Erythropoiesis

• Erythropoiesis is the body's process of creating red blood cells (erythrocytes).
• Erythropoiesis is crucial for human physiology, as it ensures efficient oxygen transport from the lungs to the rest of the body.
• Approximately 10^12 erythrocytes are made daily from haematopoietic stem cells(HSCs).
• Primitive erythroblasts fulfill the oxygen requirements of early embryos.
• Erythropoiesis primarily occurs in the bone marrow.
• This process starts in the embryonic stage and lasts an entire lifetime adapting to meet changing needs
• The areas covered are erythropoiesis, structure of erythrocytes and precursors, and the metabolism and function of erythrocytes.

Importance of Erythropoiesis

• RBCs transport oxygen from the lungs
• RBC also transport carbon dioxide from tissues back to the lungs.
• Erythropoiesis maintains the balance of RBC numbers to prevent anemia (too few) or blood clots (too many).
• Erythropoiesis increases RBC production when the body detects hypoxia

Fetal Erythropoiesis

• Fetal erythropoiesis is the process of red blood cell production in a developing fetus.
• It's important for providing adequate oxygen to support fetal growth.
• The process is regulated based on the fetus's changing needs.
• Erythropoiesis begins in the yolk sac during weeks 3-8, where primitive erythroid cells are produced
• The liver and the spleen become primary sites for RBC production from months 2-5.
• From the fifth month of gestation, the bone marrow becomes the central location for erythropoiesis.

Adult Erythropoiesis

• In adults, erythropoiesis occurs primarily in the bone marrow of bones like the pelvis, vertebrae, ribs, sternum and proximal femur
• Up to age 20, red marrow in all bones (long and flat) produces RBCs.
• After age 20, flat bones like the vertebrae, sternum, ribs, scapulas, and iliac bones takes the role as the primary site for erythropoiesis
• The vertebra, sternum, pelvis, ribs, and cranial bones keep producing RBCs.
• The shafts of long bones become yellow marrow, due to fat deposition, and lose their erythropoietic function.

Regulation of Erythropoiesis

• Kidneys detects hypoxia by sensing lower oxygen levels and starts the process of making RBC.
• In response to hypoxia, the kidneys produce erythropoietin (EPO).
• travels to the bone marrow and binds to erythroid progenitor cells..
• EPO stimulates progenitor cells to proliferate into erythroblasts (immature red blood cells).
• Erythroblasts mature and become reticulocytes, which eventually matures into red blood cells.

Steps of Erythropoiesis

• Four main cell stages: stem cells, progenitor cells, precursor cells, and mature cells.
• During erythropoiesis cell sizes decreases, and the cytoplasm volumes increase.
• As the cell matures the size of the nucleus reduces until it disappears with the condensation of the chromatin material
• The duration from proerythroblast to erythrocyte lasts 6-8 days.
• Proerythroblast to reticulocyte takes 4 days.
• Reticulocyte to erythrocyte (a time where the reticulocyte spends about 1-2 days in the marrow and 1-2 days circulating in blood).

Differentiation: HSC and Erythroid Progenitor

• Hematopoietic stem cells (HSCs) first differentiate into MultiPotent Progenitor cells(MPP).
• MPPs have limited self-renewal capacity.
• MPPs differentiate into lineage-specific progenitor cells, such as Common Myeloid Progenitor(CMP).
• CMPs differentiate into bi-potential Megakaryocyte-Erythroid Progenitors(MEPs).
• MEPs create megakaryocytes or erythroid cells.
• Special transcription factors such as GATA-1 and FOG-1 crucial for erythroid differentiation

Key Factors in Erythroid Lineage Commitment

• GATA-1 master regulator for the procedure.
• FOG-1 regulates erythroid.
• KLF1 activates genes for erythroid
• TAL1 is involved early in the process.
• BACH1 and BACH2 helps myeloid, erythroid and lymphoid.

BFU-E and CFU-E in Erythropoiesis

• The burst-forming unit-erythroid (BFU-E) and colony-forming unit-erythroid (CFU-E) are crucial stages in the process.
• Megakaryocytes and MEP give rise to erythroid cells making BFU-E and CFU-E steps.
• Those processes involves several key stages and factors

Erythropoietin (EPO)

• EPO is a glycoprotein
• EPO is 90% produced in the kidneys and 10% is produced in the liver.
• There is no preformed storage, production in the kidney tissue occurs in response to tension.
• HIF promotes the expression of EPO genes.
• Hif stabilizes production of erythropoietin production
• EPO response is affected by iron deficiency.

Proerythroblasts (ProE)

• In erythropoiesis, the next step after the CFU-E stage is the ProE stage
• They are highly mitotic and have high expression of EPO receptors.
• They are easily recognisable precursors.
• The nucleus is the centre and has a fine chromatin pattern with high N:C ration
• The cytoplasm, is deeply basophilic and has a dark border that could have earmuffs on the side and of overall size 12 - 20µm

Basophilic Erythroblasts (BasoE)

• As ProE cells differentiate, they become smaller and starting to store ribosomes
• During staining BasoE show a blue colour called prorubricyte
• Characterized by haemoglobin synthesis condensation of chromatin, roughly 1-5% in bone marrow
• The nucleus turns a dark round with higher N:C ratio of 6:1 with only 0-1 nucleoli
• Furthermore shows very dark blue on the cytoplasm, a perinuclear halo of overall dimensions 10-15µm

Polychromic Erythroblasts (PolyE)

• As BasoE cells accumulate more haemoglobin they mature to become PolyE.
• Which changes cell colour, staining everything gray-green from all the haemoglobin and ribosomes generating polychromic erythroblasts.
• Roughly 5-30% in bone marrow but not in peripheral blood is the common case
• ecccentric nucleus with a coarse chromatin of all dimensions 10 - 12µm

Orthrochromic Erythroblasts(OrthoE)

• As PolyE matures the color intensifies and that's called Orthochromatic and produces meta rubricyte.
• That's happens because the more haemoglobin stores more cells will expelled with smallest RBA precursors and can't synthesize
• But it can be seen in smears of newborns
• With eccentric fully condense nucleus
• The dimensions are 8 - 10µm with salmon like colour

Generating Reticulocytes(Retics)

• Process starts when OrthoE form Retics and turns into Polychomatic Erythrocyte
• The nucleus expelled from the cell with residual RNA and gives a polychromatic appereance with help of a Methylene blue.
• Key features are lack of Nucleus of dimensions around 8 - 8.5µm

Maturation into normochromic erythrocytes (RBC)

• Matures in 1-2 days and makes 270M haemoglobin
• it's shape increases surfacce area for gas exchange and that's only one aspect of the cells.
• The second key feature is it prevents passing through narrow capillaries.
• Key features of cytoplasm is salmon pink, the other feature is it contains central pallor, which contributes to the final diameter (7-8µm), with 1/3 on top

Membrane Function

• Consist membrane lipids that make Red cell membrane and are lipid bilayer that are 1:1 in molar ratio.
• Principles of the membrane can be affected.
• Membrane proteins like transmembrane proteins produce anions with negative outer edge and oligosaccharide attached to the surface
• They can be skeletal and are periphericals that work with ankyrin and structural internals.
• They provide function/shape of cells for structural purposes

Permeability

• Freely permeable to water and anions and (HCO3/Cl)
• Take up glucose with transport and no addition ATP
• Main types of actions are:
• impermability of Mg2/K- or monovalent or divalent +ions/cations
• Sodium and K need ATPase to function levels correctly .
• if this is the case and the cation ratio is of loss+accumulation the sodium is more abundant in the cell. This implies the flow of water increase with effect of cell swell and haemolysis.

RBC-Metabolism

• Binding for oxygen, C02 and transport does not require any energy.
• But energy dependent functions require viability for electrolytes to function with - charge or + charge with other components.
• No mitochondria is available and has to rely on Glycolysis(anaerobic) to work efficiently, so it can function correct
• With 4 factors to mention: Glycolyse pathway, Hm Pathway,
• Hemoglobin reductase and Rapoport-Luebering shunt:
• The Glycolysis: is a anaeroic ATP producer
• Hm Path: protects cell and damage when oxidant.
• Methemoglobin reductase: methemoglobin reduction, that can alterate oxygen

Glycolytic pathway,

• Depend on all anaerobic pathways, if the glucose is in the plasma its the main.
• ATP regulate concentration, and that requires the inter of internal ions.
• Abnormal cation permeability and ATP production results in shape change.
• 90=95% with glucose metabolized by pyruvate .
• But maintain key components to main pyridine glucoses with (MetHb path), Rapoport luebring path.

Key enzymes Glycoly

• Hexokinase the phosphorylation of Glucose-G-phosphate (first step
• Phosphofructokinase-1, regulatory for the process
• Adolase: splits phosphate into multiple molecules for 3C
• Glycerraldehyde-phospahte and NADh production
• converts biphosphaglycerate to ATP that in the process it releases.

Hexose Monophospate Pathway

• An ancillary pathway to reduce substances and reduce stress on the cell when there is an oxidative occurrence.
• and 5 or 10 % are metabolized to this pathway to maintain red cell
• Dependent on enzyme gdp/ghc reduce.
• and convert hssg(reduced, back to form) to produce nadphs that is needed, to maintain haemoglobin
• caused by the enzyme - sh group and results denature leading to a reduce .

Key enzymes HM

• First. Gcdp enzyme that has cruicial role for oxidative. and converts the components to 6 phosphoglucono,
• Second hydrolyzers 6phosphanol with efficient intermidiate lactones.
• Dehydrogenate : that catalyst has oxidative with nulph and 5 carbondioxide.

Methaoglobin Reductase Pathway:

• The haeme is oxidazed.
• Also Cytocrhome is also know b5
• In absence it can build up to 2to 40 %
• The first enazyme reducehaemoglobin of transport oxygen.
• Second key is a part in ezymatic and catalytise.

Enzymes Mrp:

• Cytocyrome the enxyme that reduces back cytochorme B5.
• Key is trasnfer electron from hemoglobin that cannot bind or trasport o2 for that reason.
• Citochoome B5 it plays maintining proper roles and functions to make them functional and proper.

Rapoport lubering shunt

• Bypass all functions formation to make and produce.
• The result sacrifes one step of production of ATp
• the hemoglobin is decreased to allow facilitate to the cell to provide the best .
• Also create and combine to help the production of the cell.

MRP Enzyme

• Bp mutase it help conversion and by desacrease the hemolglobin in the tissues.
• B phosphatase; that produces 3P to allow integrate better ATP and continue with proceses