestine (Gut)
 Expose to potentially damaging chemical processes = absorptive epithelium
undergo constant & rapid renewal.
 In small intestine, stem cells in the crypts generate new absorptive, goblet,
enteroendocrine and Paneth cells, replacing most of the epithelial lining of the
intestine every week.
 The diverse fate of stem cell progeny are controlled by Notch signaling
pathway, while the Wnt pathway is required to maintain the stem-cell
population
Liver
 more protected organ, can rapidly adjust it’s size by cell proliferation or cell
death when need arises.
 differentiated hepatocytes = able to divide throughout life.
 a specialized class of stem cells is not always needed for tissue renewal.
Sensory epithelia
The structure of the retina
• photoreceptors are permanent cells that
do not divide and are not replaced if
destroyed.
• photosensitive rhodopsin molecules are
not permanent but are continually
degraded and replaced.
Regeneration of blood vessels by endothelial cells
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Endothelial cells form a single cell layer that lines all blood vessels and
regulated exchanges between the blood stream and surrounding
tissues.
Provide signals for organization and development of connective tissue
cells that form the layers of blood-vessel wall.
New blood vessels can develop from walls of existing small vessels by
the outgrowth of the endothelial cells.
Have the ability to form hollow capillary tubes in culture.
Expression of different cell-surface proteins - serve as control of
proliferation.
In regions where cells are short of O2, increase in hypoxia-inducible
factor 1 (HIF-1) stimulates the production of endothelial growth factor
(VEGF) = causes endothelial cells to proliferate and invade the hypoxia
tissue to supply new blood vessels.
Renewal by pluripotent (multipotent) stem cells:
blood cell formation
Pluripotent has the potential to differentiate into any of the three germ layers:
endoderm, mesoderm, or ectoderm.
Types of white blood cells
Regeneration of blood cells
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The different types of blood cells are all derived from a common multipotent
stem cell (hemopoietic stem cells).
In adult, hemopoietic stem cells are in bone marrow and they depend on
contact-mediated signals from the marrow stromal cells (connective tissue)
to maintain their stem-cell character.
Hemopoietic stem cell normally divides infrequently to produce
either
multipotent stem cells (self-renewing) or committed progenitor cells (transit
amplifying cells) each able to give rise to one or more types of blood cells.
Committed progenitor cells = lymphoid or the myeloid type.
The process where hemopoietic stem cells divide to form committed
progenitor cells that differentiate to form blood cells is called hemopoiesis.
The committed progenitor cells divide extensively controlled by various
protein signal molecules (colony-stimulating factors, CSFs) and subsequently
terminally differentiated into mature blood cells having lifespan of several
days or weeks.
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Lymphoid progenitor cells give rise to:
T-cells (lymphocytes) develop in Thymus,
B-cells
NK cells
dendritic cells.
Myeloid progenitor cells give rise to:
monocytes (some dendritic cells, macrophages & osteoclasts),
granulocytes [neutrophils, eosinophils & basophils (devp Mast
cells)]
megakaryocyte (platelets)
erythrocytes (RBCs).
Study of hemopoiesis = enhanced by in vitro assays in which
stem
cells or committed progenitor cells form clonal colonies when
cultured in a semisolid matrix in the presence of CSF.
Rescue of an irradiated mouse by a transfusion of bone marrow
cells
A tentative scheme of hemopoiesis
Type of cell
Main function
Transport O2 and CO2
Red blood cells
(erythrocytes)
White blood cells
(leucocytes)
Granulocytes
a. Neutrophils
Phagocytose and destroy invading bacteria
b. Eosinophils
Destroy larger parasites and modulate allergic
inflammatory responses
Release histamine (and in some species serotonin) in
certain immune reactions
Become tissue macrophages, which phagocytose and
digest invading microorganisms and foreign bodies as
well as damaged senescent cells
c. Basophils
Monocytes
Lymphocytes
a. B cells
b. T cells
Natural killer
(NK) cells
Platelets
Make antibodies
Kill virus-infected cells and regulate activities of other
leucocytes
Kill virus-infected cells and some tumour cells
Cell fragments arising from megakaryocytes in bone
marrow. Initiate blood clotting
Genesis, modulation and regeneration
of skeletal muscle
• New skeletal muscle fibers form by the fusion of myoblasts
• Muscle cells can vary their properties by changing the protein
isoforms they contain
• To control mucsle cell number and muscle cell size: loss of
function mutation in myostatin, an extracellular TGFβ protein,
can cause “double-muscled” animal. Both the numbers and the size
of muscle cells seems to be increased.
Fibroblasts and their transformations:
the connective tissue cell family
Fibroblasts change their character in response to chemical signals.
• When tissue is injured, the fibroblasts nearby proliferate, migrate into the
wound and produce large amounts of collagenous matrix, which helps to
isolate and repair the damaged tissue
• The extracellular matrix may influence connective-tissue cell
differentiation by affecting cell shape and attachment.