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Syllabus Hematopoiesis

Syllabus Hematopoiesis

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Published by Ashley Kain

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Published by: Ashley Kain on Nov 01, 2010
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05/24/2012

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SBM HEMATOLOGY
HEMATOPOIESIS20
!"
Christopher Lowrey, MD(c.lowrey@dartmouth.edu)Learning objectives:1.
 
Be able to recognize normal human peripheral blood cells.
2.
 
Understand how hematopoietic stem cells give rise to mature blood cells.
3.
 
Be able to explain how sites of hematopoiesis change during development.
4.
 
Understand how hypoxia stimulates production of red blood cells.
5.
 
Understand the role of hematopoietic growth factors in regulating blood cell production.
6.
 
Understand the rationale for hematopoietic stem cell transplantation.
Reading
:
Up-to-Date
: “Overview of hematopoiesis and stem cell function.”
Note :
The most important concepts for you to know are underlined in the text of these notes.
I. Types of cells in the blood.
The cellular portion of blood is composed of seven distinct types of cells (Figure 1):a.
 
Red cells – carry oxygenb.
 
Platelets – participate in clot formation, a critical component of hemostasis.c.
 
Lymphocytes (T and B cells) – respond to viral and other types of infection.d.
 
Monocytes, Neutrophils, Eosinophils, Basophils – respond to bacterial, fungal, and parasiticinfections.
Hints for
 
identifying the different types of WBC’s 
: lymphocytes generally have small roundnuclei, minimal cytoplasm and no granules, monocytes have more cytoplasm and an indented nucleus,basophils have intense blue granules, eosinophils have intense red granules that are stained by the dye“eosin”, mature neutrophils have 3 “lobes” and pale granules, immature granulocytes are known as “bands”with a nucleus that has not yet separated into 3 lobes.
Clinical Correlation – The Complete Blood Count (CBC)WBC –
total number of all white blood cells per cubic mm (i.e., microliter).
Platelet Count -
total number of platelets per cubic mm (i.e., microliter).
Hemoglobin & Hematocrit
 – these parameters are typically used instead of the “red blood cell count”to quantify the number of red cells. See figure 2.
Red Blood CellPlateletLymphocyteMonocyteEosinophilBasophilNeutrophil (mature)Neutrophil (immature)Figure 1. Normal Human Blood Cells
October 
!"#$%&!&
 Revised September 2009September 25, 2009
 
Hematopoiesis
II. The Concept of the “Hematopoietic Stem Cell.”
All the cells of the blood arise from a common hematopoietic stem cell (HSC) (Figure 3). HSCs were firstidentified in the 1950’s and were the first (and for many years the only) example of a cell that could giverise to many other types of more mature cells. They were first identified by showing that the hematopoieticsystem of lethally-irradiated mice could be regenerated by injecting bone marrow from untreated donormice. A single HSC can regenerate the blood system of a mouse – including giving rise to more HSCs.Approximately 1 in 10,000 bone marrow cells are HSCs in adult humans. They are typically identified bythe presence of a cell surface protein known as CD34 . The function of this protein is not known. It is alsopresent on early myeloid cells and on some leukemia cells. It is estimated that humans have approximately50,000 stem cells. At any given time most of these cells are in the G
0
phase of the cell cycle with only asmall proportion contributing to hematopoiesis at any one time. The quiescent stem cells are thought to beresistant to toxic insult s such as radiation or chemicals because they are able to repair their DNA beforeentering the cell cycle at some later time point.
Translational Science Correlation – Hematopoietic Stem Cell “Plasticity”
Recent evidence, mostly from mouse experiments, has suggested the possibility that HSCs can alsogenerate non-hematopoietic cells . For example, injecting HSCs into mice that have had experimentallyinduced heart attacks may lead to regeneration of cardiac myocytes that are derived from the HSCs. Similarresults have been provided for regeneration of chemically damaged liver cells. Despite the fact that theconcept of HSC “plasticity” remains controversial , several early human trials of autologous (from the same
Hematocrit =Volume Plasma/Volume of Red CellsHemoglobin =Spectrophotometric measurementhemoglobin absorbance
WBCPlateletsHemoglobinHematocrit
AB
Figure 2. A) Calculation of hemoglobin and hematocrit values. B) Typical clinicalshort-hand often used to record the CBC.
IL-2IL-2(IL-6)NK lymphocytesT lymphocytesB lymphocytesCFU-GEMMCFUsPltsMonosPMNsRBCs(TPO)/IL-11GM-CSFG-CSF/GM-CSFEPOMATURE CELLSMATURE CELLSSTEMCELLLYMPHOIDSTEM CELL
HEMATOPOIETIC GROWTH FACTORS
Stem CellFactor(SCF)
 
MYELOIDPRECURSOR
Figure 3. All blood cells arise from a common precursor -the hematopoietic stem cell (HSC).
- 2 -
 
Hematopoiesisperson) HSC transplant for patients after myocardial infarctionhave been performed – so far there is no conclusive evidence of HSC-mediated cardiac repair or of improved survival.
Clinical Correlation Bone Marrow Transplantation
Based on the ability to reconstitute the hematopoietic system of mice and other animals following lethal irradiation, researchers inthe 1960’s began treating patients with life-threatening diseases of blood stem cells (mostly leukemia and other blood cancers) withstem cell transplants. The idea was that lethal doses of irradiationand/or chemotherapy drugs could be used to eliminate theabnormal stem cells but that this would also eliminate normalstem cells – which could be replaced by stem cells from a normaldonor. Approximately 8,000 of these allogeneic (from anotherperson) transplants were performed in 2006. These transplantsoffer the only hope for a cure for many patients. Dr. E. DonnellThomas (Figure of the University of Washington received the1990 Nobel Prize in Physiology & Medicine for his work onbone marrow transplantation.III.
The location of Hematopoiesis Changes During Human Development.
In the first few weeks of gestation, the yolk sac is the main sitefor hematopoiesis. Early in embryonic development, the firstHSCs arise in the wall of the developing aorta and then migrate tothe fetal liver and spleen. From 6 weeks until 6-7 months of fetallife, the liver and spleen are the main organs for production andcontinue to be sites until about 2 weeks after birth. The bonemarrow is the most important site from 6-7 months of fetal lifeand soon after birth is the only source of new cells. Developingcells are situated outside the bone marrow sinuses and mature cellsare released into the sinus spaces, the marrow microcirculation andthe general circulation.In infancy, all the bone marrow is hematopoietic but duringchildhood, the marrow is progressively replaced by fat in the longbones. In the adult, hematopoietic marrow is confined to the axialskeleton and proximal ends of the femurs and humeri. Even in thehematopoietic areas, the marrow consists of 50% fat. In times of need, the marrow in these sites replaced by fat may producehematopoietic cells. The liver and spleen may also become aproduction site (called extramedullary hematopoiesis).
Figure 5. The location of hematopoiesis changes during normal human development.Fig 6: Infant vs. adult sites of hematopoiesis.
Figure 4. Dr. E. Donnell Thomas - winnerof the 1990 Nobel Prize for Physiology andMedicine for his work on Bone MarrowTransplantation.
Bone marrowbiopsies are typicallyperformed at the posteriorIliac crest.
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