Hematopoiesis Flashcards
What is hematopoiesis?
Where does it occur in adults?
Hematopoiesis is the complex process that results in the formation of the mature, functional red blood cells, white blood cells, and platelets in the peripheral blood, and ultimately the functional cells of the lymphoid organs, and reticuloendothelial system.
In the normal adult, this process occurs exclusively in the bone marrow.
Pre‐natal hematopoiesis
Where are RBCs produces up to the third month of gestation?
What about fromt he second to the seventh month of gestation?
1- Primitive blood cells, primarily red cells are first produced in the yolk sac. Hematopoiesis in the yolk sac is largely finished by the third month of gestation.
2- From the second to the seventh month, the liver and to a lesser extent the spleen is the primary site of hematopoiesis. At birth, the bone marrow is firmly established as the site of hematopoiesis.
Post-Natal Hematopoiesis
As the kid hematopoiesis becomes more localized to where?
- After birth and in early childhood most of the marrow cavity is hematopoietically active. As the child ages, hematopoiesis becomes more and more localized to the axial skeleton so the by the time an individual is 18 to 20 years old 90% of hematopoietically active marrow is located in the vertebrae, pelvis, sternum, ribs and skull.
- Hematopoiesis outside of the bone marrow after birth is distinctly abnormal and is called extramedullary hematopoiesis.
What is the difference between myeloid and lymphoid tissues?
What cells are part of the lymphoid tissues?
Myeloid. The term myeloid is (typically) restricted to non‐lymphoid blood cells that are derived from the marrow, i.e. granulocytes, red cells, platelets, and monocytes.
However, “ myeloid” is at times used to refer to granulocytes only. The most notable example of this is the Myeloid to Erythroid (M:E) ratio that is estimated when a bone marrow biopsy from a patient is examined. This estimation is an assessment of the ratio of granulocytic precursors to erythroid precursors. Accordingly the use of the derivative word myelogenous will refer to non‐lymphoid blood cells, and the word myelopoiesis will refer to the production of non‐lymphoid blood cells.
Lymphoid: The lymphocyte term – T cells, B cells, natural killer cells.
What is the difference between differentiation and maturation?
DIFFERENTIATION: As a hematopoietic cell progresses from a stem cell to a functional cell in the peripheral blood, lymphoid organs, or reticuloendothelial system, it undergoes genetic changes that facilitate the expression of some genes, and restrict the expression of other genes. The pattern of gene expression that results leads to commitment of cells to a particular lineage (e.g. erythroid, granulocytic, lymphoid).
MATURATION: The difference between maturation and differentiation is not terribly clear when reading the literature. It’s best to think of maturation as the accumulation of protein products and refinement of cellular structure dictated by the pattern of gene expression in a cell committed to a particular lineage.
Who within the bone marrow creates the specialized microenvironment or niche for HSC?
How do differentiated cells enter the circulation?
What do stromal cells express that is required for stem cell homeostasis?
Marrow space is encased by cortical bone, and interspersed by trabecular (cancellous) bone lined by osteoblasts and osteoclasts.
Between trabecula is a network of vascular thin-walled sinusoids with single layer of endothelial cells
- discontinuous basement membrane and adventitial cells (‘leaky’)
- Within the interstitium lie clusters of hematopoietic cells (HPCs) and fat cells.
The bone marrow is a unique microenvironment that supports the orderly proliferation, differentiation, and release of blood cells.
Blood vessels and osteoblasts create a specialized microenvironment, or niche, for the HSCs
These “niche” cells release factors (such as CXCL12) that regulate HSC behavior in ways that are not yet completely understood.
I just mentioned that postnatal hematopoiesis is normally confined to the marrow. Why?
- We think that an important contributing factor is active homing of HSCs via the various chemokines/chemical mediators released by these niche cells.
Differentiated blood cells enter the circulation by transcellular migration through the endothelial cells.
Stromal cells expressing KIT ligand are also required for stem cell homeostasis produce the protein framework of the marrow, especially type IV collagen (reticulin):
-produce regulatory factors and adhesion molecules needed to induce and maintain hematopoiesis
What are the factors required for hematopoiesis?
HSCs have 2 essential properties, required for the maintenance of hematopoiesis:
1) pluripotency
- ability of a single HSC to generate all mature blood cells
2) capacity for self-renewal
- When an HSC divides, at least one daughter cell must self-renew to avoid stem cell depletion.
- Self-renewing divisions occur within a specialized marrow niche, in which stromal cells and secreted factors nurture and protect the HSCs.
These characteristics allow the HSCs to undergo either symmetric or asymmetric division.
What is the difference between assymetric and symmetric HSC division?
Where are assymetric cell divisions more dominant?
HSC divisions can be symmetric or asymmetric
- HSC becomes 2 committed progenitors or 2 new HSCs
- one cell remains an HSC, and the second commits to differentiation.
Asymmetric cell divisions are dominant in the bone marrow, in which the number of HSCs remains fairly constant.
Progenitor cells:
What are the two key properties that they acquire?
- With differentiation HSCs lose multipotency and the capacity for self-renewal–>progenitors
- Acquire two other key properties:
- Increased capacity for cell division (amplification)
- Expression of receptors for hematopoietic growth factors (HGFs)
Hematopoiesis is regulated by what?
What factor has the ability to effect multiple cell types?
EPO regulates_______.
TPO regulates_______
For granulocytes:
G-CSF (Colony Stimulating Factors) –> __________
M-CSF —–> ___________
IL-3 stimulates—> ___________
IL-5 stimulates–>___________
What two factors are termed multilineage growth factors, because they act on different HSC, including stem cells?
•Hematopoiesis is regulated by hematopoietic growth factors (glycoproteins)
–>Effect multiple cell types (c-KIT ligand)
–Effects restricted to specific progenitors
Specific HGFs
–EPO: RBCs (erythroid precursors)
–TPO: Megakaryocytes (platelets)
Granulocyte precursors
- G-CSF: Neutrophils
- M-CSF: Monocytic cells
- IL3: Basophils
- IL5: Eosinophils
**IL3 and GM-CSF are called multilineage growth factors.
What is the average life-span of some cells in the blood?
At what point to HSC loose their ability to self-renewal?
When HSCs divide, at least one of the two daughter cells remains an HSC (self-renewal) – a property that maintains HSC numbers.
Division of multipotent progenitors gives rise to at least one daughter cell that leaves the stem cell pool and begins to differentiate.
Once past this threshold, these newly committed cells lose the capacity for self-renewal and commence an inexorable journey down a road that leads to terminal differentiation and death.
Precursor cells
Progenitor cells give rise to precursor cells.
- These cells are the recognizable, maturing cells that are enumerated when a marrow differential is performed. Precursors are capable, up to a point, of cell division, but cannot self‐renew. Precursor cells give rise to the mature, functional cells in the peripheral blood, lymphoid organs, and reticuloendothelial system.
- Distinguishing between different types of blasts (t-lymphoblasts, b-lymphoblasts, myeloblasts, etc), whether normal or neoplastic,can usually NOT be done based on morphology alone.
From what cell do neutrophils, basophils, and eosinophils derive from?