HEMATOPOIESIS

PART 1
INTRODUCTION

 HEMATOPOIESIS
 Is a continuous, regulated process of blood cell production that includes cell renewal,
proliferation, differentiation, and maturation that results in the formation, development, and
specialization of all the functional blood cells that are released from the bone marrow to the
circulation
 Erythropoiesis – process of producing RBCs
 Leukopoiesis – process of producing WBCs
 Myelopoiesis – process of producing granulocytes
 Lymphopoiesis – process of producing lymphocytes
 Thrombopoiesis or Megakaryopoiesis – process of producing platelets
PRENATAL/FETAL/INTRAUTERINE
HEMATOPIESIS

 MESOBLASTIC PHASE
 Begins approximately 19-20 days of gestation
 Remains active only through the 8th to 12th weeks of gestation
 Cells from the mesoderm migrate to the cavity yolk sac, some of these cells form primitive
nucleated erythroblasts in the central cavity (intravascular) while others (angioblasts) surround
the yolk sac cavity and forms the blood vessels
 Embryonic forms of hemoglobin:
 Portland
 Gower I
 Gower II
PRENATAL/FETAL/INTRAUTERINE
HEMATOPIESIS

 MESOBLASTIC PHASE
 Cells of mesodermal origin also migrate to the aorta-gonad-mesonephros (AGM) region and
give rise to hematopoietic stem cells (HSCs) for definitive or permanent adult hematopoiesis.
 The AGM region has previously been considered as the only site of definitive hematopoiesis
during embryonic development, however, the precise origin of HSC remains unresolved.
 Alpha-globin chain production begins at this phase and continuous throughout life.
PRENATAL/FETAL/INTRAUTERINE
HEMATOPIESIS

 HEPATIC PHASE
 Begins at 5th to 7th weeks of gestation
 Occurs in the liver with some contribution by the spleen, thymus, lymph nodes, placenta, and
bone marrow space in the final medullary phase (extravascular)
 Cells appear to be morphologically identifiable
 Fetal hemoglobin (Hgb F – composed of alpha and gamma globin chain) predominates and is
distinguishable from the embryonic hemoglobins
 Hgb A1 and Hgb A2 are also present
PRENATAL/FETAL/INTRAUTERINE
HEMATOPIESIS
 HEPATIC PHASE
 Developing erythroblasts signals the
beginning of definitive hematopoiesis and
the decline of primitive hematopoiesis in
the yolk sac.
 Granulopoiesis – 2nd month
 Lymphopoiesis - 4th month
 Monopoiesis – 5th month
 Significant contribution of other organs:
 Thymus – T cell production
 Kidney – B cell production
 Spleen – active in:
 Erythropoiesis – until the end of normal
gestation (splenic)
 Myelopoiesis – but becomes minimal by
the 5th month
 Lymphopoiesis – lifetime
 Lymph none
PRENATAL/FETAL/INTRAUTERINE
HEMATOPIESIS

 MEDULLARY (MYELOID) PHASE

 5th month of gestation
 Hematopioiesis occurs in the bone marrow cavity
 HSCs and mesenchymal cells migrate into the core of the bone
 The bone marrow becomes the chief site of hematopoiesis by the 24 th week of gestation
 The myeloid-to-erythroid ration (M:E ratio) approaches 3:1 (adult level)
 After 3 weeks postpartum, the bone marrow (red marrow) becomes the only normal site of
blood cell production.
ADULT HEMATOPOIETIC TISSUE
 BONE MARROW
 The chief site of hematopoiesis; contains developing erythroid,
myeloid, lymphoid, and megakaryocytic cells
 Has 2 major components:
 Red marrow – hematopoietically active
 Yellow marrow – hematopoietically inavtive (adipocytes,
undifferentiated mesenchymal cells, and macrophages)
 Retrogression
 process of replacing red marrow by the yellow marrow during
development
 Between 5-7 years of age, adipocytes become more abundant and
start to occupy the spaces in the long bones previously dominated by
red marrow
ADULT HEMATOPOIETIC TISSUE

 BONE MARROW
 Retrogression eventually results in restriction of the red
marrow in adult to the:
 R – ribs
 S – skull, sternum, scapula
 V – vertebrae
 P – pelvis proximal end of long bones
 Posterior/anterior superior iliac crest – preferred site of
MB collection in adults
 Tibia – preferred site of MC collection in children < 2
y.o.
 Yellow marrow has the ability to revert back to active
marrow in case of increase demand
ADULT HEMATOPOIETIC TISSUE

 BONE MARROW
 Normal marrow cells
 Developing hematopoietic cells
 Macrophages  Bone marrow cellularity – is the ratio of
 Mast cells marrow cells to fat (Red:yellow marrow)
 Osteoblasts
 Normocellular – 30-70% HC

 Osteoclasts
 Hypercellular/hyperplastic - >70% HC
 Hypocellular/hypoplastic - <30% HC
 Aplastic – few or no HC
ADULT HEMATOPOIETIC TISSUE
 BONE MARROW
 Marrow differential
 Recommended: at least 500 cells (preferably
1,000 cells) be counted
 500 cells on each of 2 slides
 Myeloid to erythroid ratio
 Ratio of granulocytes and their precursors to
nucleated erythroid precursors
 M:E ratio in adults: 2:1 to 4:1 (Normal)
10:1 (leukemia
 Bone marrow aspiration
 Needle is inserted into the soft corner of the
bone and small quantity of bone marrow is
aspirated using 30-35 mL syringe
 As much as 1-3 mL of BM is aspirated
 Disturbs BM architecture
 Used for analysis of individual cell
morphology
 BM smears should be retained for 10 yrs
ADULT HEMATOPOIETIC TISSUE
 BONE MARROW
 Bone marrow biopsy
 A piece of the bone marrow is removed intact
without disturbing the bone architecture
 Needle biopsy – done with a thick, hollow
biopsy needle, and core sample of the bone
marrow is taken
 Trephine biopsy – trephine is a small
instrument used to remove a circular section of
tissue
 Advantage: gives a better picture of the real
structure of the marrow
 Used for analysis of BM architecture
ADULT HEMATOPOIETIC TISSUE

 EXTRAMEDULLARY ERYTHROPOIESIS
 Hematopoiesis in tissues other than the BM
 Occurs when hyperplasia of marrow cannot meet physiologic blood needs of tissue
 SPLEEN
 The largest lymphoid organ of the body
 Vital but nor essential for life and functions as an indiscriminate filter of the circulating blood
 Contains about 350 mL of blood
 The spleen uses culling, in which cells are phagocytized with subsequent degradation of cell organelles, and
pitting, in which splenic macrophages remove inclusions or damaged surface membrane from circulating RBCs
 LIVER
 the lumen of the sinusoids of a hepatocyte contains Kupffer cells (macrophages) that remove senescent cells and
foreign debris from the blood that circulates through the liver.
ADULT HEMATOPOIETIC TISSUE

 LYMPH NODES
 oval structure throughout the body connected by lymphatic vessel that carry a fluid called lymph
 Acts as filter to remove foreign blood contaminants (extremely important part of the body’s infection
defense)
 Contain many phagocytic cells and lymphocytes
 Immature lymphocytes produced in the BM collect and mature in the tissue on the node
 THYMUS
 Responsible for normal development of some of the lymphocytes
 Located in the neck
 Maximum development in childhood, atrophies with age
HEMATOPOIETIC STEM CELLS

 STEM CELL THEORY

 Monophyletic theory – suggests that all blood cells are derived from a single progenitor stem
cell called a pluripotent hematopoietic stem cell
 Polyphyletic theory – suggests that each of the blood cell lineages is derived from its own
unique stem cell

 HEMATOPOIETIC STEM CELLS (HSCs)

 Capable of self-renewal
 Pluripotent and give rise to different progeny
 Reconstitute the hematopoietic system of a lethally irradiated host
 Express CD34 marker
HEMATOPOIETIC STEM CELLS

 The undifferentiated HSCs can differentiate into lineage-specific progenitor cells:

 Common myeloid progenitor (CMP) – proliferates and differentiates into individual
granulocytic, erythrocytic, monocytic, and megakaryocytic lineages
 Common lymphoid progenitor (CLP) – proliferates and differentiates into T, B, and natural
killer lymphocytes, and dendritic lineages

 HSCs are directed to one of three possible fates:

 Self-renewal
 Differentiation
 apoptosis
HEMATOPOIETIC STEM CELLS

 Stem cell phenotypic and functional characterization

 The earlies identifiable human HCSs capable of initiating long-term culture are CD34 +
 Expression of CD38 and HLA-DR is associated with a loss of “stemness”
 CD33 –committed myeloid progenitors
 CD10 – committed lymphoid progenitors
 CD7 – T-lymphoid progenitor cells and NK cells
 CD19 – B-lymphoid progenitors

 How does HSCs develop?

 Through chemical signals by cytokines, interleukins, and growth factors
HEMATOPOIETIC STEM CELLS

 COLONY FORMING UNITS (CFU)

 CFU-GEMM - Granulocyte, Erythrocyte, Megakaryocyte, Monocyte
 CFU-E - erythrocyte
 CFU-Meg - megakaryocyte
 CFU-M - monocyte
 CFU-GM - granulocyte, monocyte
 CFU-BASO - myeloid to basophil
 CFU-EO - myeloid to eosinophil
 CFU-G - myeloid to neutrophil
 CFU-pre-T - T lymphocyte
 CFU-pre-B - B lymphocyte
END