Cell growth and division Flashcards
What is cell growth?
Increase in size of cells without division
When is cell growth and proliferation coupled?
In renewing tissues (e.g. epidermis) - hyperplasia
In resting tissues (e.g. liver) -regeneration
What drives cell cycle/proliferation?
Growth, if you increase growth increase rate of cell cycle.
BUT increasing rate of cell cycle cells don’t necessarily growth
What factors control cell growth?
Extracellular growth factors/inhibitors
Contact with ECM
True or false organ final size is controlled intrinsically?
True
What can modulate the final organ size (in addition to intrinsic control)?
Reduced/excess extrinsic growth factors
What is hyperplasia?
Coupled cell growth and proliferation
What is neoplasia?
Uncontrolled/unregulated cell growth and proliferation occurs in disease and underpins tumour growth
What is cell growth needed for?
Maintenance of normal tissue structure and function
Major determinant of organ and body size
What is morphogenesis?
The regulation of the pattern of anatomical development
How can cell growth and proliferation uncouple?
Cleavage: proliferation but no growth
Hypertrohpy: growth but no proliferation e.g. skeletal muscle (growth and DNA replication but no cytokinesis)
What are requirements for cell growth?
Increase in cell mass and volume e.g. macromolecule synthesis
Movement at cell surface
(potentially) change in shape
How can GFs arrive at cell?
Autocrine: produced by cell itself but acts on itself
Paracrine: short range soluble molecules produced by cells near affected cell
Endocrine: GF produced at far distance to affected cells and carried to it by blood
What do local factors (autocrine and paracrine) do?
Control growth of specific organs
What do global factors (endocrine) do?
Regulate coordinated growth of many organs
What allows proportional growth of organism in development?
Local factors controlling individual organs and global factors controlling coordinated growth
What is a checkpoint?
A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be halted until conditions are favourable.
GF typically act as …
Mitogens
What are examples of GF that arrive by each pathway?
Local: control growth of specific organs E.g. NGF (nerve growth factor) so don’t diffuse in blood.
Global: an regulate coordinated growth (nutrition dependent) of many organs. E.g. IGF-1 (insulin like growth factor from liver), IGF-2 (embryo/foetus).
How is normal tissue structure and function maintained?
Cell growth and division, controlled by EC GF and balanced by cell loss, GI and apoptosis
How do growth inhibitors work?
Bind to cell receptor
Cause increased transcription of genes which code for inhibitors of cell cycle.
How do growth factors act?
GF binds to a specific cell surface receptor (often G-protein or kinase)
This triggers a signal transduction chain to nucleus, where a transcription factor is activated (e.g. by phosphorylation), so increased macromolecular synthesis/ changed cyclin expression
More macromolecules synthesised this stimulates growth, more cells pass into and through cell cycle.
Change in cyclin, changes in CDK leads to progression through the cell cycle
So GF drives growth of cell
What two receptors do GF bind to, how do they transduce?
GPCR - linked to second messenger molecule
Tyrosine Kinase - intrinsic enzyme activity on its intracellular domain initiates a cascade
What two ways (by regulating transcription) is a cell triggered to divide by?
Stimulates formation of macromolecules by increasing number and activity of ribosomes in cell, more proteins, stimulates growth.
Increased transcription of mitogenic genes (Cyclin’s) are coded for.
What two factors can induce morphogenic responses?
Hormones and toxic chemicals
What, other than autonomous control by GF/GI is essential for growth and development of an organ?
Growth to be coordinated with patterning.
Localised expression of GFs and signalling molecules is very important.
Describe growth after birth in renewing tissue, give an example
Skin (stratified squamous keratinised epithelium) epithelium - basal layer contains stem cells which proliferate and move through layers of skin. Stem cells become increasingly keratinised as they diff and are eventually sloughed off
Gut: lining of SI contains multipotent stem cells in crypts, can divide to form goblet, absorptive and enteroendocrine cells, rise up through crypts
Describe growth of resting tissue after birth, give an example
Liver: cells only multiply to repair damage.
Hepatocytes have high capacity for cell division so are unipotent stem cells - used for tissue repair in liver.
Skeletal muscle: satellite cells fuse to form myofibres when myofibres damaged
Describe growth after birth in non dividing tissues
Neurone: post mitotic cells don’t multiply after birth
Cardiac muscle: almost no regenerative capacity after childhood
What is apoptosis?
Regulated cell death
How is apoptosis different from necrosis?
Necrosis involves death of many adjacent cells due to extrinsic factor e.g. ischaemia
Apoptosis is not pro inflammatory
What is characteristic morphology of apoptosis?
Membrane blebbing (bulge in membrane)
Cell shrinkage
Condense chromatin
Fragmentation of DNA
Phagocytosis of neighbouring cells
What can initiate apoptosis?
Deprivation of survival factor
Pro-apoptotic cytokines
Irradiaton (gamma, UV light)
Anti cancer drugs
What are roles of apoptosis in development?
Loss of redundant tissue during organ development
Intracellular regulators of apoptosis include …
P53 – induces apoptosis in case of irreplaceable DNA damage
bcl-2: suppresses the apoptotic pathway
What is the role of apoptosis in adult life?
Control of cell number
Death of mutated/damaged cells
Give examples of where apoptosis is increased and decreased in disease
Increased: AIDs, post ischaemic injury
Decreased: malignancies, autoimmune disorders
What are stem cells?
Undifferentiated cells capable of long term self renewal and divide without limit
What happens to stem cell potency as they differentiate?
Progressive restriction of developmental potential/loss of potency.
Under certain conditions what can stem cells do?
Differentiate into specialised cell types and terminally differentiate
In which organs do stem cells divide continuously?
Gut, bone marrow
What 2 options can happen every time a stem cell divides?
Produce transient amplifying cell and another stem cell
Produces 2 populations of stem cells, one reproduces itself other produces purely transit amplifying cells
What are totipotent stem cells?
Cells from early mammalian embryo, can form entire blastocyst, embryonic tissue and placenta around it
What are pluripotent stem cells?
Can form embryo but not surrounding placental tissue. Give rise to ectoderm, endoderm and mesoderm
What are unipotent stem cells?
Only give rise to one cell type (committed stem cell)
What are multipotent stem cells?
Can give rise to many cell types.
What is a TAC?
Transit amplifying cell
Progenitor for terminally differentiated cell, fate determined
Limited number of divisions
What happens to a cell when it becomes terminally differentiated?
G0 cell cycle phase
No longer divides
What are iPS cells?
Arise from adult specialised cells that have been reprogrammed to be like stem cells
Differentiate into desired cell types for in vitro models of disease
How are iPS cells created?
Artificially reprogrammed by expressed transcription factors that are normally expressed in stem cells.
How do differentiated cells take on different identities?
Selective gene expression due to transcription factors and chromatin modification or alternative splicing, RNA editing and genomic rearrangements
Is the genome of differentiated cells normally altered in sequence during differentiation?
No, only the epigenome
Which cells can dedifferentiate?
Hepatocytes, dedifferentiate and reenter cell cycle
What maintains cells differentiated state?
Transcription factors and epigenetic chromatin modification
What do transcription factors that maintain differentiation often do?
Have dual function and show positive autoregulation
Upregulate protein for differentiation and inhibit cell division
How do cells signal and induce differentiation?
Diffusible ligand binds to an intracellular receptor
Cell surface ligand and receptor of adjacent cells interact this is juxtracrine signalling (contact dependent signalling).
Gap junctions also juxtracrine.
True or false, is there an increase in nuclei in hypertrophy?
False
What is a physiological and pathological example of hypertropy?
Physiological: Skeletal muscle in exercise (e.g. biceps in weightlifters)
Pathological: Cardiac hypertrophy (increased size of myocytes, but not increase function of myocytes. Predisposes to heart failure.
What is a physiological and pathological example of hyperplasia?
Physiological: Skin in response abrasion, cells deeper in epithelia grow and divide.
Seen in bone marrow with increased erythropoiesis (produciton of RBC) at high altitudes.
Pathological: Thyroid hyperplasia in Graves’ diseases due caused by auto-immune antibodies against the TSH receptor
How can you tell diseased (hyperplasia) thyroid from normal thyroid?
Normally thyroid has maximal epithelial surface which is one cell thick throughout the tissue.
Hyperplasia shows increased number of epithelial cells in some places more than one cell thick
What does neoplasia result in?
Tumour formation
What are three most common cell types for tumour formation?
Epithelia (carcinoma, adenocarcinoma)
Mesenchymal (sarcomas)
Hematological (advanced = lymphoma)
What is characteristic of benign tumour growth and differentiation?
Grow by local expansion (not affecting distant tissues)
Do not invade adjacent tissue
Differentiation usually resembles that seen in normal tissue
What is characteristic of malignant tumour growth and differentiation?
Grow by invasion of adjacent tissue, traverse basement membrane and spread to distant sites
Differentiation is incomplete to some extent (pleomorphism, anaplasia – no defined pattern of growth)
How are malignant cell nuclei different?
Nuclei are often large, and lead to mitotic abnormalities (i.e. cells undergo mitosis with broken chromosomes)
How do benign and malignant tumours cause harm?
Benign: May cause harm through pressure (e.g.nerves), obstruction or secretion of hormones
Malignant: Cause harm through destruction of normal tissue function (may also induce cachexia due to recruitment of inflammatory cells)
What is agenesis, give an example?
The complete failure to develop e.g. renal agenesis (in Potter’s syndrome) or pulmonary agenesis.
What is hypoplasia, give examples ?
Partial failure to develop e.g. testes in Klinefelter’s syndrome (47,XXY), ovaries in Turner’s syndrome (45,X), or pulmonary hypoplasia (one lung fails to develop properly).
What is atrophy?
Decrease in size of organ/tissue as a result of decrease in size of constituent cells/their number.
What are two types of physiological atrophy?
Remnant structures - during development (thyroglossal duct usually atrophies and closes off before birth).
Organs - after physiological stimulus to hyperplasia/hypertrophy has been removed. (e.g. Uterus after birth, skeletal muscles after retiring from weight training, thymic involution - the shrinking of the thymus with age)
How does the H&E of a thymus change with age?
Young thymus, very cellular, T cells undergoing positive and negative feedback
Older people, most space of thymus occupied by fat
What are three different types of pathological atrophy?
General - affects many tissue/organs e.g. wasting in starvation or cachexia in malignancy.
Tissue specific - e.g. osteoporosis , or brown atrophy in neurones/cardiac muscle.
Local atrophy - e.g. In disuse like bone and muscle wastage of an immobilised limb (maybe due to fracture cast).
In Ischemia, cells decrease in size to reduce their metabolic needs and to maintain survival.
A property of cells in primary cell culture …
Will only grow and proliferate for a limited number of cell cycles
A term which best describes the developmental versatility of haematopoietic stem cells…
Pluripotent
A term which describes skeletal muscle tissue after a long period of denervation…
Atrophic
Muscle wasting after nerve injury…
Neuropathic
Physiological atrophy of thymus at puberty..
Involution
The partial failure of ovaries to develop in Turner’s syndrome…
Hypoplasia
The developmental potential of human stem cells derived from a 4-cell stage embryo..
Totipotent
When do totipotent stem cells become pluripotent?
Morula - 16 cell stage, inner and outer cell mass are pluripotent
