Cellular Growth and Differentiation

Differentiation

qualitative change in the characteristics of a cell or cell population

reflects change in gene expression (genome reprogramming; up/downregulate gene expression) Þ requires cell division

in neoplasms: well differentiated = like parent cell = more likely benign; poor differentiation = more malignant

cell cycle: length of G₁ phase separates slowly and rapidly dividing cells

stabile cells enter G₀ quiescent phase; they can later be reactivated to enter the cell cycle

regeneration: injured labile or stabile cells can be replaced by cells of the same type (i.e. liver)

replacement: injured permanent cells are replaced by cells of another type (i.e. fibroblasts replace dead myocytes)

regeneration ability of an organ is determined by the predominant cell type of that organ (labile, stable, permanent)

Cellular Adaptations

adaptation is the state between a normal unstressed state and an overstressed or injured state

adaptation can be either physiologic or pathologic

atrophy: shrinkage of cell due to loss of cell substance; could lead to organ shrinkage if enough cells are involved

cells are not dead but have diminished function

physiologic: during fetal development and postnatal life (thymus, uterine after pregnancy, brain with age)

major causes:

decreased workload (cast on leg)

denervation Þ muscle paralysis

ischemia

poor nutrition (anorexia nervosa)

loss of endocrine stimulation

aging

hypoplasia: congenitally underdeveloped organ (hypoplastic lung)

aplasia: organ never developed or cells have failed to multiply (bone marrow in aplastic anemia)

atresia: ‘no orifice’ congenital absence or closure or imperforation

mechanisms: autophagy, necrosis, apoptosis; replacement by fatty or scar tissue may occur

lipofusin: intracellular pigment that may persist and resist digestion (brown atrophy)

ß of anabolic stimuli (oxygen, nutrients) may tip synthesis/degradation balance toward degradation

hypertrophy: increase in the size of cells or an organ (no new cells)

can also occur at the intracellular level as increased smooth ER in response to drug detox (phenobarbital)

physiologic: i.e. growth of uterus in pregnancy

pathologic: in heart and blood vessels with hypertension Þ aortic stenosis, hypertrophic cardimyopathy

in heart: hemodynamic overload (pressure or volume) Þ increased cardiac muscle protein production Þ increased size; also get phenotypic changes: switching contractile proteins to fetal or neonate forms Þ slower contraction; nuclei are enlarged due to polyploidy (DNA synthesis without mitosis)

mechanisms: trophic/hormonal stim (estrogens, angiotensin II); mechanical stress/strain stimulation Þ reduction in vascular supply, diminished oxidation in mito, altered protein synth/degrad Þ dysfunction

hyperplasia: increase in number of cells (not with permanent cells); reversible process

physiologic: i.e. pregnant uterus (hormonal); liver regeneration (compensatory)

pathologic: xs growth factor or hormonal stim i.e. hepatic or pulnonary fibrosis, arteriosclerosis

angiogenesis: good in wound healing; bad in tumors

mechansims: extracellular signals: hormones (estrogen, progesterone, insulin, ANGII); growth factors and inhibitors; extracellular matrix proteins; mechanical stress/strain, radiation, hypoxia, etc. Þ gene expression is controlled by both soluble (growth factors) and insoluble (ECM) stimuli

growth factors: extracellular binding Þ signal transduction Þ activation of transcription factors(nuclear level)

mitogenesis, proliferation: PDGF; NGF; FGF; IGF; TGF; ILs; EGF; peptides; HGF; VEGF; CSF

cytostasis, growth inhibition, cell cycle arrest: TNF; heparin; prostaglandins; interferons, steriods; TGF; angiostatin; endostatin

action of growth factors differs depending on cell type and location

autocrine: normal physiologic conditions Þ growth factor acts on the cell that released it

paracrine: occurs during normal wound healing (i.e. FGF produced by macrophages) and in various disease processes – produced by one cell type and acts on neighboring cells of a different cell type

also juxtacrine (between cells) and intracrine (occur within the cell)

role of ECM: may serve to guide regeneration or act as a reservior for growth factors

desmoplasia: stroma produced by cancer cells in a tumor

matrix metalloproteinases: degrade ECM proteins; provide balance with collagen and proteoglycan deposition – production of matrix proteins is balanced by their degradation

integrins on cell surface recognize and bind to ECM proteins (ECM ligands) Þ changes in cell size and shape; movement or function

ECM systhesis: collagens; elastin; glycoproteins; GAGs; proteoglycans

ECM degradation: collagenases; gelatinases; stromelysins; membrane bound MMPs; metalloelastases

metaplasia: one adult cell type replaced by another; reversible process – occur in epithelial and connective tissue

old cell is sensitive to injury, new cell is better suited to survive (usually response to persistent injury) Þ gene expression is controlled by both soluble (growth factors) and insoluble (ECM) stimuli

most common metaplasia is columnar to squamous due to chronic irritation (i.e. in bronchi)

cannot clear mucus effectively – arise from genetic reprogramming of stem cells in epithelia or undifferentiated mesenchymal cells in connective tissue

Barrett’s esophagus: gastric reflux (heartburn) leads to squamous Þ gastric columnar metaplasia

gastric ulcer: gastric mucosa Þ intestinal crypt-like mucosa (may lead to intestinal type cancer in stomach)

also occurs in mesenchymal cells: fibroblasts Þ osteoblasts or chondroblasts (osseous metaplasia)

mechanism: probably genetic reprogramming of stem cells (i.e. by retinoids - derivatives of vit A)

metaplasia may lead to carcinoma

	Type of Metaplasia	Site	Mechanism (Causative Factors)
Epithelial	Squamous	Bronchus Endocervix Bladder (Gall, UT) Pancreas	Cigerette smoking, chronic inflammation Chronic inflammation Chronic inflammation, schistosomiasis Stones ?
Epithelial	Intestinal	Esophagus Stomach	Acid Reflux (Barrett's esophagus) Alkaline reflux, chronic inflammation
Epithelial	Gastric	Esophagus Intestine	Acid reflux ?
Epithelial	Serous (mucinous)	Ovary (germinal)	Trauma of multiple ovulation
Mesenchymal	Osseous	Fibrous scars Calcification	? ?
Mesechymal	Myeloid	Spleen, liver	?

dysplasia: disordered growth, bad development or abnormal function, partial loss of control and organization

may occur in epithelial or mesenchymal tissue; may often occur in metaplastic squamous epithelium
common cellular changes:

nuclear: increased size, inc nucleus-to-cytoplasm, inc chromatin; chromatin clumping, nuclear membrane thickening or wrinkling
cytoplasmic: abnormal differentiation (i.e. lack of keratinization of squamous cells)
increased multiplication: hyperplasia with evidence of mitotic figures

dysplasia is often reversible
carcinoma in situ: pre-invasive dysplastic lesion that spans many layers
squamous intraepithelial lesion (SIL): in cervical tissue

low grade (1/3 progress to high grade); high grade (1/3 progress to malignant neoplasm)

anaplasia: lack of differentiation and sometimes regression from adult to a more primative cell type; malignancies that contain undifferentiated cells

most likely due to lack of differentiaion rather than dedifferentiation
similar to dysplasia but more extreme
high mitotic index

high mitotic index does not necessarily mean malignancy – could just be a high turnover tissue

features: bizarre, atypical mitotic figures (disorganized chromatid separation, etc.); giant tumor cells; loss of polarity; disorganization