Lecture 34 - Disorders Of Differentiation
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Disorders of Differentiation By Prof. J.T. Anim Department of Pathology
Definitions Growth:
- increase in size and mass from synthesis of tissue components
• Multiplicative: - increase in numbers (mitoses) • Auxetic: - increase in size of individual cells • Accretionary: - increase in intercellular components eg. bone
Definitions
Differentiation
•
Morphogenesis
•
Development of overt specialised morphology and or function which distinguishes from parent cell Development of structural shape and form of organs etc. from primitive cell masses during embryogenesis (co-ordination of growth and differentiation as well as programmed cell death – apoptosis)
Cell turnover
•
Balance between cell proliferation and cell death (proliferation > cell death in foetus; decreases in adult)
Disorders of Differentiation and Morphogenesis
Congenital: - chromosomal (3-5%); non-chromosomal (2%)
• Whole chromosomes
• Autosomal: Trisomy 21 (Down), 18 (Edward), 13 (Patau) • Sex chromosomes: Klinefelter (47XXY), Turner (45X0)
• Parts of chromosomes
• Cri-du-chat syndrome (46XX, 5p- or 46XY, 5p)
• Single gene alterations
• 80-85% familial; 15-20% new mutations
Abnormalities of Organogenesis
Agenesis:- Failure of development of an organ or structure
• • •
Failure to develop ureteric bud (blastema) – Renal agenesis Thymic agenesis – Di George syndrome Defect in neural tube - anencephaly
Atresia: - Failure of development of lumen in a normally tubular epithelial atructure
•
Esophageal atresia with or without tracheo-espohageal fistula; biliary atresia, urethral atresia Hypoplasia: - Failure of development of normal size of organ
•
May affect only part of the organ eg. kidney Maldifferentiation: - Failure of normal differentiation of an organ – often retains primitive atructures
•
Kidney (renal dysplasia) – abnormal metanephric differentiation
Ectopia and heterotopia: - Small areas of mature tissue from one organ which are present within another tissue
•
Gastric or pancreatic tissue in Meckel’s diverticulum; Endometriosis in peritoneum
Abnormalities of Organogenesis • • • • • •
Embryo division abnormalities: Incomplete separation (siamese twins) Failure of cell and organ migration – undescended testis, Hirschsprung’s disease, situs inversus Failure of fusion (dysraphia) – spina bifida, cleft palate Failure of separation – webbed digits (syndactyly) Failure of involution – thyroglossal cyst Failure of organ to move from site of development (dystopia) eg. pelvic kidney, undescended testis (cryptorchidism)
Acquired Disorders of Differentiation and Growth
Metaplasia (transdifferentiation)
•
Reversible transformation of one type of terminally differentiated cell into another fully differentiated cell type
• • •
Dysplasia (atypical hyperplasia)
•
Squamous metaplasia in bronchi or urinary bladder Gastric cardiac epithelium in esophagus – reflux esophagitis Mesenchymal tissue eg. bone in soft tissue
A premalignant condition characterised by increased cell growth, presence of cellular atypia and altered differentiation
Neoplasia (new growth)
•
Abnormal tissue mass showing excessive growth that is uncoordinated with that of normal tissue and persists after removal of inducing stimulus
Control of Differentiation
Genetic control
•
Genes are switched on and off to control synthesis of gene products
• Transcription – controlling formation of RNA • Transport – controlling export of mRNA from nucleus to • • •
ribosomes in cytoplasm Translation – controlling formation of gene products Degradation – controlling destabilisation of some mRNAs in cytoplasm Control of protein activity (sequestration/inactivation)
Control of Differentiation Master control gene influence
Control gene influence
Some switched on and off
Transcription
Control of Differentiation
Cell determination – the determined cell must:
• • •
have differences which are heritable from one cell generation to another be committed and commit their progeny to specialised development change its internal character, not merely its environment
Cells may be determined but not differentiated eg. stem cells of bone marrow, basal cells of skin.
Control of Differentiation
Organs contain multiple distinct populations of cells which originate separately, but later interact Differentiation in one cell may be controlled by another – induction
• • •
Mesoderm + ectoderm → neural tube Mesoderm + ectoderm → skin and appendages Ureteric bud (mesonephric) induces metanephric blastema → kidney
Inductive phenomena may also occur in cell migration
Definitions Growth:
- increase in size and mass from synthesis of tissue components
• Multiplicative: - increase in numbers (mitoses) • Auxetic: - increase in size of individual cells • Accretionary: - increase in intercellular components eg. bone
Definitions
Differentiation
•
Morphogenesis
•
Development of overt specialised morphology and or function which distinguishes from parent cell Development of structural shape and form of organs etc. from primitive cell masses during embryogenesis (co-ordination of growth and differentiation as well as programmed cell death – apoptosis)
Cell turnover
•
Balance between cell proliferation and cell death (proliferation > cell death in foetus; decreases in adult)
Disorders of Differentiation and Morphogenesis
Congenital: - chromosomal (3-5%); non-chromosomal (2%)
• Whole chromosomes
• Autosomal: Trisomy 21 (Down), 18 (Edward), 13 (Patau) • Sex chromosomes: Klinefelter (47XXY), Turner (45X0)
• Parts of chromosomes
• Cri-du-chat syndrome (46XX, 5p- or 46XY, 5p)
• Single gene alterations
• 80-85% familial; 15-20% new mutations
Abnormalities of Organogenesis
Agenesis:- Failure of development of an organ or structure
• • •
Failure to develop ureteric bud (blastema) – Renal agenesis Thymic agenesis – Di George syndrome Defect in neural tube - anencephaly
Atresia: - Failure of development of lumen in a normally tubular epithelial atructure
•
Esophageal atresia with or without tracheo-espohageal fistula; biliary atresia, urethral atresia Hypoplasia: - Failure of development of normal size of organ
•
May affect only part of the organ eg. kidney Maldifferentiation: - Failure of normal differentiation of an organ – often retains primitive atructures
•
Kidney (renal dysplasia) – abnormal metanephric differentiation
Ectopia and heterotopia: - Small areas of mature tissue from one organ which are present within another tissue
•
Gastric or pancreatic tissue in Meckel’s diverticulum; Endometriosis in peritoneum
Abnormalities of Organogenesis • • • • • •
Embryo division abnormalities: Incomplete separation (siamese twins) Failure of cell and organ migration – undescended testis, Hirschsprung’s disease, situs inversus Failure of fusion (dysraphia) – spina bifida, cleft palate Failure of separation – webbed digits (syndactyly) Failure of involution – thyroglossal cyst Failure of organ to move from site of development (dystopia) eg. pelvic kidney, undescended testis (cryptorchidism)
Acquired Disorders of Differentiation and Growth
Metaplasia (transdifferentiation)
•
Reversible transformation of one type of terminally differentiated cell into another fully differentiated cell type
• • •
Dysplasia (atypical hyperplasia)
•
Squamous metaplasia in bronchi or urinary bladder Gastric cardiac epithelium in esophagus – reflux esophagitis Mesenchymal tissue eg. bone in soft tissue
A premalignant condition characterised by increased cell growth, presence of cellular atypia and altered differentiation
Neoplasia (new growth)
•
Abnormal tissue mass showing excessive growth that is uncoordinated with that of normal tissue and persists after removal of inducing stimulus
Control of Differentiation
Genetic control
•
Genes are switched on and off to control synthesis of gene products
• Transcription – controlling formation of RNA • Transport – controlling export of mRNA from nucleus to • • •
ribosomes in cytoplasm Translation – controlling formation of gene products Degradation – controlling destabilisation of some mRNAs in cytoplasm Control of protein activity (sequestration/inactivation)
Control of Differentiation Master control gene influence
Control gene influence
Some switched on and off
Transcription
Control of Differentiation
Cell determination – the determined cell must:
• • •
have differences which are heritable from one cell generation to another be committed and commit their progeny to specialised development change its internal character, not merely its environment
Cells may be determined but not differentiated eg. stem cells of bone marrow, basal cells of skin.
Control of Differentiation
Organs contain multiple distinct populations of cells which originate separately, but later interact Differentiation in one cell may be controlled by another – induction
• • •
Mesoderm + ectoderm → neural tube Mesoderm + ectoderm → skin and appendages Ureteric bud (mesonephric) induces metanephric blastema → kidney
Inductive phenomena may also occur in cell migration
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