Chapter 4

Hematopoiesis

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Introduction

Hematopoiesis is the process of blood cell production,

differentiation, and development.
The hematopoietic system consists of the bone marrow,
liver, spleen, lymph nodes, and thymus.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Origin of Blood Cells
Types of human stem cells
Functionally, three types of human stem cells exist:
Totipotential stem cells. These cells are present
in the first few hours after an ovum is fertilized.
Totipotential stem cells, the most versatile type of
stem cell, can develop into any human cell type,
including development from embryo into fetus.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Origin of Blood Cells (cont.)
Pluripotential stem cells. These cells are present
several days after fertilization. Pluripotent stem cells can
develop into any cell type, except they cannot develop
into a fetus.
Multipotential stem cells. These cells are derived from
pluripotent stem cells. They can be found in adults but
they are limited to specific types of cells to form tissues.
For example, bone marrow stem cells can produce all
type of blood cells, bone cartilage, and adipose (fat)
cells.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Early Development of Blood Cells

Figure 4.1 Cross-sectional view of the embryo at the time of mesoderm migration. The mesoderm cells
coalesce into three distinct clumps, or colonies. The paraxial mesoderm tracks the path of the notochord.
The intermediate mesoderm hovers just beside it for a short stretch of the embryo's length. The lateral
plate mesoderm fills the rest of the space and forms an important contact with the ectoderm above
(dorsally) the endoderm below (ventrally) and the extraembryonic shell to the outside. (Reprinted with
permission from Hartwig W. Fundamental Anatomy, Baltimore, MD: Lippincott Williams & Wilkins, 2008.)
Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins
Anatomical Sites of Blood Cell
Development

Figure 4.2 Hemopoiesis in various organs before and after birth. (Reprinted with permission from Rubin E,
Farber JL. Pathology, 3rd ed, Philadelphia, PA: Lippincott Williams & Wilkins, 1999.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function

Figure 4.3 Normal bone marrow biopsy. (Reprinted with permission from Handin RI, Lux SE, Stossel TP.
Blood: Principles and Practice of Hematology. 2nd ed, Philadelphia, PA: Lippincott Williams & Wilkins,
2003.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function (cont.)

Figure 4.4 Bone marrow biopsy sections demonstrate normal cellularity. Approximately 40% to 50%
cellularity in an otherwise healthy 60-year-old man. (Reprinted with permission from McClatchey KD.
Clinical Laboratory Medicine, 2nd ed, Philadelphia, PA: Lippincott Williams & Wilkins, 2002.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function (cont.)

Figure 4.5 Bone marrow biopsy sections demonstrate normal cellularity. Virtually 100% cellular marrow from
a newborn boy. (Reprinted with permission from McClatchey KD. Clinical Laboratory Medicine, 2nd ed,
Philadelphia, PA: Lippincott Williams & Wilkins, 2002.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function (cont.)

Figure 4.6 The development of blood cells: humerus bone, cortical bone, red bone marrow, and yellow bone
marrow. (Asset provided by Anatomical Chart Co.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function (cont.)

Figure 4.7 Normal peripheral blood cells. A: Lymphocytes. B: Basophils. C: Eosinophils. D: Segmented
neutrophils. E: Monocytes. F: Band form neutrophil.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function (cont.)

Figure 4.8A Sites of red bone marrow activity. A: Child. Red bone marrow (red-shaded areas) is located
throughout the skeletal system in children. (Reprinted with permission from Dzierzak E. Ontogenic
emergence of definitive hematopoietic stem cells, Curr Opin Hematol, 10(3):230, 2003.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Bone Marrow Sites and Function
(cont.)

Figure 4.8B Sites of red bone marrow activity. B: Adult. Yellow marrow replaces red marrow (dark-shaded
areas) in the adult skeletal system. Red marrow activity occurs in the central portion of the skeleton.
(Reprinted with permission from Dzierzak E. Ontogenic emergence of definitive hematopoietic stem cells,
Curr Opin Hematol, 10(3):230, 2003.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cellular Elements of Bone Marrow

Figure 4.9 Over a lifetime, the size of the HSC population may decrease (a), remain the same (b), or
increase (c). (Reprinted with permission from Liang W, Van Zant G. Genetic control of stem-cell
properties and stem cells in aging, Curr Opin Hematol, 10(3):200, 2003.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cellular Elements of Bone Marrow (cont.)
Hematopoietic cells can be divided into three phases according
to cell maturity:
Primitive, multipotential cells. The most immature
group capable of self-renewal and differentiation into all
blood cell lines
Intermediate cells. This group consists of committed
progenitor cells destined to develop into distinct cell lines.
Mature cells. The most developed group with specific
functions

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)

Figure 4.10 A general model of hematopoiesis. (Reprinted with permission from Kaushansky K. Lineage-
specific hematopoietic growth factors, NEJM, 354(19):2035, 2006. Copyright 2006. Massachusetts
Medical Society. All rights reserved.)

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Erythropoiesis
Erythropoiesis occurs in distinct anatomical sites
called erythropoietic islands, specialized niches in
which erythroid precursors proliferate, differentiate,
and enucleate.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Granulopoiesis
Myeloid cells account for 23% to 85% of the
nucleated cells in normal bone marrow.
Granulopoiesis can be recognized as a maturational
unit.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Lymphopoiesis
Unlike other cell lines, lymphocytes and plasma cells
are produced in lymphoid follicles.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Megakaryopoiesis
Megakaryopoiesis takes place adjacent to the sinus
endothelium.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Other cells found in bone marrow
Marrow stromal cells
The meshwork of stromal cells is composed of
reticulum cells, histiocytes, adipose cells, and
endothelial cells.
Mast cells
Tissue mast cells, a connective tissue cell of
mesenchymal origin, are normally observed in
bone marrow.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Progenitor Cells (HPCs)
(cont.)
Macrophages
Macrophages, also called reticulum cells or
histiocytes, appear as large cells in the bone marrow.
Bone cells
Osteoblasts are bone matrixsynthesizing cells that
resemble plasma cells and are usually observed in
groups.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Interleukins
Protein molecules that work in conjunction with
hematopoietic growth factors to stimulate proliferation
and differentiation of specific cell lines are the
interleukins.
Interleukins are cytokines that act independently or in
conjunction with other interleukins to encourage
hematopoietic growth. Interleukins are cell signaling
molecules and a part of the cytokine super family of
signaling molecules.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Interleukins (cont.)
The interleukins were first described as signals for
communication between (interbetween) white blood
cells (leukfrom leukocytes).
Currently, it is well-known that these molecules are
produced and used as signaling molecules in many cells
of the body, in addition to immune cells.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Interleukins (cont.)
Interleukins are basically the method of immune cross
talk and communication.
Interleukins are the primary messengers and directors of
the immune system.
There are currently 35 well-known interleukins; however,
there are many more to be found and characterized.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Growth Factors
Each hematopoietic growth factor is encoded by a single
gene.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Hematopoietic Growth Factors (cont.)
Examples of various factors and the target cells include
the following:
G-CSF and GM-CSF predominantly affect myeloid cells
IL-7 stimulates T and B lymphocytes
IL-12 targets natural killer cells

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

 Examination of Maturing Blood Cells
A comprehensive examination of bone marrow involves
examination of both bone marrow smears and
histological tissue sections.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

General Cellular Characteristics
The identification and stage of maturation of stained
blood cells can be guided by a variety of systematic
features.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

General Cellular Characteristics (cont.)
Two important characteristics to observe initially in cell
identification are as follows:
Overall cell size
Nuclear-cytoplasmic ratio

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Nuclear Characteristics
Nuclear characteristics play an important role in cell
identification. Important features of the nucleus include
the following:
Chromatin pattern
Nuclear shape
The presence of nucleoli

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Nuclear Characteristics (cont.)
Chromatin patterns
Lymphocytes exhibit a smooth or homogeneous pattern of
chromatin throughout development until the mature stage,
when clumped heterochromatin is more obvious.
Granulocytes progress from having a fine to a highly
clumped pattern.
Monocytes have a lacy pattern, which becomes finer as
the cell matures.
Erythrocytes continue to develop a more clumped pattern
as maturation progresses, until the extremely dense
(pyknotic) nucleus is lost (extruded) from the mature cell.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Nuclear Characteristics (cont.)
Nuclear shape
Lymphocytes usually continue to have a round or
oval nucleus. Some cells may have a small cleft in the
nucleus.
Monocytes have a kidney beanshaped nucleus, but
folded or horseshoe shapes are common.
Mature neutrophils, eosinophils, and basophils
have segmented nuclei attached to one another by
fine filaments. The number of distinctive lobes ranges
from two to five depending on the cell type.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Nuclear Characteristics (cont.)
Presence of nucleoli
The presence or absence of nucleoli is important in
the identification of cells.
The three cell lines of erythrocytes, leukocytes, and
megakaryocytes all have nucleoli in the earliest cell
stages.
As cells mature, nucleoli are usually not visible. These
changes in the appearance of the nucleoli are related
to the rate of synthesis of ribosomal RNA.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Nuclear Characteristics (cont.)
Lymphoblasts have one or two nucleoli.
Myeloblasts have one to five nucleoli.
Monoblasts usually have one or two nucleoli but
occasionally may have three or four.
Erythroblasts may not have any nucleoli or may have
up to two nucleoli that may stain darker than in other
types of blast cells.
Megakaryoblasts typically have one to five nucleoli.

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Cytoplasmic Characteristics
Staining color and intensity
Granulation
Shape
Quantity of cytoplasm
Vacuolization
Inclusion bodies

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins

Mature Blood Cells in Peripheral Blood

Copyright 2012 Wolters Kluwer Health | Lippincott Williams & Wilkins