CHAPTER 2: HEMATOPOIESIS

 A continuous, regulated process of blood cell production that includes cell renewal, proliferation, differentiation,
and maturation.
 These processes result in the formation, development, and specialization of all of the functional blood cells that
are released from the bone marrow to the circulation
 In healthy adults hematopoiesis is restricted primarily to the bone marrow. During fetal development,
hematopoiesis occurs in different areas of the developing fetus
A. ORIGIN OF BLOOD CELLS
 Hematopoietic stems cells (HSCs) are the foundation of the adult hematopoietic system.
TYPES OF HSCs:
o Totipotential stem cells – cells present in the first few hours after an ovum is fertilized; most versatile
type of stem cell, can develop into any human cell type, including development from embryo to fetus
o Pluripotential stem cells - cells present several days after fertilization; can develop into any cell type
except they cannot develop into a fetus
o Multipotential stem cells – 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 only produce
all types of blood cells, bone cartilage and adipose cells.
 Hematopoietic phases:
o Embryonic/Prenatal phase
- Mesoblastic phase
- Hepatic phase
- Myeloid phase
o Post-natal phase
- Medullary hematopoiesis
- Extra medullary hematopoiesis
 Stages of Hematopoiesis:
1. Mesoblastic phase (Yolk-sac phase)
- Begins around the 19th day of gestation.
- Occurs intravascularly (within a developing blood vessel)
- Characterized by the development of primitive erythroblast that
produce hemoglobin.
- Primitive erythroblasts arise from mesodermal cells.
2. Hepatic phase
- Begins at 4-5th gestational weeks
- Characterized by clusters of developing erythroblasts, granulocytes,
and monocytes which signals definitive hematopoiesis
- Lymphoid cells begin to appear
- Liver is the major site of hematopoiesis and retaining activity until 1-2 weeks after birth
- The spleen, kidney, thymus, and lymph nodes contribute to the hematopoietic process (Thymus-first fully
developed organ in the fetus, major site of T cell production; Kidney, spleen – produce B cells)
- Detectable levels of Hgb F, A, A2 may be present
- Production of megakaryocytes also begins
3. Medullary phase
- At 5th month of fetal development, hematopoiesis begins in the Bone marrow
- M:E ratio reaches adult levels of 3:1 at 21 weeks of gestation
- Measurable levels of Hgb A1, fetal Hgb, Hgb A2
 - After the first 3 weeks postpartum, the bone becomes the only normal site of blood cell production and remains
so through in life.
 ADULT HEMATOPOIETIC TISSUE
1. Bone Marrow
2 types:
a. Red marrow
 Hematopoietically active; predominant type during infancy and childhood
 Composed of extravascular chords that contain all developing cells
 At 18 years of age, the only active hematopoietic sites are sternum, skull, vertebrae, ribs, pelvis, proximal
extremities of long bones.
b. Yellow marrow
 Hematopoietically inactive, comprised of adipocytes
 Between ages 5-7, adipocytes become more abundant
 The process of replacing the red marrow by the yellow marrow is called retrogression
 Capable of reverting back to active marrow in cases of increased demand
 Approximately, there is equal amount of red and yellow marrow in adults
2. Liver
 Significant role in hematopoiesis in the 2nd trimester and major site during hepatic stage
 Capable of extra medullary hematopoiesis in case of bone marrow shutdown
3. Spleen
 Removes senescent RBCs
 Sequesters approximately 30% of platelets (synthesizes IgM in germinal centers which serves as storage sites for
platelets)
 3 types of tissues:
a. White pulp – consists of scattered follicles with germinal centers containing lymphocytes, macrophages, and
dendritic cells
b. Marginal zone – forms a reticular meshwork containing blood vessels, macrophages, and specialized B-cells
c. Red pulp – comprised of dendritic processes that create filter, cords of Billroth stagnates and depletes the
glucose supply of RBCs hat lead to their removal
 The spleen uses 2 methods for removing senescent RBCs from the circulation:
a. Culling – cells are phagocytosed with subsequent degradation of cells organelles
b. Pitting – splenic macrophages remove inclusions or damaged surface membrane from the circulating RBCs.
4. Lymph nodes
 Organs of the lymphatic system located along the lymphatic capillaries, not part of the circulatory system.
 Play a role in the formation of new lymphocytes
 Involved in the processing of specific immunoglobulins
 Filter particulate matter, debris, and bacteria entering the lymph node
5. Thymus
 Densely populated with progenitor lymphoid cells that migrated from the bone marrow and will soon give rise
to T-cells
B. STEM CELL CYCLE KINETICS, THEORIES AND CYTOKINES
 Hematopoietic Stem cells and Progenitors
o Pluripotential HSCs give rise to multipotent progenitors, followed by lineage-committed progenitors. In
the standard model of hematopoiesis, multipotent progenitors give rise to common myeloid
progenitors and common lymphoid progenitors
o The progenitor of all blood cells is called the multipotential HSC.
 Stem Cell Theory
o Primitive hematopoiesis – blood cell production that occurs during the mesoblastic stage
o Definitive hematopoiesis – begins during the fetal liver stage and continues through adult life
o Morphologically unrecognizable hematopoietic progenitor cells can be divided into two major types: (1)
noncommitted/undifferentiated stem cells; (2) multipotential and committee progenitor cells
o These two groups give rise to all of the mature blood cells.
 Theories
Originally, there were two theories describing the origin of hematopoietic progenitor cells.
o Monophyletic theory – suggests that all blood cells are derived from a single progenitor stem cell called
a Pluripotential stem cells (most widely accepted theory among experimental hematologists today)
o Polyphyletic – suggests that each of the blood cell lineages is derived from its own unique stem cell
 Hematopoietic stem cells
o Capable of self-renewal
o Give rise to differentiated progeny
o Able to reconstitute the hematopoietic system of a lethally irradiated host
 Progenitor cells – the progenitor cells for blood cells are commonly called colony-forming units (CFUs), because
they give rise to colonies of only one cell type when cultured or injected into a spleen. Four major types of
progenitor cells:
o CFU-E
o CFU-Meg
o CFU-GM
o CFU-L
 CFU-S – Mice spleens and bone marrows are irradiated, afterwards, marrow cells are intravenously
injected into the mice. Colonies of HCSs are observed after7-8 days and were referred to as CFU-s,
which will correspond to CFU-GEMM today
 COMMON LYMPHOID PROGENITOR – T cell, B cell, and NK cell lineage
 COMMON MYELOID PROGENITOR – Granulocytic, Eryhtrocytic, Monocytic, and Megakaryocytic
lineage.
SUMMARY OF HEMATOPOIESIS