Week 7 - Cellular Adaptations Flashcards
What controls cell proliferation?
Signals from the microenvironment
- They either stimulate or inhibit cell proliferation
- Proto-oncogenes regulate normal cell proliferation
How do cells in a multicellular organism communicate?
Through chemical signals
What does the size of a cell population depend on?
The rate of: - Cell proliferation - Cell differentiation - Cell death by apoptosis Increased cell numbers are seen with either increased cell proliferation or decreased cell death
Why may cell proliferation occur?
As the result of physiological or pathological conditions
What can cell-to-cell signalling be via?
- Local mediators
- Direct cell-cell or cell-stroma contact
- Hormones
What are growth factors?
Polypeptides that act on specific cell surface receptors
- Coded for by photo-oncogenes
- Bind to specific receptors and stimulate transcription of genes that regulate entry of cell into cell cycle and the cell’s passage through it
- Local mediators involved in cell proliferation
What can growth factors affect?
- Cell proliferation and inhibition
- Locomotion
- Contractility
- Differentiation
- Viability
- Activation
- Angiogenesis
What is epidermal growth factor?
It is mitogenic for epithelial cells, hepatocytes and fibroblasts
- Binds to epidermal growth factor receptor
- Produced by keratinocytes, macrophages and inflammatory cells
What is vascular endothelial growth factor?
A potent inducer of blood vessel development (vasculogenesis)
- Has a role in growth of new blood vessels (angiogenesis) in tumours, chronic inflammation and wound healing
What is platelet-derived growth factor?
A growth factor that is stored in platelet alpha granules
- Released on platelet activation
- Also produced by macrophages, endothelial cells, smooth muscle cells and tumour cells
- Causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes
What is granulocyte colony-stimulating factor?
- Stimulates the bone marrow to produce granulocytes, particularly neutrophils
- Releases them into the blood
- Used as a treatment to stimulate poorly functioning bone marrow (e.g. during chemotherapy)
What are the roles of checkpoints in the cell cycle?
- They can sense damage to DNA
- Ensure cells with damaged DNA do not replicate
Describe the cell cycle
- Begins at M: mitosis and cytokinesis
- G1: gap 1, presynthetic, cell grows
- G0: at the same time as G1, cells can fluctuate between G0 and G1
- R point: towards the end of G1, majority of cells that pass the R point will complete the full cell cycle
- S: DNA synthesis
- G1 checkpoint
- G2: gap 2, pre-mitotic, cell prepares to divide
- G2 checkpoint
What happens to the cell following cell cycle completion?
Either:
- Re-starts the process from G1
- Exits (G0) until further signals occur
What happens to cells in G0?
They can undergo terminal differentiation where there is a permanent exit from the cycle
What is the R point in the cell cycle?
The most critical checkpoint
- The majority of cells that pass the R point will complete the full cell cycle
- If checkpoint activation occurs the p53 protein comes into play
- – This protein suspends the cell cycle and triggers DNA repair mechanisms
- – If the DNA cannot be repaired, apoptosis occurs
- Found towards the end of G1
How is the cell cycle controlled?
- Progression through is tightly regulated by proteins called cyclins and associated enzymes called cyclin-dependent kinases (CDKs)
- CDKs become activated by binding to and complexing with cyclins
- Activated CDKs drive the cell cycle by phosphorylating proteins that are critical for progression of the cell to the next stage of the cell cycle
- CDK activity is tightly regulated by CDK inhibitors
- Some growth factors work by stimulating production of cyclins
What are labile stem cells?
Cells that continue to multiple throughout life
- E.g. bone marrow
What are stable stem cells?
Cells that can multiply in a regenerative burst but are usually quiescent
- E.g. liver, kidney
What are permanent stem cells?
Cells that cannot proliferate
- E.g. cardiac muscle
Which tissues can undergo regeneration well?
- Bone
- Epithelia
- Liver
- Mesothelia
- Smooth muscle
Which tissues have limited regeneration?
Striated muscle
Which tissues have poor regeneration?
- Tendons
- Articular cartilage
Which tissues have no regenerative capacity?
- Adipocytes
- CNS
What is regeneration?
The replacement of cell losses by identical cells in order to maintain the size of a tissue or organ
What is cell adaptation?
The state between a normal unstressed cell and an overstressed injured cell
- The ability of a cell to respond to challenges that are not severe enough to cause injury, by adaptations that are not truly pathologic
- Usually reversible
What are the important types of cell adaptation?
- Regeneration: multiply to replace losses
- Hyperplasia: increase in number above normal
- Hypertrophy: increase in size
- Atrophy: become smaller
- Metaplasia: replacement by a different type of cell
When can regeneration occur?
- It can be a normal process
- Can occur after injury if the harmful agent is removed and if there is limited tissue damage
When can regeneration not occur following tissue injury?
- If the harmful agent persists
- If there is extensive tissue damage
- If the damage occurs to a permanent tissue
Where can regeneration be seen?
- In the liver (after partial hepatectomy)
- In the epidermis (by keratinocytes following a skin burn)
How similar are regenerated cells to the original cells?
They are usually as good as the original cells
- But not always and not immediately
- Can take weeks, months or years to reach morphological and functional maturity
- This can confer an advantage to cells
How can cells be induced to regenerate?
- Growth factors in the microenvironment
- Cell-to-cell communication
- Electric currents and nervous stimuli
What is reconstitution?
The replacement of a lost part of the body
- It requires the coordinated regeneration of several types of cells
- Different to regeneration
Can reconstitution occur in mammals?
Yes, but the ability is minimal
- Small blood vessels can be reconstituted
- Children less than 4.5 years old have been reported to reconstitute the tip of a finger if it is cleanly severed and the amputation is beyond the distal phalangeal joint
What is hyperplasia?
An increase in tissue or organ size due to increased cell numbers
- A response to increased functional demand and/or external stimulation
- Can only occur in labile or stable cell populations
- Under physiological control
- Reversible
- Biologically similar to regeneration
- Can occur secondary to a pathological cause
What is physiological hyperplasia?
Either:
- Hormonal: the result is an increase in functional capacity
- Compensatory: there is an increase in tissue mass after tissue damage
Usually occurs secondary to hormonal stimulation or growth factor production
What is a risk in hyperplastic tissue?
Neoplasia
- The repeated cell divisions that occur expose the cell to the risk of mutations
What are some examples of physiological hyperplasia?
- Increased bone marrow production of erythrocytes in response to low oxygen levels
- The proliferation of the endometrium under the influence of oestrogen
What are some examples of pathological hyperplasia?
- Epidermal thickening in chronic eczema or psoriasis
- Enlargement of the thyroid gland in response to iodine deficiency
What is hypertrophy?
An increase in tissue or organ size due to an increase in cell size without an increase in cell numbers
- Cells become bigger because they contain more structural components
- Hence the cellular workload is shared by a greater mass of cellular components
- A response to increased functional demand and/or hormonal stimulation
- The cells are synthesising more cytoplasm
- When the stimulus for hypertrophy disappears, the cells and organs become normal size again
Where can hypertrophy occur?
In many tissues
- Seen especially in permanent cell populations, as these cell populations have little or no regenerative potential, so any increase in organ size must occur via hypertrophy
- In cells where division is possible, hypertrophy may still occur but often alongside hyperplasia
What are some examples of physiological hypertrophy?
- Skeletal muscle hypertrophy of a bodybuilder
- Smooth muscle hypertrophy of a pregnant uterus
What are some examples of pathological hypertrophy?
- Ventricular cardiac muscle hypertrophy in response to systemic hypertension or valvular disease
- Smooth muscle hypertrophy above an intestinal stenosis due to the extra work
How does hypertrophy of cardiac muscle occur in athletes?
Physiologically not pathologically
- The heart is under strain for only a few hours/day and has the rest of the day to recover
What is seen with cardiac hypertrophy?
- The number of capillaries in the heart increases, but not sufficiently to satisfy the increased muscle mass
- This means that in a pathologically hypertrophic heart, there is relative anoxia
- Fibrosis is also seen in pathologically hypertrophic hearts
- This decreases the compliance of the cardiac muscle and hence its effectiveness
- Progressive pathological cardiac hypertrophy eventually leads to myocardial exhaustion
What is compensatory hypertrophy?
If 1 of 2 paired organs is removed the other enlarges
- This is a combination of hypertrophy and hyperplasia
What is atrophy?
The shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells
- A form of adaptive response which may result in cell death
- It is linked with disease
- Also linked with senescence
- Reversible up to a point
How can atrophy occur?
Due to a reduced supply of growth factors and/or nutrients
- Can occur by cell deletion or cell shrinkage, depending on he type of tissue involved
What is organ/tissue atrophy usually due to?
A combination of cellular atrophy and apoptosis
- In organs undergoing atrophy by cell deletion, parenchymal cells will disappear before stream cells so they contain a large amount of connective tissue
What is cellular atrophy usually due to?
Shrinkage in the size of the cell to a size at which survival is still possible
- Cell contains a reduced number of structural components and has reduced function
How does cell shrinkage occur?
By self-digestion
- Most cellular organelles are essential for survival, so there is a limit to cell shrinkage; some non-essential organelles can be pared down
What is bone atrophy?
Loss of bone matrix
- Osteoporosis
What are the different types of pathological atrophy?
- Reduced functional demand/workload = atrophy of disuse
- Loss of innervation = denervation atrophy
- Inadequate blood supply
- Inadequate nutrition
- Loss of endocrine stimuli
- Persistent injury
- Aging = senile atrophy
- Pressure
What is metaplasia?
The reversible replacement of 1 adult differentiated cell type by another of a different cell type
- Cells of 1 phenotype are eliminated and replaced by cells of a different phenotype
- Can be considered as ‘abnormal regeneration’
- End result = to change 1 cell type to another more suited to an altered environment
- Sometimes adaptive and useful
- Can be of no apparent use and may be detrimental
- Can sometimes be a prelude to dysplasia and cancer
How does metaplasia occur?
The stem cells within the tissue are reprogrammed and switch to producing a different type of progeny
- Involves expression of a new genetic programme which results in cells assuming a different structure and function
- Occurs secondary to signals from molecules such as cytokines and growth factors
- – Often induced by stimuli that cause cell proliferation
- – E.g. chemical or mechanical irritants, such as cigarette smoke
Where can metaplasia occur?
In cell populations that can replicate
- Within varieties of epithelia (most commonly)
- Within varieties of connective tissue
What are the effects of metaplasia on columnar epithelium?
Undergoes metaplasia to become squamous epithelium
- Common on surface linings
- The metaplastic epithelium may lose functions that the original epithelium performed
What is dysplastic epithelium?
Disorganised and abnormal differentiation
What is cancerous epithelium?
Disorganised and abnormal differentiation, irreversible
What are some examples of useful metaplasia?
- If the bone marrow if destroyed by disease, splenic tissue undergoes metaplasia to bone marrow
- The columnar epithelium lining ducts can change to stratified squamous epithelium secondary to chronic irritation to cells
What are some examples of metaplasia that has no apparent use?
- Transformation of bronchial pseudostratified ciliated columnar epithelium due to the effect of cigarette smoke
- Flat, non-secreting epithelium can be replaced by secretory epithelium/glands
- – Such as in the lower oesophagus when the oesophageal stratified squamous epithelium changes to gastric or intestinal type epithelium with persistent acid reflux (Barrett’s oesophagus)
- Connective tissue to bone
- – Can develop in skeletal muscle following trauma
- – Fibroblasts in the muscle tissue undergo metaplastic change to osteoblasts
What is aplasia?
The complete failure of a specific tissue or organ to occur
- An embryonic development disorder
- Also used to describe an organ whose cells have ceased to proliferate
What are some examples of aplasia?
- Thymic aplasia (results in infections and autoimmune problems)
- Aplasia of the kidney
- Aplasia of bone marrow in aplastic anaemia (example of an organ whose cells have ceased to proliferate)
What is involution?
The normal programmed shrinkage of an organ
- A term which overlaps with atrophy
What are some examples of involution?
- Uterus after childbirth
- Thymus in early development
What is hypoplasia?
The congenital underdevelopment or incomplete development of a tissue or organ
- There is an inadequate number of cells within the tissue which is present
- An embryonic development disorder
What are some examples of hypoplasia?
Renal/breast/testicular hypoplasia
What is atresia?
‘No orifice’
- The congenital imperforation of an opening
What are some examples of atresia?
Atresia of anus or vagina
What is dysplasia?
The abnormal maturation of cells within a tissue
- Potentially reversible
- Often a pre-cancerous condition
