MOD 7 Flashcards
What is autocrine signalling?
Cells responding to signals that they themselves produce.
What is intracrine signalling?
A type of autocrine signalling where a cell synthesises a factor which has an effect by binding to intracellular receptors within that cell, the factor is therefore not secreted by the cell.
What is paracrine signalling?
A cell produces the signalling molecule, this acts on adjacent cells. The responding cells are close to the secreting cell and are often of a different type.
What is endocrine signalling?
Hormones are synthesised by cells in an endocrine organs, they are then conveyed in the blood stream to target cells to effect physiological activity.
What are growth factors?
Are a type of local mediator that are particularly important for cell proliferation. They are polypeptides that act on specific cell surface receptors. They can be considered as ‘local hormones’ as they only act over short distances or even on the secreting cell itself. They are coded for by proto-oncogenes.
Name the different phases of the cell cycle?
- G1 - gap 1 phase
- S - synthesis phase
- G2 - gap 2 phase
- M - mitotic phase
(5. G0 - resting phase)
The phases between the M-phase are collectively called interphase.
What are the checkpoints of the cell cycle?
- Restriction (R) point towards the end of G1 = most critical (the majority of cells that pass this point will complete the full cell cycle)
- G1/S transition (checks for DNA damage before replication)
- G2/M (checks for DNA damage after replication)
What are the role of cyclins in the cell cycle?
They tightly regulate the cell cycle by binding to and complexing with cyclin-dependent kinases (CDKs).
What are the role of CDKs in the cell cycle?
Cyclin-bound (activated ) CDKs drive the cell cycle by phosphorylating proteins, e.g. RB protein, which are critical for progression of the cycle to the next stage.
What is the role of the RB protein in the cell cycle?
It inhibits the cell cycle until it is phosphorylated by CDKs -> its deactivation.
What are labile tissues?
Tissues which can proliferate even though they consist of mature differentiated cells. This is because the cells in this tissue are short-lived and are continually being replaced by cells derived from stem cells.
Give examples of labile tissues:
- EPITHELIUM e.g. epidermis or bowel epithelium (replaced by stem cells situated in basal layer of epidermis and epithelial crypts in the bowel)
- BONE MARROW - stem cells continuously divide to replenish loss.
What are permanent tissues?
Tissues where cells have terminally differentiated (left the cell cycle and cannot replicate). In these tissues although stem cells can be present, they cannot mount an effective proliferative response to significant cell loss.
Give examples of permanent tissues:
- Cardiac muscle
- Skeletal muscle
- Neural tissue
What are stable tissues?
Are intermediate between labile and permanent tissues. In these tissues the mature cells as well as stem cells are involved in proliferation. These mature cells are usually non-replicating but can be induced to enter the cell cycle and replicate if necessary (e.g. they are in G0 but can enter G1). This requires activation of a number of genes (proto-oncogenes, genes for ribosome synthesis and protein translation). Stem cells are present in these tissues and are normally quiescent or proliferate very slowly but can proliferate perisistently when required.
Give examples of stable tissues:
- Liver hepatocytes
- Kidney cells
- Fibroblasts
- Smooth muscle cells
- Vascular endothelial cells
- Osteoclasts
What are stem cells?
They are present in many adult tissues. They are cells with prolonged proliferative activity which show assymetric replication.
Define regeneration:
A type of cell adaptation in which cells multiplies to replace losses with identical cells in order to maintain the size of a tissue or organ.
Which tissues can undergo regeneration and which cannot?
- Liver - after partial hepatectomy
- Epidermis - following a skin burn
- Bone marrow - replaced lost RBCs and WBCs
- After injury - if harmful agent removed and there is limited tissue damage
Define hyperplasia:
An increase in tissue or organ size due to increased cell numbers. It is a response to a functional demand and/or external stimulation. It is under physiological control and is reversible (cf to neoplasia). It is biologically similar to regeneration but causes an increase in the size of tissue or organ.
Which tissues can undergo hyperplasia?
It can only occur in labile or stable cell populations.
When does physiological hyperplasia occur? Give an example of physiological hyperplasia:
Either hormonal (-> increased functional capacity) or compensatory (increase in tissue mass after tissue damage), e.g:
- Increased bone marrow production production of RBCs in response to low oxygen
- Proliferation of endometrium under the influence of oestrogen.
When does pathological hyperplasia occur? Give an example of pathological hyperplasia:
This usually occurs secondary to excessive hormonal stimulation or growth factor production e.g. epidermal thickening in chronic eczema or psoriasis and enlargement of the thyroid gland in response to iodine deficiency.
Define hypertrophy:
An increase in tissue or organ size due to an increase in cell size without an increase in cell numbers. Cells become bigger, not due to swelling, but because they contain more structural components. It is a response to increased functional demand and/or hormonal stimulation. Due to the increased structural components the cellular workload is shared by a greater mass of cellular components.
Which tissues can undergo hypertrophy?
It can occur in many tissues but is seen especially in permanent cell populations as these cell populations have little of no replicative potential and so any increase in organ size must occur via hypertrophy. In cells where division is still possible, hypertrophy may still occur but often alongside hyperplasia.
Give an example of physiological hypertrophy:
- Skeletal muscle hypertrophy in a body-builder
- SMC hypertrophy in pregnant uterus (hyperplasia also occurs) - increases 70 fold during pregnancy!
- Cardiac heart muscle in athletes (this is not pathological like the hypertrophy seen in systemic hypertension because the heart has time to recover after exercise).
Give an example of pathological hypertrophy:
- Ventricular cardiac muscle hypertrophy in response to systemic hypertension of valvular disease
- SMC hypertrophy above an intestinal stenosis due to extra work-load pushing intenstinal contents through the narrowing.
- SMC hypertrophy with bladder obstruction e.g. caused by prostate enlargement.
What is compensatory hyperplasia?
An increase in size of an organ or part of an organ or tissue, when called upon to do additional work or perform the work of destroyed tissue or of a paired organ (e.g. removal of one kidney).
Define atrophy:
The shrinkage of a tissue or organ due to an acquired decrease in size and/or number of cells. Cellular atrophy is a decrease in size, whereas organ/tissue atrophy is typically due to a combination of cellular atrophy and apoptosis and occurs when many cells in the tissue undergo atrophy and apoptosis. Whether atrophy occurs by cell deletion or cell shrinkage depends on the tissue involved.
Give an example of physiological atrophy:
- Ovarian atrophy in post-menopausal women
2. Decrease in size of uterus after partuition
Give an example of pathological atrophy:
- Reduced functional demand/workload (atrophy of disuse) e.g. muscle atrophy after disuse due to immobilisation in a cast
- Loss of innervation (denervation atrophy) e.g. wasted striated thenar muscles after median nerve damage.
- Inadequate blood supply e.g. thinning of skin on legs with peripheral vascular disease.
Define metaplasia:
The reversible replacement of one adult DIFFERENTIATED cell type by another of a different cell type. Cells of one type are eliminated and replaced by cells of a different phenotype. The stem cells within the tissue are reprogrammed and switch to producing a different type of progeny.
Why does metaplasia occur?
It occurs secondary to signals from molecules such as cytokines and growth factors. It is often induced by stimuli that cause cell proliferation e.g. chemical or mechanical irritant (cigarette smoke). These result in expression of a new genetic programme (different activation of genes) which results in cells assuming a different structure and different function.
Give some examples of useful metaplasia:
- Columnar epithelium (fragile) lining ducts can change to squamous epithelium (more resilient), secondary to chronic irritation by stones.
- If bone marrow is destoyed by disease splenic tissue undergoes metaplasia to bone marrow (myeloid metaplasia).
Define aplasia:
The complete failure of a specific tissue or organ to develop. It is an embryological developmental disorder e.g. aplasia of a kidney. Aplasia is also used to describe an organ whose cells have ceased to proliferate e.g. aplasia of bone marrow in aplastic anaemia.
Define involution:
This term overlaps with atrophy. It is the normal programmed shrinkage of an organ e.g. uterus after childbirth, thymus in early life, temporary foetal organs such as the pro- and mesonephros.
Define hypoplasia:
Congenital underdevelopment or incomplete development of a tissue or organ = an inadequate number of cells within the tissue which is present. It is an embryological disorder which is on a spectrum with aplasia. It is not the opposite of hyperplasia as it is a congenital condition.
Define atresia:
‘no orifice’ - the congenital imperforation of an opening, e.g. atresia of the anus or vagina.
Define dysplasia:
Abnormal maturation of cells within a tissue. It is potentially reversible but is often a pre-cancerous condition.
What factors determine the size of a cell population? When does a cell population increase?
- Rate of cell proliferation
- Rate of cell differentiation
- Rate of apoptosis
Therefore increased numbers are seen when there is either increased proliferation or decreased cell death.
What are the role of proto-oncogenes?
They regulate normal cell proliferation.
What, ultimately, are the final outcomes of cell signalling?
- Divide (enter cell cycle)
- Differentiate (take on a specialised form and function)
- Survive (resist apoptosis)
- Die (undergo apoptosis)
What three ways can cells signal to each other?
- Local mediators
- Direct cell-cell or cell-stroma contact
- Hormones (which means ‘stimulators’)
How specific is the mechanism of action of growth factors?
Some act on many cell types, whereas some have restricted targets.
List some functions that growth factors can stimulate on their target cell:
- Cell proliferation
- Cell inhibition
- Cell locomotion
- Contractility
- Differentiation
- Viability
- Activation
- Angiogenesis
What is the mechanism of action of growth factors?
They bind to specific receptors and stimulate transcription of genes that regulate the entry of the cell into the cell cycle and the cell’s passage through it.
What is the function of epidermal growth factor?
It is produced by keratinocytes, macrophages and inflammatory cells. It binds to epidermal growth factor receptors (EGFR) and is mitogenic for epithelial cells, hepatocytes and fibroblasts.
Define mitogenic:
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis.
What is the function of vascular endothelial growth factor?
It is produced by tumours, wound healing and chronic inflammation and causes vasculogenesis (induces blood vessel development) and angiogenesis (growth of new blood vessels).
What is the function of platelet-derived growth factor?
It is stored in apha-granules of platelet and released upon activation and is also produced by: macrophages, endothelial cells, smooth muscle cells and tumour cells. It causes migration and proliferation of fibroblasts, smooth muscle cells and monocytes.
What is the function of granulocyte colony-stimulation factor?
It is produced by endothelium, macrophages and a number of other immune cells. It stimulates bone marrow to produce granulocytes, particulary neutrophils, and release them into the blood.
Why is granulocyte colony stimulation factor (G-CSF) used in chemotherapy?
It is used to stimulate poorly functioning bone marrow.
When does a cell enter the cell cycle?
When it receives instruction e.g. from a growth factor, to divide.
What are the two options for a cell once it has completed the cell cycle?
It can re-start the process and go from M phase to G1 phase OR it can exits the cell cycle and enter the G0 phase until further growth signals occur.
How can cells permanently exit the cell cycle?
Cells in G0 can undergo terminal differentiation and exit permanently.
In terms of the cell cycle, how can increased tissue growth occur?
Either by:
- Shortening the cell cycle
- Conversion of quiescent cell to proliferating cells by making them enter the cell cycle.
Which parts of the cell cycle can be observed under the light microscope?
Only mitosis (nuclear division and cytokinesis), interphase is deceptively uneventful under the microscope.
What happens in the G1 phase of the cell cycle?
Cell growth (pre-synthetic)
What happens in the S phase of the cell cycle?
DNA synthesis
What happens in the G2 phase of the cell cycle?
The cell prepares to divide (pre-mitotic) - therefore DNA replication and protein synthesis for growth in cell size occurs.
How is the cell cycle controlled?
Key “checkpoints” which sense damage to DNA and ensure cells with damaged DNA do not replicate.
What is the effect of defective cell cycle checkpoints in cancer cells?
They are a major form of genetic instability.
How is the activity of cyclin-dependent kinases tightly regulated?
By CDK inhibitors.
How do some growth factors affect cell cycle control?
Some growth factors work by stimulating the production of cyclins and some work by shutting off the production of CDK inhibitors.
What role does p53 protein have in cell cycle checkpoints?
p53 protein is known as the ‘guardian of the genome’. It comes into play if checkpoint activation has occurred. The proteins suspends the cell cycle and triggers DNA repair mechanisms or if the DNA cannot be repaired, apoptosis.
Stem cells show assymetric replication. What is assymetric replication?
When one of the daughter cells remains as a stem cell while the other differentiates into a mature, non-dividing cell.
What is the difference between embryonic stem cells and adult stem cells?
Embryonic stem cells are pluripotent and can give rise to any cell in the body, whereas adult stem cells are lineage-specific - they can only give rise to one adult cell type.
What happens if neurones are damaged?
Neurones are a permanent cell population. Therefore the cells cannot proliferate and replace those that are lost, therefore the tissue space where they were is filled by glial cells (gliosis).
What happens if skeletal muscle is damaged?
Skeletal muscle has only very limited regenerative capacity through stem cells (satelite cells) that are attached to the endomysial sheath.
What happens if cardiac muscle is damaged?
No stem cells are present in cardiac muscle, so damage to the heart, e.g. myocardial infarction, causes a scar.
What is the regenerative capacity of tendons?
Poor - they heal very slowly as they have few cells and few blood vessels. Therefore, secondary rupture at a site of previous injury is not uncommon.
What is the regenerative capacity of bone?
Very good - fibroblasts and osteoclasts are stable cell populations.
What is the regenerative capacity of articular cartilage?
Poor - poor blood supply.
What is the regenerative capacity of adipocytes?
Nil - new fat cells are formed by undifferentiated but committed cells that lie among the adipocytes.
What is the regenerative capacity of epithelia?
Very good - surface epithelia will regenerate over denuded areas. (Exceptions are: lens of the eye and renal podocytes).
What is the regenerative capacity of liver?
Very good - Transplanted livers adjust their size to the size of the recipient and if more than 70% of a human liver is removed, the original weight is restored in 6 months.
What is the regenerative capacity of mesothelia?
Good.
What is the regenerative capacity of melanocytes?
Tend to proliferate too little of too much - scars in pigmented skin are usually pale, but keloid scar formation can also occur.
What is the regenerative capacity of smooth muscle?
Very good - smooth muscle cells retain their mitotic activity can can form new SMCs. This is particularly evident in the pregnant uterus where the muscle walls become thicker by hypertrophy and hyperplasia (mitosis) of individual cells.
What is the regenerative capacity of striated muscle?
Limited - regeneration if from satellite cells (muscle stem cells) that are attached to the endomysial sheath.
What is the regenerative capacity of peripheral nerves?
Regenerate in a predictable way - Sprouting axons grow at 1-3mm/day. If the gap the regenerating axons have to cross is too wide they form a disorganised tangle which can result in a painful amputation neuroma.
What is the regenerative capacity of the CNS?
In humans none - neuones cease to multiply before birth, therefore severed neuones to not grow back effectively. Thus people who have had a stoke recover by the ability of the CNS to establish alternative pathways = plasticity.
What is cell adaptation?
The state between a normal unstressed cell and an overstressed injured cell. It is a cellular response to challenges that are not truly pathologic, although they may open the door to disease. It is usually reversible.
What are the 5 important types of cell adaptation?
- Regeneration
- Hyperplasia
- Hypertrophy
- Atrophy
- Metaplasia
Do cells created by regeneration differ from those that they have replaced?
Regenerated cells are usually as good as their original cells but not always and not immediately. They can take weeks, months or years to reach morphological and functional maturity.
What is the Hayflick number?
It is the number of cell divisions that can occur in a species’ life - this is dependent on the lifespan of the species because of their telomere length. In humans it is 61.3.
How are cells induced to regenerate?
- Growth factors in their microenvironment
- Cell-to-cell communication
- Electric currents and nervous stimuli also appear to play a role in the reconstitution of limbs in amphibians.
What is the difference between reconstitution and regeneration?
Reconstitution is the replacement of a lost body part - it requires the coordinated regeneration of several types of cells (e.g. regrowth of a lizard’s tail or a deer’s antlers). Regeneration is the replacement of the loss of a single type of cell with identical cells in order to maintain the size of an organ or tissue.
Many cell types in mammals can regenerate well but the ability to reconstitute a body part is minimal. What are the few exceptions?
- Small blood vessels (capillaries, small arteries and veins) - if this didn’t take place wound healing would be impossible.
- Children less than 4.5 years old have been reported to reconstitute the tip of a finger if it is cleanly severed and amputated beyond the distal PIP joint.
- Rabbits and cats can repair holes punched in their ears up to a point.
Why is neoplasia a risk in hyperplastic tissues?
The repeated cell divisions that occur in hyperplasia expose the cell to the risk of mutations (which commonly occur during DNA replication).
Why can pathological cardiac hypertrophy result in heart failure?
In cardiac hypertrophy the number of capillaries in the heart increases but not sufficiently to satisfy the increased muscle mass. Therefore in a pathological hypertophic heart there is relative anoxia. Perhaps as results of cell damage due to this anoxia, fibrosis is seen. This decreases the compliance of the cardiac muscle and therefore its effectiveness. Progressive pathological cardiac hypertrophy eventually leads to myocardial exhaustion.
Why is the hypertrophy seen in athlete’s hearts not pathological?
Because athletes, unlike those with valvular disease or systemic hypertension, are able to rest their hearts between exercise. Therefore their hearts are not continuously in a situation of relative hypoxia like those of pathologically hypertrophied hearts.
What happens to cells and organs once the stimulus for hypertrophy and hyperplasia disappears?
Cellular adaptations are reversible, therefore the cells and organs become normal sized once again.
How does cellular atrophy occur?
It involves the shrinkage in size of the cell to a size at which survival is still possible. The cell contains a reduced number of structural components and has reduced function.
In tissue atrophy, what occurs to those cells which undergo apoptosis?
If they are situated on the external surface the cell remnants will be lost into the lumen or from the surface of the body. Otherwise they will be removed by phagocytosis either by macrophages or by neighbouring cells.
In organs undergoing atrophy by cell deletion which cell types undergo apoptosis first?
Parenchymal cells will disappear before stromal cells. Therefore atrophic organs often contain a large amount of connective tissue.
What is the mechanism behind cell shrinkage during cellular atrophy?
Non-essential organelles (e.g. fibrillar material in skeletal muscle) can be paired down by autophagoctosis -> residual bodies containing lipofuscin and remains or organelles that can’t be digested.
Why does bone atrophy occur in astronauts?
A major stimulus to bone formation is mechanical stress, without gravity this mechanical stress does not occur and the extracellular matrix of bones can be lost in atrophy - as it does to bed-ridden patients.
What causes baldness in men?
Hair follicle atrophy.
How is atrophy best treated?
Atrophy is reversible up to a point but after years or months it is less so, especially when parenchymal cells are replaced by connective tissue. The best way to treat atrophy is therefore by removal of its cause.
In which tissues does metaplasia occur?
In adult mammals, metaplasia only occurs within varieties of epithelia and connective tissue. It only occurs in cell populations that can replicate. There is no proven metaplasia across germ lines (e.g. bone to nerve or connective tissue to epithelium).
Give some examples of detrimental metaplase?
- Bronchial pseudostratified ciliated columnar epithelium -> stratified squamous epithelium due to cigarette smoke. There is a loss of the mucocilliary escallator.
- Barret’s oesophagus
- Connective tissue-> bone
- Muscle -> bone can occur when fibroblasts undergo metaplasia to osteoblasts (often seen in young ppl following premature return to activity before proper healing has occurred).
Certain types of metaplasia can predispose to pathological tissue changes?
Metaplasia can sometimes prelude to dysplasia and cancer. Several types of epithelial metaplasia predispose to malignant epithelial cancers e.g. Barrett’s epithelium and intestinal metaplasia of the stomach (due to chronic H.pylori infection).
