divisions of hemopoiesis 1. prenatal hemopoiesis

Part I – Chapter 10- 1

` ‘

HEMOCYTOPOIESIS • Continuous formation of the cells, corpuscles, and platelets of the blood

is necessary to keep their numbers relatively constant as they wear out or are lost from the body.

• The formation is called hematopoiesis or hemopoiesis for short.

DIVISIONS OF HEMOPOIESIS 1. Prenatal Hemopoiesis

a. Mesoblastic phase: Blood cell formation begins 2 weeks after conception in the mesoderm of the yolk sac, where mesenchymal cells aggregate into clusters known as blood islands. The peripheral cells of these islands form the vessel wall, and the remaining cells become erythroblasts, which differentiate into nucleated erythrocytes.

b. Hepatic phase; by the 6th week of gestation, the erythrocytes still have nuclei, and leukocytes appear by the 8th week of gestation.

c. Splenic phase; begins during the second trimester, and both hepatic and splenic phases continue until the end of gestation

d. Myeloid phase; by the end of the second trimester. Although postnatal the liver and the spleen are not active in hemopoiesis, they can revert to forming new blood cells if the need arises.

2. Postnatal Hemopoiesis; Postnatal hemopoiesis occurs almost exclusively in bone marrow mostly in the axial skeleton - skull, ribs, sternum, parts of the vertebrae and pelvis.

Chapter 10 HEMOCYTOPOIESIS


THEORETICAL CONSIDERATIONS OF HEMOPOIESIS Stem, Progenitor, and Precursor Cells: • Stem cells are the least differentiated cells responsible for the formation

of the formed elements of blood; stem cells give rise to progenitor cells whose progeny are the precursor cell.

• All blood cells arise from Pluripotential Hemopoietic Stem Cells (PHSCs), which account for about 0.1% of the nucleated cell population of bone marrow.

• They are usually amitotic but may undergo bursts of cell division, giving rise to more PHSCs as well as to two types of multipotential hemopoietic stem cells (MHSCs):

o Colony-Forming unit-lymphocyte (CFU-Ly) cells and o Colony-Forming unit-granulocyte, erythrocyte, monocyte,

megakaryocyte (CFU-GEMM) cells, previously known as colony-forming unit-spleen [CFU-S] cells.

• These two populations of MHSCs are responsible for the formation of various progenitor cells:

o CFU-GEMM cells are predecessors of the myeloid cell lines (erythrocytes, granulocytes, monocytes, and platelets).

o CFU-Ly cells are predecessors of the lymphoid cell lines (T cells and B cells).

• Both PHSCs and MHSCs resemble lymphocytes and constitute a small fraction of the null-cell population of circulating blood.

• Stem cells are commonly in the G0 stage of the cell cycle but can be driven into the G1 stage by various growth factors and cytokines.

• Early stem cells may be recognized by specific marker molecules CD34 on their plasma membranes.

• Progenitor cells are resembling small lymphocytes but are unipotential (i.e., committed to forming a single cell line, such as eosinophils). Their mitotic activity and differentiation are controlled by specific hemopoietic factors. These cells have only limited capacity for self-renewal


• Precursor cells arise from progenitor cells and are incapable of self-renewal. They have specific morphological characteristics that permit them to be recognized as the first cell of a particular cell line. Precursor cells undergo cell division and differentiation, eventually giving rise to a clone of mature cells.

Hemopoietic Growth Factors (Colony-Stimulating Factors)

• Hemopoiesis is regulated by a number of cytokines and growth

factors, such as interleukins, colony-stimulating factors, macrophage inhibiting protein-a, and steel factor.

• Hemopoiesis is regulated by numerous growth factors produced by various cell types.

• Each factor acts on specific stem cells, progenitor cells, and precursor cells, generally inducing rapid mitosis, differentiation, or both

• Some of these growth factors also promote the functioning of mature blood cells. Most hemopoietic growth factors are glycoproteins

• Three routes are used to deliver growth factors to their target cells: 1. Transport via the bloodstream (as endocrine hormones), 2. Secretion by stromal cells of the bone marrow near the

hemopoietic cells (as paracrine hormones) 3. Direct cell-to-cell contact (as surface signaling molecules).

• Certain growth factors-principally, steel factor (also known as stem cell factor), granulocyte-macrophage colony-stimulating factor (GM-CSF) and two interleukins (IL-3 and IL-7)-stimulate proliferation of pluripotential and multipotential stem cells, thus maintaining their populations.

• Additional cytokines, such as granulocyte colony-stimulating factor (G-CSF), monocyte colony-stimulating factor (M-CSF), IL-2, IL-5, IL-6, IL-11, IL-12, macrophage inhibitory protein-α (MIP-α), and erythropoietin,


• Steel factor (stem cell factor), which acts on pluripotential, multipotential, and unipotential stem cells, is produced by stromal cells of the bone marrow and is inserted into their cell membranes. Stem cells must come in contact with these stromal cells before they can become mitotically active. It is believed that hemopoiesis cannot occur without the presence of cells that express stem cell factors, which is why postnatal blood cell formation is restricted to the bone marrow (and liver and spleen, if necessary).

• Colony-stimulating factors (CSFs) are also responsible for the stimulation of cell division and for the differentiation of unipotential cells of the granulocytic and monocytic series.

o Erythropoietin activates cells of the erythrocytic series, whereas

o thrombopoietin stimulates platelet production. • Hemopoietic cells are programmed to die by undergoing apoptosis

unless they come into contact with growth factors. • Such dying cells display clumping of the chromatin in their

shrunken nuclei and a dense, granular-appearing cytoplasm • On their cell surface, they express specific macromolecules that are

recognized by receptors of the macrophage plasma membrane. These phagocytic cells engulf and destroy the apoptotic cells.


CHANGES IN DEVELOPING BLOOD CELLS ERYTHROCYTES

1. Large, weakly basophilic pro-erythroblast increases the free ribosomes in its cytoplasm to become a basophil erythroblast.

2. Cell size decreases, and organelles are lost. Nucleus, initially large and pale, with nucleoli, gets smaller and stains more darkly.

3. Cytoplasm acquires hemoglobin at the expense of ribosomal ribonucleoprotein (RNP) - thus its staining affinity changes from basophilia to acidophilia; the mixed-hued halfway stage is the polychromic/polychromatophil erythroblast.

4. Small cell, with orange cytoplasm and a round dark nucleus, is the orthochromic erythroblast/normoblast.

5. Nucleus, in a little cytoplasm, is extruded for phagocytosis. 6. Reticulocyte/polychromatophil erythrocyte is an RBC that is released

into the blood still with RNP in its cytoplasm. Supravital staining with brilliant cresyl blue causes this material to clump as a blue network (reticulum) in around 2 per cent of the RBCs of normal blood.

GRANULOCYTE

• Myeloblast/granuloblast develops into a: • Promyelocyte synthesizes non-specific azurophil granules (lysosomes)

in the cytoplasm, and with its nucleus getting smaller and darker. • Myelocyte, after a pause, then makes additional granules specific for

one of the three kinds of granulocyte in their staining affinity. • Nucleus elongates and indents, and chromatin becomes coarser, giving

the metamyelocyte (now unable to divide). • More granules form and the nucleus becomes sausage-shaped -

band/juvenile granulocyte. Then the nucleus starts segmenting, as the cell becomes the mature granulocyte.


PLATELETS

1. Haemocytoblast enlarges to become a megakaryoblast. 2. The nucleus experiences several rounds of DNA replication, but each

time with reassembly of a single nuclear envelope and no segregation into separate nuclei. Thus the nucleus takes on a distinctive lumpy, polyploid form. (The single, large, lumpy nucleus is the criterion for distinguishing megakaryocytes from nearby osteoclasts in bone sections.).

3. Fine cytoplasmic azurophil granules accumulate as the cell becomes a very large granular megakaryocyte.

4. Many paired membranes of smooth ER (demarcation membranes) appear and contribute plasmalemma to the formation of

5. Pseudopodia, which are extended into the lumen of a sinusoid, where they cast off in the blood as platelets.

6. Megakaryocyte cytoplasm might also serve as a transcellular migration pathway for some new leucocytes passing from the marrow into the blood.

AGRANULAR LEUCOCYTES

• In developing, they do not become so strikingly different from their stem cells as do granulocytes and RBCs.

• Monocytes form from monoblast/pre-monocyte precursors in bone marrow.

• Lymphocytes develop from lymphoblasts in bone marrow and lymphoid organs.

• Some circulating lymphocytes appropriately stimulated can also become lymphoblasts.


BONE MARROW • The naked-eye appearance of fresh, unstained marrow may be red from

many developing RBCs, or yellow from mainly fat cells. • Red marrow has many elements:

A. Blood sinusoids are lined by endothelial cells on an incomplete BL. Collagen fibrils (reticular fibers) support these, and

B. Adventitial stromal/reticular cells, similar to fibroblasts, but extending processes between, and greatly influencing, the haemopoietic cells.

C. Macrophages cleanse blood, and detect and destroy worn-out RBCs and other elements. The iron recovered is stored, combined with protein as ferritin granules, before release to the labile pool and reuse.

D. Blood cells develop extravascular, are stored, and then released through the sinusoidal wall into the circulation.

E. Megakaryocytes form and release platelets. F. Fat cells are present, large and empty of fat in embedded sections. G. Bone surface cells act as an enclosing sac for the marrow.

• Microscopic methods for marrow include sections, and smears of aspirated sternal marrow stained with a blood stain.

CELL COMPARTMENTS, POPULATIONS AND KINETICS • Although the marrow smear picture appears static, it represents part of

a dynamic system of cell populations. For example, an RBC may be: (a) in the marrow developing, (b) in the marrow being stored or (c) circulating in the blood. The population of each compartment at any time represents the balance between the numbers entering and leaving.

• Most cells of the RBC sequence/erythroid complex/erythron are circulating; whereas the granular leucocytes system has most of the cells developing or being stored in the marrow, and only a minority in circulation. Many of these leucocytes in the vessels hug the wall as a barely moving, marginated reserve.


Arrow= immature neutrophils, Largest cell is megakaryocyte

*= Adipocytes 1-4 stages of megakaryocytes

divisions of hemopoiesis 1. prenatal hemopoiesis

Documents