BLOOD CELL FORMATION (HEMATOPOIESIS)

I. INTRODUCTION A. Definition Hematopoiesis is the proliferation of progenitor cells, which are maintained by the stem cells and their differentiation into all the cellular components of blood. B. Sites of hematopoiesis p depend on the presence of disease and on the developdevelopmental state of the individual. 1. Normal conditions p originate in the bone marrow

Some components (e.g., erythrocytes and platelets) complete their development at medullary (i.e., bone marrow) sites, whereas other components (e.g., T and B cells) complete their development at extramedullary. Foetus : 0 2 months p yolk sac 0 7 months p liver, spleen 5 9 months p bone marrow Infants : Bone marrow (practically all bones) Adults : vertebrae, ribs, sternum, skull, sacrum, proximal ends of femur

2. Disease In the presence of disease, extramedullary sites can serve as primary sites of blood cell development. II. BONE MARROW A. Stem cells } CFU (Colony - Forming Unit) are found within the BM as the origin of all blood cells.

~ Blood cells are formed by a process of differentiation from the least developed stem cells to highly specialized blood cells. (Table 1) ~ Stem cells : 1. pluripotential stem cells p 3 main marrow cell lines : a). erythrocytes (red cells) b). granulocytes monocytes (white cells) c). thrombocytes (platelets) and probably lymphocytes (T & B lymp.,plasma cells).

2. Multipotential stem cells p myeloid multimultipotential stem cells and lymphoid multipotenmultipotential stem cells. - Myeloid multipotential stem cells : * CFU-GEMM (CFU-S) p CFU granulocytes, CFU(CFUerythrocytes, monocytes and megakaryocymegakaryocytes; the earliest detectable myeloid precursor * CFU-C (CFU-GM) p CFU - granulocytes CFU- (CFUand monocytes

* CFU-E and BFU-E CFUBFU- CFU-E p CFU erythropoiesis CFU- BFU-E p Burst - Forming Unit - erythroid p BFUcommitted to erythropoiesis and precursor of the CFU-E CFU- CFU-E and BFU-E are dependent on Epo CFUBFU* CFU-Meg CFU- progenitor of megakaryocytes - derives from CFU-GEMM CFU- controlled by thrombopoietin
Figure 1. Schematically summarizes the role of the major progenitor cells of hematopoiesis

Pluripotent stem cell

CFUGEMM

Lymphoid stem cell

BFUE

CFUGMEo

CFUbaso

Erythroid Progenitors CFUE

CFUEo CFUMeg CFUGM

Thymus CFUCFU-M CFU-G CFU-

B
Red Cells FIGURE 1. Platelets MonoMonocytes NeutroNeutrophils EosinoEosinophils BasoBasophils

Lymphocytes

Tabel 1. Some hematopoietic progenitors cells

Term
CFUCFU-LM

Required stimulus
Multiple GF

Postulated Role
Pluripotent stem cell Pluripotent stem cell Committed progenitor of granulopoiesis

CFUCFU-GEMM GM-CSF, G-CSF, GMG(CFU(CFU-S) M-CSF, IL-3 ILCFUCFU-GM (CFU(CFU-C) BFUBFU-E GMGM-CSF, G-CSF, GM-CSF, IL-3 IL-

Erythropoietin, helper T Committed progenitor of lymphocytes (IL-1, GM- erythropoiesis (early) (IL- GMCSF, IL-3, IL-4) IL- ILErythropoietin IL-3, GM-CSF, G-CSF. IL- GMGthrombopoietin Committed progenitor of erythropoiesis (late) Committed progenitor of thrombopoiesis

CFUCFU-E CFUCFU- Meg

~ Lymphoid multipotential stem cells p leave the bone marrow and complete diff. in lymph nodes (B cells) and thymus (T cells) B. Hematopoietic Growth Factors } CSF (Colonystimulating factor) Classification : a. Non-lineage-specific GF p act on pluripoNon-lineagepluripotential and multipotential stem cells to initiate self-renewal and differentiation self-

~ IL-3 (Multi-CSF) p induces the formation IL- (Multiof colonies granulocyte, monocytes, eosinophils, erythroid cells,megakaryocytes and mast cells production ~ GM-CSF p stimulates granulopoiesis and GMmacrophage production b. Lineage-specific GF p act on the commitLineagecommitted progenitor cells and are involved in the diff. and maturation of blood cells in the later stages of hematopoiesis.

These factors include : ~ Epo p stimulates erythropoiesis, mediates its feed-back control feed~ G-CSF p inducing formation of granulocyte Gand stimulates proliferation of some leukeleukemic cells ~ M-CSF p influencing macrophage prod. ~ Thrombopoietin p influencing CFU-mega CFU(Table 2)

Table 2. Myeloid Hematopoietic Growth Factor

Factor
Erythropoietin (Epo) GMGM-CSF G-CSF M-CSF

Major Biological Activities in Vivo

Stimulates erythropoiesis. Mediates its feedback control Stimulates granulopoiesis and macrophage production Stimulates granulopoiesis and proliferation of some leukemic cells Stimulates macrophage production

IL-3 (Multi-CSF) Stimulates granulocyte, monocyte, eosinophils, IL- (Multierythroid cells, megakaryocyte and mast cells production CFUThrombopoietin Influencing CFU-mega

C.

Lymphokines and monokines - released by lymphocytes and monocytes wide(macrophages) p have wide-ranging h.poietic effects through extensive network of interaction involving immune responses to infection and tumor invasion.

- IL (Interleukin) : secreted by lymphocytes, affect the function of other leukocytes (com(communication links between leukocytes) - engage in complex interactions with other IL, HGF and many other protein such a TNF and lymphotoxins (Table 3)

Table 3. Lymphoid Hematopoietic Growth Factors

Name
IL - 1 IL - 2 (T
cells GF)

Source
Macrophages, T and B cells, fibroblasts T cells

Function
Stimulates growth of T and B cells, mediates inflammation, inhibits growth of some cancer cells. Binds to receptors on cytotoxic T cells, promote their growth, stimulates growth of helper T cells.

IL - 4 IL 5
(Eo (EoGF)

T cells, NK cells, Stimulates & regulates growth and diff. of T mast cells and B cells, eosinophils and basophils. T cells Regulates production of eosinophils. Activates mature eosinophils. Promotes macrophage formation. Stimulates IgG production by B cells. Supports long-term survival of B and T longcells in vitro. Enhancement of neutrophil function

IL - 6 IL-7 ILIL - 8

Lymphocytes, fibroblasts Stromal Cells Fibroblasts, vasc. endot.

Common General Features of Hematopoietic Growth Factors

1. All are glycoproteins 2. Regulators of blood cell development and maturation and enhancers of mature cell functions, which are active at very low concentration 3. Active both in vitro and in vivo 4. Produced by cells of many types

5. Usually have both unique and overlapping specificities 6. Active on both stem (progenitor) cells and end cells 7. Biologic affects are mediated after binding to a small number of specific high - affinity receptors on the surfaces of target cells

8. Also bind to receptors on some nonhema - topoietic cells. The significance of this is unknown 9. Display synergy or additive effects with other growth factor 10. Also act on neoplastic counterparts of normal cell type

III. SPLEEN
The chief organ of RES, which also includes BM, lymph nodes, liver, circulating monocytes and fixed tissue macrophages. macrophages. Its chief role in hematopoiesis occurs in utero ; its postnatal participation is limited. limited. Extramedullary hematopoieis in the spleen occurs in several circumstances

Functions :
Participates in immunologic and phagocytic activities Produces stem cells p capable of differentiating along hematopoietic, histiocytic and fibroblastic cell lines Play roles in the autoantibody response and determining blood volume.

IV. EVALUATION OF THE BONE MARROW 1. Indication for a bone marrow aspirate : Evaluation of decreased numbers of cells from a single lineage Ev. Ev. of patients with decreased blood cell counts (bicytopenia or pancytopenia) and leukemias (stem cell defects & disorder) Ev. Ev. of iron stores and abnormal iron in erythroid precursor

Diagnosis of tumor involvement To demonstrate possible infection by intracellular organism To investigate an immunologic disorder Diagnosis of nonhematopoietic diseases 2. Indications for a BM biopsy Failure to obtain an adequate marrow aspirate

Evaluation of pancytopenia or bicytopenia Leukoerythroblastic peripheral blood smear Evaluation of hematologic malignancies and tumor staging To defined endpoint of aplasia findings in the

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