MoD session 7: cellular adaptations Flashcards
Outcomes of cell communication
Division: entry into cell cycle
Differentiation: to specialised function
Survive: resist apoptosis
Die: apoptosis
Types of cell signalling
AUTOCRINE: cells respond to signals that they produce
INTRACRINE: a type of autocrine. Cell makes factor that binds to intracellular receptor in cell (but factor is not secreted)
PARACRINE: cell produces signalling molecule that acts on adjacent cells.Responding cells are close to secreting cell and are often of a different type
ENDOCRINE: hormones produced by endocrine cells are moved in blood to targets
What is a growth factor?
A local mediator or hormone that acts over a short distance or on the cell itself. They are polypeptides coded for by proto-oncogenes. Bind to a receptor and stimulate transcription of genes that regulate the entry of the cell into cell cyle.
Some have many targets whereas some are more restricted.
Effects: cell proliferation/inhibition, locomotion, contractility, differentiation, viability, activation, angiogenesis
Epidermal growth factor EGF
Mitogenic for epithelial cells, hepatocytes and fibroblasts
Produced by keratinocytes, macrophages and inflammatory cells
Binds to EGFR
Vascular endothelial growth factor VEGF
Induces vasculogenesis, role in angiogenesis in tumours, CI and wound healing
Platelet-derived growth factor PDGF
Stored in platelet alpha granules and released when platelets activated; also produced by macrophages, endothelial cells, smooth muscle cells and tumour cells.
Causes migration and proliferation of fibroblasts and smooth muscle cells
Granulocyte colony-stimulating factor G-CSF
Stimulates bone marrow to produce granulocytes and release them into blood; especially neutrophils.
SUed in chemotherapy to stimulate bone marrow
Describe the cell cycle
G0: terminally-differentiated cells. Can feed into G1 if not permanent
G1: presynthetic, cell grows
R: restriction point-most important checkpoint at which p53 can repair DNA or induce apoptosis
Another checkpoint: to check for DNA damage
S: DNA synthesis
G2: premitotic, followed by another checkpoint checking for DNA damage
M: mitosis and cytokinesis. Distinctive appearance under light microscope
How does the cell cycle influence growth?
Cell cycle shortens
or
Conversion of quiescent cells into proliferating cells by making them enter the cycle
Control of the cell cycle
Cyclins and cyclin-dependent kinases
CDKs activated when bind to cyclins, and drive the cycle by phosphorylating proteins. Activity of these are regulated by CDK inhibitors
Some growth factors stimulate cyclin production, and some inhibit
What are stem cells?
Adult: lineage-specific cells with prolonged proliferative activity and asymmetric replication (one daughter cell remains a stem cell whilst the other divides into a mature cell type)
Embryonic: pluripotent
Describe the different types of tissue
PERMANENT: contains terminally-differentiated cells. Stem cells can be present but not enough to cause an effective proliferative response to cell loss, so tissue can’t proliferate. E.g. cardiac muscle (scar after MI), skeletal muscle (v. limited regeneration through stem cells in endomysium) and neurones (damaged space filled with glial cells)
LABILE: can proliferate even though has mature non-differentiated cells; cells short-lived and continually replaced by stem cell derivatives. E.g. epithelium, bone marrow
STABLE: intermediate tissue type. Cells usually non-replicating (in G0), but can be induced into G1 if necessary by activation of genes such as proto-oncogenes and genes for ribosome synthesis. Stem cells usually quiescent but can replicate. E.g. hepatocytes, osteoclasts, fibroblasts, smooth muscle cells, vascular endothelial cells
Describe tissue regeneration. Why does it occur, how is it induced and what are the outcomes?
Cells multiply to replace losses, and are replaced by identical cells to maintain tissue/organ size.
Occurs physiologically as blood replacement by bone marrow, or in response to injury where the harmful agent has been removed and there’s limited tissue damage.
Induced by growth factors, cell-to-cell communication and electric currents.
Outcome is species and lifespan dependent, quality not always as good as original cells, can take years to reach morphological and functional maturity
Give examples of regeneration in different tissues
Bone: very good
Epithelium: very good except lens and renal podocyte
Liver: very good. E.g. in transplants
Smooth muscle: very good
Mesothelium: good
Tendons: poor; heal slowly as few cells and vessels so secondary rupture common
Articular cartilage: poor
Striated muscle: poor, from satellite cells in endomysium
CNS: none. Recover through alternative pathways
Peripheral nerves: axons grow 1-3mm/day
Melanocytes: too much or too little
Adipocytes: none-new fat cells formed by undifferentiated cells
What is reconstitution?
Replacement of a lost part of the body, so a coordinated regeneration of several cell types. E.g. regrowth of a lizard tail
Does not occur in mammals, except:
- small blood vessles ‘reconstitute’ during wound healing
- children
What is hyperplasia, and in what tissue types can it occur?
Increase in tissue/organ size due to an increase in cell numbers; only occurs in labile or stable populations.
Is under physiological control and is reversible
Give some physiological and pathological examples of hyperplasia
PHYSIOLOGICAL: hormonal to increase functional capacity or compensatory to increase tissue mass after injury. E.g.:
- increased bone marrow production of erythrocytes in low O2
- proliferation of endometrium with oestrogen
PATHOLOGICAL: hyperplasia occurring secondary to a pathology, but this is a normal response to an abnormal condition. Usually due to excess hormone/growth factor. E.g.
- epidermal thickening in eczema and psoriasis
- enlargement of the thyroid in iodine deficiency
Why is there an increase risk of neoplasia due to hyperplasia?
More cell divisions, so more chance of mutation
What is hypertrophy and where does it occur?
Increase in tissue/organ size due to an increase in cell size. More structural components (not swelling!) as cells make more cytoplasm allowing cellular workload to be shared between a greater mass of cellular components.
Occurs in many tissues but mainly permanent tissues, as they can only increase by hypertrophy not hyperplasia.
In stable/labile usually occurs alongside hyperplasia as triggered by the same stimulus, e.g. endocrine stimulation
Give some physiological and pathological examples of hypertrophy
Physiological:
- skeletal muscle in body builder
- smooth muscle of pregnant uterus (with hyperplasia)
Pathological:
- ventricular cardiac muscle due to systemic HTN or valvular disease
- smooth muscle above an intestinal stenosis (more work)
- bladder smooth muscle when obstructed due to enlarged prostate (which has undergone HT and HP)
Why can athletes develop physiological cardiac hypertrophy?
Heart under strain for a few hours a day but has time to recover so not pathological.
Cardiac hypertrophy involves generation of more capillaries, but insufficient for level of growth. In pathological conditions this causes anoxia as is not sufficient to meet increased demands, but because athlete increased demand is only when exercising the myocardium can recover.
Compensatory hypertrophy
When one of a paired set of organs is removed, the other enlarges by hypertrophy and hyperplasia (e.g. kidneys).
When stimulus disappears, become normal size again
Cellular result of excess nutrition
Increased fat tissue and increase protein synthesis
Once fat cells are made they are with us for life, so childhood obesity is very problematic
What is atrophy?
Shrinkage of a tissue or organ due to an acquired decrease in the size and/or number of cells. Due to decreased supply or growth factors and/or nutrients. It is reversible up to a point, but less reversible over months/years, especially when parenchymal cells are replaced by connective tissue, therefore it is best treated by removal of the cause.
Cellular atrophy: shrinkage in cell to a size where survival possible, but reduced structural components and reduced function. An adaptive response that may lead to cell death
Organ/tissue atrophy: combination of many cells in the tissue undergoing cellular atrophy and apoptosis
Method of atrophy
Depends on type of tissue involved:
1. CELL DELETION: certain cells picked out and induced to apoptosis, cell remnants lost into lumen/surface of body, or removed by phagocytosis. Parenchymal cells will disappear before stromal cells, therefore atrophic organs have a loss of connective tissue
- CELL SHRINKAGE: has limits because most organelles are essential, but some non-essentials can be shrunk, e.g. the fibrillar material of skeletal muscle. Occurs by self-digstion; see residual bodies, ubiquitin (a HSP) is involved by targeting proteins for destruction
What are residual bodies?
Autophagosomes containing lipofuscin and the remains of organelles, that are seen following cell shrinkage atrophy
Senescence
The process of growing old.
E.g. baldness is adult males is the result of atrophy of hair follicles
Examples of physiological atrophy
Ovarian atrophy in post-menopausal women
Examples of pathological atrophy
DISUSE: decreased functional demand causes atrophy. Can be reversed with activity/electrical activity
DENERVATION: motor damage e.g. of median nerve causing wastage of striated muscle, or sensory damage e.g. skin in feet becomes thinner and scaly
ISCHAEMIC: partial and prolonged inadequate blood supply, e.g. thinning of skin of legs in peripheral vascular disease
LOSS OF ENDOCRINE STIMULATION: e.g. in breast and ovaries after menopause, or in the adrenal gland due to loss of pituitary ACTH following hypophysectomy
PERSISTENT INJURY e.g. polymyositis (muscle inflammation)
SENILE: in permanent tissues e.g. brain and heart; liver kidney and spleen weight also decrease in old age; immune response lower
PRESSURE: e.g. tissues around an enlarging tumour can atrophy, or thoracic aortic aneurysm can erode sternum
OCCLUSION: of a secretory duct. Causes apoptosis of parenchymal cells. E.g. in pancreas causes disappearance of exocrine ducts, leaving CT and IoL
TOXINS e.g. on bone marrow and testes
X-RAYS: direct cellular and microcirculatory damage
IMMUNOLOGICAL: e.g. atrophic gastric mucosa in pernicious anaemia, as body produces autoantibodies against parietal cells so can’t absorb vitamin B12
What is metaplasia and in which cells does it occur?
Reversible replacement of one adult differentiated cell phenotype by another of a different type, to suit an altered environment. Steam cells reprogrammed to produce different cells; “abnormal regeneration”:
- cells express a new genetic programme so assume a different structure and function
- occurs due to signals from cytokines and growth factors
- often induced by stimuli that cause cell proliferation
Only occurs in stable/labile tissues, and only in epithelia and connective tissue cells.
NONE across germ layers (e.g. bone to nerve) or from a CT to epithelium
Describe metaplasia of epithelia
Most common form of metaplasia.
Often from columnar to stratified squamous epithelium (changing to a more resilient type) so often on surface linings exposed to insult
May cause loss of function, e.g. loss of mucous secretion
Describe how metaplasia can be beneficial
- MYELOID METAPLASIA: when bone marrow destroyed by disease, splenic tissue becomes bone marrow
- Columnar–>stratified squamous in ducts of salivary gland/pancreas/bile/renal due to chronic inflammation by stones so offers protection from mechanical abrasian
What can metaplasia be a prelude to?
Dysplasia and cancer
Describe examples of detrimental metaplasia
Bronchial pseudostratified ciliated columnar–>stratified squamou epithelium due to smoking. Mucous not produced and cilia destroyed, so muco-ciliary escalator ineffective causing more infections
Barrett’s oesophagus: stratified squamous changes to gastric/intestinal type due to persistent acid reflex. Predisposes to malignancy (adenocarcinoma)
Aplasia
Complete failure of a specific tissue/organ to develop: embryonic developmental issue. E.g. thymic aplasia causing infections/autoimmune issues; aplasia of a kidney
Also used to describe an organ whose cells have stopped proliferating, e.g. aplasia of bone marrow in aplastic anaemia
Involution
Overlaps with atrophy; is the NORMAL programmed shrinkage of an organ. E.g.:
- uterus following childbirth
- thymus in early life
- temporary foetal organs
Hypoplasia
NOT OPPOSITE OF HYPERPLASIA: as congenital. Underdevelopment or incomplete development of tissue/organ due to too few cells
E.g. renal, breast, testicular (in Klinefelter’s), chambers of heart
Atresia
‘No orifice’
Congenital imperforation of an opening e.g. of anus or vagina
Dysplasia
Abnormal maturation of cells within a tissue. Potentially reversible, but often pre-cancerous. Dysplastic epithelium is disorganised with abnormal differentiation
Skin diseases
Chronic eczema: chronic dermatitis, no reason, itchy scaly skin
Psoriasis: inflammatory dermatitis. Scaly silvery skin, raised pink lesions, may itch/hurt/bleed. Microscopic: cutaneous CI and epidermal hyperproliferation. Clubbed epidermal projections interdigitating with dermis; stratum granulosum often missing/thinned. Commonly affects the scalp, sacrum and extensor parts of knees and elbows. Caused by hyperproliferation of keratinocytes. Can also affect nails and cause arthritic psoriasis
Goitre
Seen in iron deficiency: thyroid gland swells by hyperplasia to make more hormone
or
Hyperthyroidism: increased TSH acts on thyroid causing swelling
Left ventricular hypertrophy
Due to aortic stenosis, aortic regurgitation, mitral regurgitation and hypertension. Muscle works harder=gets bigger
Benign prostatic hyperplasia
Transitional area of prostate enlarges, DOES NOT ncrease cancer risk but most elderly men have both
When this area is enlarged it pushes the peripheral zone towards the rectum, therefore enlarged prostate can be felt on examination.
Tightens urethra causing urinary symptoms (chronic retention and increased infection susceptibility). Can lead to hypertrophy of bladder muscle wall causing incontinence due to distended wall and renal failure
Myositis ossificans
Fibroblasts metaplase to osteoblasts, often when there is premature activity before fully-healed from trauma
Endometrial hyperplasia
Usually persistently high oestrogen. May denote premalignancy.
Microscopically there is thicker epithelia with more glands present. May also have polyps (multi focal lesions)
Risk factor: obesity, as adipose releases androgens which are converted to oestrogen; this stimulates endometrial proliferation
Osteoporosis of disuse
Bone atrophy. ECM lost as mechanical stress is main factor for osteogenesis. NOT LOSS OF CALCIUM
What is a pipelle biopsy?
Biopsy of uterus: tube passed through cervix and into uterus, biopsy taken by slight suction using a flexible polypropylene suction cannula
Cerebral atrophy
On brain see: shrinkage, bigger sulci, smaller gyri
Caused by ageing, Alzheimer’s disease, TIA, stroke, atheroma, MS, epilepsy, diabetes..
