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IMS: Microanatomy > Hematopoiesis > Flashcards

Hematopoiesis Flashcards

1
Q

Hematopoiesis

A

The formation and maturation of cells and platelets of blood.

Occurs in the bone marrow of adults.

All cells replaced on an ongoing basis throughout life.

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2
Q

Fetal Hematopoiesis

Mesoblastic Phase

A
  • From 2-3 weeks to about 8 weeks gestation
  • Blood islands form in the wall of the yolk sac
  • Cells of blood islands give rise to:
    • nucleated erythrocytes
    • endothelium of vessels
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3
Q

Fetal Hematopoiesis

Hepatic & Splenic Phases

A

Hepatic Phase

  • From ~ 2 months to 7 months gestation
  • Hematopoiesis occurs in the space of Disse
    • Space immediately surrounding each sinusoid that seperates the vessels from the hepatocytes
  • Anucleate erythrocytes are producted first
  • Megakaryocytes and granulocytes follow

Splenic Phase

  • From ~ 10th week to 6-7 months
  • Produces similar products as hepatic phase
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4
Q

Fetal Hematopoiesis

Myeloid

(Bone Marrow)

Phase

A
  • Begins following ossification and marrow space development ~ 6 months gestation till death
  • Extramedullary hematopoiesis decreases and stops after birth
    • Can resume after severe blood loss or in pathology
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5
Q

Red Marrow

A
  • Site of active hematopoiesis
  • Predominates from birth to 4-5 y/o
  • Contains few “fat cells”
    • Adventitial reticular cells that have accumulated lipid
  • By age 20, red marrow found only in certain bones
    • Sternum
    • Ilia
    • Vertebral bodies
    • Ribs
    • Clavicles
    • Cranial bones
    • Proximal ends of the femora and humeri
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6
Q

Yellow Marrow

A
  • Begins to replace red marrow after 4-5 y/o
  • Less active in hematopoiesis due to few hematopoietic cells
  • Many large fat-filled adventitial reticular (stromal) cells
    • Regulate their size by regulating lipolysis
    • Lipogenesis stimulated by glucocorticoids but insensitive to insulin
    • Free FA not released during starvation
  • Yellow marrow can revert to red marrow under conditions of prolonged increase in demand for blood cells
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7
Q

Marrow Cavity

A
  • Marrow found in:
    • Hollow centers of long bone diaphyses
    • Trabecular spaces of all bones
  • Endosteum lines marrow cavity
  • There are two compartments within bone marrow:
    1. Vascular compartment
    2. Hematopoietic compartment
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8
Q

Vascular Compartment

A
  • Part of the cardiovascular system
  • Nutrient arteries pass through the compact bone of the cortex and enter into the marrow cavity
    • Branches into ascending and descending arteries
    • Anastomose with metaphyseal and epiphyseal arteries at the ends of the bone
  • Arteries to the marrow lead into wide, leaky sinusoids
    • Formed from very flat endothelial cells
  • Sinusoids ⇒ collecting sinuses ⇒ central longitudinal vein ⇒ veins that leave the bone alongside the feeding arteries
  • Newly formed blood cells leave the marrow cavity by entering the lumen of sinusoids
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9
Q

Hematopoietic Compartment

A
  • Where bood cell formation occurs
  • Surrounds the sinusoids in the marrow
  • Stroma consists of:
    • Adventitial reticular cells
      • Covers 40-60% outer surface of sinusoids
      • Produce reticular fibers
      • Have elongated processes that extend into the hematopoietic compartment along the reticular fiber network
      • Accumulates lipid with age
      • Secrete hematopoietic growth factors (HGFs)
    • Reticular fibers
      • Forms a mesh around the areas of blood cell formation
      • Provides mechanical support
    • Macrophages
      • Found as part of erythroblastic islets
      • Phagocytize:
        • Extruded nuclei of developing RBCs
        • Senescent red cells
        • Malformed cells
        • Debris in the blood stream
      • Produce hematopoietic growth factors
      • Can extend processes between endothelial cells into the sinusoids
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10
Q

Transcytosis

A

Process where blood cells formed in the hematopoietic compartment cross the walls of the sinusoids through a transient opening (migration pore) in the cytoplasm of an individual endothelial cell rather than by passing between two cells in order to enter circulation.

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11
Q

Pluripotential Hematopoietic Stem Cell

(PHSC or PPSC)

A
  • A nonophyletic pluripotent stem cell which gives rise to all the blood cells including RBC, WBC, and platelets
  • Capable of self-renewal
    • PHSC divides: one daughter cell remains a PHSC while the other differentiates into progenitor cells
  • Express CD34+ on surface
  • PHSC ⇒ multipotential progenitor cells ⇒ lineage-specific precursors
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12
Q

Progenitor Cells

A

Common Myeloid Progenitor (CFU-GEMM)

or

Common Lymphoid Progenitor (CFU-L)

  • Cannot replicate indefinitely
  • Developmental possibilities limited
  • Generally known as CFU’s (colony forming units)
  • Express CD34+ and additional markers
  • Descendents of CFU’s that are committed to a specific single line of development are called committed precursor cells
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13
Q

Common Myeloid Progenitor Cell

(CFU-GEMM)

A

Gives rise to all forms of circulating blood cells except lymphocytes.

Differentiates into more narrowly committed but still multipotential progenitors: MEG/ERY & GRAN/MONO

​

  1. MEG/ERY then gives rise to:
    • BFU-E (burst forming unit-erythroid)
      • Committed to the formation of erythrocytes
      • High rate of proliferation
      • Gives rise to CFU-E
      • CFU-E ⇒ Erythrocytes
    • CFU-Meg
      • Gives rise to megakaryocytes
  2. GRAN/MONO lineage gives rise to:
    • CFU-M
      • Fully differentiates into monocytes
    • CFU-Gran gives rise to:
      • CFU-EO which differentiates into eosinophils
      • CFU-B which differentiates into basophils (and possibly mast cells)
      • CFU-G which differentiates into neutrophils
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14
Q

Common Lymphoid Progenitor Cell

(CFU-L)

A

Gives rise to the lymphocytes.

CFU-L can differentiate along the following pathways:

  1. CFU-L(T/NK)
    • Gives rise to T-lymphocytes and natural killer cells
  2. CFU-L (B)
    • Gives rise to B-lymphocytes
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15
Q

Erythroblastic Islets

A
  • Location of erythropoiesis
  • Central macrophage surrounded by multiple cells in varying stages of erythrocyte development
  • Macrophages:
    • Supply iron for heme synthesis
    • Produce growth factors and cytokines for differentiation
    • Phagocytize extruded nuclei and defective cells
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16
Q

Erythropoiesis

Stages Overview

A

PHSC

⇒ MEG/ERY

⇒ BFU-E

⇒ CFU-E

⇒ Proerythroblasts

⇒ Basophilic erythroblasts

⇒ Polychromatophilic erythroblasts

⇒ Orthochromatic erythroblasts

⇒ Reticulocytes

⇒ Mature erythrocyte

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17
Q

BFU-E

&

CFU-E

A
  • First cell committed to form erythrocytes
    • Committed presursor cell
  • Gives rise to CFU-E
    • Highly sensitive to erythropoietin
18
Q

Proerythroblasts

A
  • Arise from CFU-E
  • Are the first morphologically recognizable presursors to erythrocytes
  • Characteristics
    • Moderately basophilic cytoplasm
    • Two nucleoli
  • Number of polyribosomes increases with maturity
  • From this stage onward cell size decreases
  • Cells and nuclei remain round
19
Q

Basophilic

Erythroblasts

A
  • Arise from proerythroblasts
  • Characteristics:
    • Intensely basophillic cytoplasm due to numerous free polyribosomes
    • Slightly coarser chromatin pattern
  • Produce small amounts of hemoglobin
20
Q

Polychromatophilic

Erythroblasts

A
  • Arise from basophilic erythroblasts
  • Are the last cells in the erythrocyte lineage capable of mitosis
  • Characteristics
    • Gray or lilac cytoplasm
      • Due to relative amounts of polyribosomes (purple) and hemoglobin (pink)
    • Highly condensed chromatin
    • No nucleolus
21
Q

Orthochromatic

Erythroblasts

(aka. normoblasts)

A
  • Arise from polychromatophilic erythroblasts
  • Characteristics:
    • Salmon pink cytoplasm due to loss of polyribosomes which unmasks large amounts of hemoglobin
    • Few cytoplasmic organelles
    • Heterochromatic nucleus
      • Becomes eccentric
      • Extrudes at the end of this stage
22
Q

Reticulocytes

A
  • Anucleate erythrocytes
  • Initially slightly larger than mature RBCs
  • Slight greenish-blue tint d/t ribosomes
  • When stained with brilliant cresyl blue ribosomes clump and form a bluish network in the cytoplasm
  • Released into circulation as immature RBC
    • Transformation into mature erythrocyte over first few days of circulation
    • Loss of:
      • Transferrin receptors
      • Remaining cytoplasmic organelles
23
Q

Sideroblastic Anemia

A
  • Condition in which erythroblasts cannot synthesize heme
  • Due to abnormality in mitochondrial enzyme that catalyzes the first reaction of the process
  • Iron builds up in mitochondria
    • When iron reaches high enough concentrations it can be stained with Prussian blue producing a ring of blue mitochondria around the nucleus = ringed sideroblasts
  • Some RBC’s will be hypochromic but others may contain normal amounts of hemoglobin because defect is not uniformly expressed
24
Q

Granulopoiesis

Neutrophils

Stages

A

PHSC

⇒ CFU-GEMM

⇒ Gran/Mono

⇒ Gran

⇒ Myeloblasts

⇒ Promyelocytes

⇒ Neutrophilic myelocytes

⇒ Metamyelocytes

⇒ Neutrophilic band cells (stab cells)

⇒ Mature neutrophil

25
Q

Myeloblasts

Neutrophils

A
  • Are the first morphologically recognizable precursor cells in the granulocyte pathway
  • Myeloblasts which given rise to the 3 granulocytes are not distinguishable from one another
  • Capable of mitosis
  • Give rise directly to promyelocytes
26
Q

Promyelocytes

Neutrophils

A
  • Formed when myeloblasts begin to produce azurophilic granules
  • Azurophilic granules
    • Are primary lysosomes
    • In neutrophils they contain myeloperoxidase in addition to usual hydrolases
    • Stain magenta with common stains (Wright’s stain)
    • Are produced only during the promyelocyte stage
  • Promyelocytes of the 3 granulocyte lineages cannot be distinguished from one another
27
Q

Neutrophilic

Myelocytes

A
  • Formed when the cells begin to produce specific granules
    • Specific granules are produced at this stage only!!!
    • Size/contents/staining of specific granules used to distinguish the three types of granulocytes
  • First stage where granulocytes are distinguishable from one another
  • Last stage that is capable of mitosis
  • Characteristics:
    • Specific granules of neutrophilic myelocytes are small and stain poorly = inconspicuous
    • Myelocytes smaller than promyelocytes
    • Nucleus is flattened or slightly indented
28
Q

Neutrophilic

Metamyelocytes

A
  • Have a deeply indented nucleus
    • V-shaped
29
Q

Neutrophilic

Band Cells

(Stab Cells)

A
  • Formed when the nuclear indentation becomes deeper
  • Nuclei have a cylindrical central portion with two slightly larger end pieces
    • Resembles a curved dumbbell
  • As nucleus becomes constricted the band cell becomes a mature neutrophil with lobulated nucleus
30
Q

Neutrophil Count

A
  • Large reserve (10x daily production) of band cells and neutrophils kept in the bone marrow and can be rapidly released during infection
  • Myelosuppresion during chemotherapy results in an increased risk of infection
31
Q

Granulopoiesis

Eosinophils & Basophils

A

PHSC

⇒ CFU-GEMM

⇒ Gran/Mono

⇒ Gran

⇒ Myeloblasts

⇒ Promyelocytes

⇒ (Eosinophilic or Basophilic) Myelocytes

⇒ (Eosinophilic or Basophilic) Metamyelocytes

⇒ Mature Eosinophil or Basophil

32
Q

Eosinophilic

Myelocytes

A

First recognizable stage!

  • Synthesize large eosinophilic specific granules
    • Contains crystalloid composed mainly of major basic protein
      • Anti-parasitic agent
33
Q

Basophilic

Myelocytes

A

First recognizable stage!

  • Synthesize large basophiic granules that may obscure the nucleus.
  • Granule content includes histamine and heparin.
  • Next recognizable stage usually the mature basophil (possibly the basophilic metamyelocyte)
34
Q

Monopoiesis

A

PHSC

⇒ CFU-GEMM

⇒ Gran/Mono

⇒ CFU-M

⇒ Promonocytes

⇒ Monocytes

  • Promonocytes can either:
    • Proliferate rapidly and mature into monocytes
    • Form a pool that can be matured quickly to meet special demand
  • Monocytes become tissue macrophages after they leave the circulation.
35
Q

Thrombopoiesis

A

PHSC

⇒ CFU-GEMM

⇒ Meg/Ery

⇒ CFU-Meg

⇒ Megakaryoblast

⇒ Megakaryocyte

⇒ Platelets

36
Q

Megakaryoblast

A

Undergoes a process of DNA replication called endomitosis:

  • DNA replicates
  • No cytokinesis or karyokinesis occurs
  • Neither the cell nor the nucleus divides
  • Cell & nucleus become very large
  • Chromosomes separate on spindles
37
Q

Megakaryocyte

A
  • Formed from megakaryoblast after endomitosis complete.
  • Elaborate invaginations of the plasma membrane called platelet demarcation channels form and fuse
    • Divides the cytoplasm into elongated processes that push through the openings in the sinusoidal endothelium and into circulation
  • Each megakaryocyte can produce up to 6 processes
  • Each process can form 1,000 platelets or more
38
Q

Lymphopoiesis

A
  • Common lymphoid progenitor (CFU-L) gives rise to two types of progeny:
    1. CFU-LyB
      1. Gives rise to B-cells
      2. Bone marrow derived
      3. Can subsequently differentiate into antibody-producing plasma cells
    2. CFU-LyT
      1. Gives rise to T-cells
      2. Thymus-derived
      3. Form of lymphocyte involved in cell-mediated immunity
  • Lymphopoiesis characterized by a p_rocessive decrease in cell size_
  • Mature small lymphocytes undergo blast transformation after activation in immune response and increase in size
  • Mature T and B lymphocytes r_etain the ability to proliferate_
    • Occurs mainly in lymphoid tissue and lymphoid organs
      • Lymph nodes
      • Spleen
39
Q

Purpose of Hematopoiesis Control

A
  1. Maintain a characteristic constant number of each cell type during normal times.
  2. Synthesize more cells quickly in situations such as:
    • Blood loss
    • Inflammation
    • Infection
    • Changes in altitude
40
Q

Control of Hematopoiesis

A
  • Controlled by soluble factors known as hematopoietic growth factors (HGFs)
    • Type of cytokine
    • Can act via endocrine, paracrine, or cell-cell contact
  • Differentiation of an individual cell type involves multiple HGFs
  • Cells that are not induced to continue division/development/differentiation die by apoptosis
  • Variety of cells can produce HGFs:
    • T-cells
    • Endothelial cells
    • Adventitial reticular cells
    • Fibroblasts
    • Macrophages
    • Monocytes
    • Neutrophils
    • Mast cells
41
Q

Types of HGFs

A

Factors can be divided into:

  1. Early HGFs
    • Act only on early stem & progenitor cells incudling PHSC
  2. Intermediate HGFs
    • Do not affect the earliest cell types but do act on precursors of several different cell lineages
  3. Late HGFs
    • Affect one (or mainly one) lineage
42
Q

Therapeutic HGFs

A

Uses include treatment of side effects during chemotherapy that result in myelosuppression.

  • G-CSF - Neupogen
  • GM-CSF - Leukine
  • Erythropoietin - Epogen, Procrit
  • Interleukin-11 - Neumega

IMS: Microanatomy (16 decks)

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