V.C - M - Haematopoiesis (Foetal/Adult) in vertebrae - Marrow, Cell lineages, Inherited disorders, Hypo/hyperplasia, Thalassemia Flashcards
Define haematopoeisis?
This is the process by which all the blood cells and blood cellular components are formed
When does haematopoeisis begin? What are the types of mature blood cells?
Haematopoeisis begins from as early as 3 weeks gestation in the yolk sac and continues throughout life in order to reproduce and replenish the blood supply Mature blood cells Erythrocytes (red blood cells) Thrombocytes (platelets) Leukocytes (white blood cells)
The earliest place that blood cell formation is seen in the embryo is in the yolk sac at around three weeks gestation. When does haematopoeisis in the yolk sac continue until?
The yolk sac continues producing blood cells up until the 10th week of gestation
How does blood first appear from the yolk sac?
Around week 3 of development, blood islands form in the yolk sac arising from mesodermal cells that form hemangioblasts which are precursors to blood cell formation
Three waves of cells then arise from the yolk sac one after the other. What is this process known as?
The process of the three waves of cells arising from the yolk sac is known as extraembryonic haematopoeisis
What is the first wave arising from the yolk sac in extraembryonic haematopoeisis?
The first wave of cells serve the immediate needs of the growing embryo and are mainly large nucleated erythrocytes
The first wave in extra-embryonic haematopoisis is to serve the immediate needs of the embryo and binucleated erythrocytes are formed in the yolk sac What are the second wave of cells formed in the yolk sac?
The second wave of cells formed in the yolk sac rapidly follows the first one and consists of erythromyeloid progenitors and lymphoid progenitors that seed the foetal liver
The second wave of cells from the yolk sac rapidly follow the first wave and consist of erythromyeloid progenitors and lymphoid progenitors that seed the liver What is the third wave of cells produced in the yolk sac during extra-embryonic haematopoeiss?
The third wave of cells includes self-renewing haematopoieitc cells and it gives rise to the permanent adult haematopoietic system
What is the debate in the literature regarding the third wave of cells from the yolk sac?
There is debate in the literature about whether the haemapoietic stem cells actually arises from the aorto-gonad-mesoneprhos region or from precursor cells in the yolk sac If the HSC actually arise from the aorto-gonad-mesonephros region, then this would support the theory that the cells actually arise in vitro (locally)
Lets talk about the aorto-gonad-mesonephos region What is this region and what definitive cells arise from here?
The aorto-gonad-mesonephros region is an area of mesoderm surrounding the aorta which is where definitive haematopoeitic stem cells arise from
After the HSC arise in the aorto-gonad-mesonephors region, where do they go?
These cells will then go on to colonise the liver in order for it to become the major haematopoietic organ of the embryo/foetus before colonising the bone marrow near birth
As said the liver is colonised by haematopoeitc stem cells that have migrated to the liver via the blood stream from the mesoderm around the aorta What period is the liver the major site of haematopoeisis in the embryo? What happens to the livers blood forming function after this? Which other organ do the HSC colonise to some extent?
The liver is the major site of haematopoesis from the second to seventh month of gestation After this the liver loses its blood forming function as the HSC migrate to the bone marrow The HSC also colonize the spleen to some extent after being produced in the aorta-gona-mesonephros region
When does the bone marrow become colonized by stem cells? What part of the bone does the HSC from the liver colonize?
The bone marrow becomes colonized by stem cells from the liver at 7 months gestation As the bone develops it forms cavities, it is these cavities that the cells colonize
The red bone marrow in and adult skeleton acts as a lifelong reserve of HSC and is the site which haematopoiesis takes place. Which organs still carry some residual haematopoietic activity after birth when needed? Where is the main sites of haematopoiesis in children and adults?
The spleen and liver still carry some residual haematopoeitc activity after birth when needed Main sites of haematopoesis in children - long bones Main sites of haematopoeiss in adults - no longer in long bones but mainly in the pelvis, sternum, ribs, cranium, vertebrae and proximal aspect of long bones (the axial skeleton mainly)
What is bone marrow and where is it found? What percentage of the body weight does it account for?
Bone marrow is the soft, spongy gelatinous tissue found in the hollow cavities of flat and long bones It accounts for 5% of the body weight
Bone marrow is made of hematopoietic tissue islands and adipose cells that are surrounded by vascular sinusoids. What part of the bone are these haematopoietic tissue islands and aipose cells interspersed within? What are the two types of stem cells that can be found in the bone marrow?
The bone marrow is interspersed within the network of trabeculae within the cancellous bone The two types of stem cells found in bone marrow or haematopoeitc stem cells (blood) and mesenchymal stem cells (cartilage and bone)
The scaffolding of the bone marrow is comprised of components of the extra cellular matrix. It is this scaffolding which provides stiffness to the bone marrow making it the ideal environment for hematopoietic stem cells to differentiate. What is the difference in blood supply to the bone marrow in flat and long bones?
Flat bones, bone marrow blood supply - numerous blood vessels entering via large and small canals Long bones, bone marrow blood supply - one or more arteries passing through the cortical bone network to enter the bone marrow
Two types of bone marrow are red and yellow bone marrow Which replaces the other with age? Which is mainly made up of adipose cells? Which is the haematopoietic portion of bone marrow? Which can be converted to the other in times of stress?
Red marrow is mainly made up of haematopoietic stem cells and yellow marrow is mainly made up of adipose tissue The red marrow is replaced with yellow marrow in aging process In times of stress, the yellow marrow can be converted into the red marrow
What is the difference between where red and yellow marrow is found in adults? What is the difference in function of red and yellow marrow?
Red bone marrow is found in flat and short bones, articular ends of long bones, bodies of vertebrae, cranium, sternum and ribs Yellow marrow is found in the shafts of long bones * Red marrow serves to produce and remove blood cells from circulation * The function of yellow marrow is uncertain and it is thought that it may provide surface and nutritional support for red marrow
Bone marrow is a complex tissue, and as we have already seen it contains hematopoietic, mesenchymal and endothelial cells. It is also organized into distinct niches in order to regulate haematopoiesis. What are the two niches organised within the bone marrow?
The two niches organised within the bone marrow are the endosteal and perivascular niche
There are two niches within the bone marrow which are the perivascular and endosteal niches and they both act differently to influence HSC function. Where is the endosteal and perviascular niches located?
The endosteal niche is located at the bone-bone marrow interface The perivascular niche is located within the bone marrow
What haematopoietic stem cells are located in the endosteal and perivascular niche?
The long term haematopoietic stem cells are located within the endosteal niche of the bone at the bone-bone marrow interface The short term haematopoietic stem cells are located within the perivascular niche near the sinusoid and perivascular cells within the bone marrow
Which niche supports HSC proliferation and maturation?
The perivascular iche supports HSC proliferation and maturation
Another structure located at the niches within the bone is the haemosphere. What has there function been found to be? When are haemospheres formed?
The function of the haemosphere has been found to recruit and maintain HSCs The haemasopheres are formed whenever bone is remodelled around a blood vessel and it is maintained by singaling through the vascular endothelial growth factor receptor 2 (VEGFR 2) located on endothelial cells
There is a hierarchal system for the process in which HSC are driven down specific cell pathways to form specific cell types Production of blood cells controlled by growth factors and hormones. Produced locally in bone marrow or are systemic. How do the LT-HSC give rise to the myeloid and lymphoid lineages?
LT-HSC are at the top of the hierarchal system and are capable of self-renewal and multilineage differentiation They will differentiate to form ST-HSC which are capable of multilineage differentiation which differentiate to form multipotent progenitor cells - these descend to either common myeloid progenitors or lymphoid multipotent progenitor cells
The CMP differentiates to form GMP and MEP cells What do these acronyms stand for? What do GMP and MEP cells produce?
CMP - common myeloid progenitor - forms GMP and MEP GMP - graanulocyte macrophage progenitor - forms granulocytes and macrophages MEP - megakaryocyte-erythrocyte progenitor - forms platelets and red blood cells (erythrocytes)
What do lymphoid multipotent progenitor cells give rise to?
LMPP cells give rise to Common lymphoid progenitors (CLP) which form lymphoid lineages B cells T cellls Natural killer cells (and dendritic cells)
What is the most abundant type of blood cell? What is its function? What are they derived from in embryos and adults?
The most adunant type of blood cell in the body is the red blood cell (erythrocyte) It functions to carry oxygen to all of the body tissues In embryos there is a primitive and definitive lineage of eryhtrocytes In adults, all red blood cells are produced from HSCs found in the red bone marrow
What is the difference between the primitive and definitive lineages in the embryo?
The first lineage of primitive erythrocytes develops early in gestation and produced nucleated red blood cells The second lineage of definitive erythrocytes is produced in the foetal liver and this continues throughout pre-natal life (by month 7, bone takes over as major organ responsible for haematopoeisis)
What are platelets derived from? When can platelet production be increased?
Platelets are derived form very large cells known as megakarycoytes which remain in the bone marrow Platelet production can be increased in times of excess
The megakaryocytes produced platelets by undergoing multiple duplications of its nuclear material but never undergoes nuclear or cellular division. The platelets are formed from the extensions of the margins of the shell that have been fragmented off. After the cell has produced thousands of platlets the cell will undergo cell death by apoptosis. What are the extensions of the megakaryocytes that allow the platelets to enter the sinusoids and later the circulation known as?
These extensions from which platelets extend from the megakaryocyte are known as proplatelets
The granulocytes are divided into three groups - neutrophils, eosinophils and basophils What is the function of ll three cells?
Neutrophils are important as a 1st line in defence and phagocytose bacteria Eosinophils reside mainly in the spleen, lymph and GI tract and are important for fighting parasitic infections and hypersensitivity Basophils contain histamine & heparin which are released in the presence of an allergen
What cells do B cells give rise to? What do T cell deficiencies include? (name the two big hitters)
B cells give rise to plasma cells which produce antibodies to fight infection and disease Tcell deficiencies can lead to HIV and AIDS
Bone marrow failure syndromes are a group of rare genetic blood disorders in which there is usually some form of aplastic anaemia which is the failure of the bone marrow to produce blood. What is amegakaryocytic thrombocytopenia? What is the inheritance?
This is a rare inherited (congenital) or acquired disorder resulting in a reduction or absence of megakaryocytes in the bone marrow causing a severe platelet deficiency Amegakaryocytic thrombocytopenia is inherited in an autosomal recessive fashion
What is Diamond Blackfan Anaemia? What is it also known as? What is its inheritance?
Diamond-blackfan anaemia - aka congenital red cell aplasia This is a rare ribosomopathy - arises due to mutation in the genes which provide instructions to make several different ribosomal proteins Dimond Blackfan Anaemia is inherited in an autosomal dominant fashion
What are the symptoms in Diamond Blackfan syndrome?
Children develop with an unusually small head (microcephaly), wide set eyes and droopy eyelids (ptosis), a small lower jaw (micrognathia), Individuals may also have a cleft palate with or without a cleft lip and shoulder blades that are smaller and higher than usual As well as absent thumbs
Dyskeratosis congenita is a rare progressive congenital disorder than can have a highly variable phenotype and affect many parts of the body What is it caused by?
Dyskeratosis congenita aises due to a mutation in the telomere repair genes leading to short telomeres that do not function correctly
What is the treatment of dykeratosis congenita?
Treeatment includes androgen therapy and stem cell transplantation
What is fanconi anaemia? What does it arise due to? What is there a high risk of transformation to?
Fanconi’s anaemia is a rare inherited disorder that can cause aplastic anaemia It arises due to gene mutations causing the inability to repair inter-strand cross links that have damaged DNA With Fanconi’s anaemia, the individual is at an increased risk of developing acute myeloid leukaemia
What is severe congenital neutropenia characterised by? What is it also known as?
Severe congenital neutropenia is characterised by a profound lack of neutrophils in the blood ( 9 /litre) causing affected individuals to be very prone to infections Severe congenital neutropenia aka Kostmann syndrome
Schwachman Diamond Syndrome is a rare autosomal recessive multi-systemic inherited disorder What is usually the presentation in blood and what can it progress to? What parts of the body does it particularly affect?
Most individuals usually present with a neutropenia that can progress to a pancytopenia The disease may progress to acute myeloid leukaemia in a significant number of patients Uusally the syndrome affects the bone marrow, pancreas and skeletal syndrome
What is thought to the be the cause of Schwachman Diamond Syndrome?
In 90% of cases Schwachman Diamond Syndrome arises due to a a bi-alleic mutation in the SBDS gene which plays an important role in the maturation of the 60S ribosomal subunit and therefore important in ribosome biogenesis
We will now Discuss The Aetiology and Effects of Hypoplasia and Hyperplasia of the Bone Marrow of the Vertebral Column What is hypoplasia? What does bone marrow hypoplasia result in?
Hypoplasia is the underdevelopment or incomplete development of an organ or tissue Bone marrow hypoplasia results in a decrease in all three cell lineages and can be idiopathic or secondary from other causes
What are factors that can injure the bone marrow? What are the symptoms of bone marrow hypoplasia? What is the treatment?
Factors that can injure bone marrow: Drugs, Radiation and chemo Tx Exposue to toxic chemicals Autoimmune disorders, Pregnancy, Viral infecitons Symptoms - Fatigue High risk of infection Uncontrolled bleeding Treatment- Medications Blood transfusion Stem cell transplant
