Semester 1Hematopoietic & Lymphoreticular Systems
Dr. Mary S. Moore Fall, 2011
Learning Objectives Hematopoeisis After this lecture, the student should be able to: 1) recite where blood cells are produced at different stages of development. 2) list the two types of bone marrow and the basic structure of bone marrow. 3) explain how a single type of pluripotential stem cell gives rise to two lineages (myeloid cells and lymphocytes), and then each of those two lineages gives rise to all the mature blood cells. 4) list the stages of each lineage of blood cell development and what happens in each stage. You will NOT be expected to recognize each stage visually, but you will be expected to know the characteristics of the cells at each stage of development. You will be responsible for knowing each stage of erythropoiesis, granulocytopoiesis, monocytopoiesis, megakaryocytopoiesis, and lymphocytopoiesis. 5) explain the general effects of growth factors on blood cell development and how mature blood cells enter the bloodstream from the bone marrow.
Hematopoiesis (also called Hemopoiesis) definition: the process of blood cell formation from established blood cell precursors
-Mature blood cells have a relatively short life-span, must be continuously replaced by the progeny of stem cells -Erythrocytes, granular leukocytes, monocytes, lymphocytes, and platelets are all produced from stem cells -Under normal conditions, the production of blood cells can adjust rapidly to the need of the body, increasing several-fold in a short time. In a healthy adult person, approximately 1011–1012 new blood cells are produced daily in order to maintain steady state levels in the peripheral circulation
Lineages of Connective Tissue Cells
Mast cell is the exception, it is a “fixed” cell but it comes from an hematopoeitic stem cell, see later in lecture
In general, “transient” cells of connective tissue come from hematopoietic stem cells (top), “fixed” cells of connective tissue (bottom) come from mesenchyme (1 exception)
Alberts MBOC Fig. 23-5
The definition of a stem cell Each daughter produced when a stem cell divides can either remain a stem cell or go on to be terminally differentiated. In many cases, the daughter that opts for terminal differentiation undergoes additional cell divisions before terminal differentiation is completed.
but cannot become extraembryonic cells/tissues
.Totipotent-can become both embryo and extraembryonic cells/tissues
Pluripotent (blastocyst inner cell mass) can become all cell types of embryo.
. lymph nodes.***All blood cells arise from a single type of stem cell in the bone marrow This pluripotential stem cell first gives rise to two lineages 1 lineage will develop in red bone marrow to form the myeloid cells (erythrocytes. monocytes. granulocytes. These are formed in bone marrow initially but mainly differentiate in the lymphoid organs (spleen. and megakaryocytes/platelets) but not lymphocytes the other lineage forms the lymphocytes.
blood cells derived from stem cells in bone marrow.
.3rd-4th week of gestation: blood precursor cells arises from the yolk sac mesoderm 5th week: Liver and spleen are temporary hematopoietic tissues About 5th month of gestation: Bone marrow becomes increasingly important hematopoietic tissue After birth. The bone marrow also produces cells (T cells) that migrate to the lymphoid organs where they become immune competent.
Bone Marrow -One of the largest organs of the body and the main site of hematopoiesis Bone marrow is considered a type of connective tissue -Found in the medullary canals of long bones and the cavities of cancellous bones
Two types of bone marrow exist based on their appearance1) Red bone marrow .color is produced by the presence of a great number of adipose cells
.color is produced by the presence of blood and blood-forming cells 2) Yellow bone marrow .
scapulae. humeri).all marrow is red As the child grows. pelvis and upper half of sacrum. most of the bone marrow changes gradually into the yellow variety 25-year old: red marrow is confined to cancellous bonethe proximal quarters of the long bones (femora. skull bones. vertebrae. clavicle.New born. ribs. sternum.
hemonectin. laminin. and a few adipocytes Stroma of bone marrow contains collagen types I and III.Structure of red bone marrow
(2 parts . and another cell-binding substance. interact with cell receptors to bind cells to the stroma
. fibronectin. Laminin and fibronectin.stroma and sinusoids ) Stroma: 3-dimensional meshwork of reticular cells and a delicate web of reticular fibers containing hematopoietic cells. macrophages. and proteoglycans.
these touch projections of other reticular cells.What are reticular cells? (also called adventitial cells) -reticular cells send projections outward (away from basal lamina of endothelial cells). cords (islands) then basal lamina. then reticular cells c
. forming a 3D network surrounding discrete hemopoietic endothelial cells line sinusoidal capillaries.
-reticular cells secrete reticular fibers composed of type III collagen (reticular cells are fibroblasts) -secrete several cytokines that stimulate the development of progenitor cells into blood cells
2nd component of red bone marrow Sinusoids-formed by sinusoidal capillaries (between arteries and veins) lined by endothelial cells sitting on a discontinuous basal lamina Sinusoids are where RBCs. and platelets enter the circulation after their production in the bone marrow
Note the thinness of the blood capillary wall. Medium magnification.Figure 13—3. Giemsa stain. Five blood sinusoid capillaries containing many erythrocytes are indicated by arrowheads.
. Section of active bone marrow (red bone marrow) showing some of its components.
. granulocytes. and megakaryocytes/platelets) but not lymphocytes the other lineage forms the lymphocytes. These are formed in bone marrow initially but mainly differentiate in the lymphoid organs (spleen.***All blood cells arise from a single type of stem cell in the bone marrow This pluripotential stem cell first gives rise to two lineages
1 lineage will develop in red bone marrow to form the myeloid cells (erythrocytes. lymph nodes.
monocyte.CFU (colony forming unit)
PPSC: can differentiate into any type of blood cell. also capable of selfrenewal
GEMM (granulocyte. erythrocyte. megakaryocyte)
the other goes on to differentiate and divide multiple times
.When stem cell divides1 daughter cell remains a stem cell.
then they migrate to populate specific regions of peripheral lymphoid organs
Some differentiate into B lymphocytes within the bone marrow and then migrate to peripheral lymphoid organs
.Development of Lymphocytes (you will get a lot more on this in the study of the immune system in semesters 1 and 3) Pluripotential cells PPSC
Lymphoid multipotential cells some migrate to thymus where they become T lymphocytes.
Erythropoiesis development of erythrocytes (come from myeloid stem cell)
-gradually loses ribosomes. and organelles -gradually gains hemoglobin From first recognizable (proerythroblast) to release into bloodstream takes ~7 days
. mRNA.CFU-GEMM and CFU-E are intermediates
General trends in the development of erythrocytes -cell gets smaller -nucleus condenses.
Basophilia of #1 and #2 is caused by the large number of polyribosomes involved in the synthesis of hemoglobin 3)Polychromatophilic erythroblast -During this stage. polyribosomes decrease. no visible nucleoli. Thus.Comes from CFU-E which is not morphologically distinguishable
1)Proerythroblast -large cell. basophilic cytoplasm.visible nucleoli 2)Basophilic erythroblast -strongly basophilic cytoplasm. this stage cell stains both colors (basophilic and acidophilic)
. and areas of cytoplasm begin to be filled with hemoglobin which is acidophilic.
* 6) Erythrocyte -the mature form. has lost all polyribosomes
. Still has a few polyribosomes that aggregate (when treated with dye cresyl blue) to form a stained “reticular” network.4) Orthochromatophilic erythroblast -Nucleus continues to condense. becomes a reticulocyte. lose evident basophilia (but not quite all polyribosomes) resulting in uniform acidophilia 5) Reticulocyte -after it expels its nucleus. Reticulocyte leaves the bone marrow and passes into the bloodstream.
**nearly all erythrocytes are released into the circulation (in reticulocyte form) as soon as they are formed bone marrow is not a storage site for erythrocytes
Blood smear stained with cresyl blue to show reticulocytes (arrows)
In the graph. followed by extrusion of a pyknotic nucleus. The stippled part of the cytoplasm (on the left) shows the continuous increase in hemoglobin concentration from proerythroblast to erythrocyte. The times are the average life span of each cell type.
. There is also a gradual decrease in nuclear volume and an increase in chromatin condensation. 100% represents the highest recorded concentrations of hemoglobin and RNA.each of these stages divides several times
Summary of erythrocyte maturation.
The cell is shown extruding its nucleus to become an immature erythrocyte (a reticulocyte) which then leaves the bone marrow and passes into the bloodstream. The reticulocyte will lose its mitochondria and ribosomes within a day or two to become a mature erythrocyte. can increase after blood loss)
.A developing red blood cell (erythroblast). (reticulocytes are about 1-2% of RBCs in bloodstream.
which phagocytoses and digests the nuclei discarded by the erythroblasts.megakaryocyte
Drawing by Dr. Aidi Yin
Macrophage (nurse cell) sinusoid
Reticular cells Reticular fibers
**Erythrocyte clones develop in the bone marrow on the surface of a macrophage (also called a nurse cell).
*These hemopoietic growth factors are all secreted proteins that bind to receptors on their target cells. control rates of hematopoeisis of stem cells
Students-EPO is the only growth factor on this table you need to remembersynthesized by
are hydroxylated and proteosomally digested in the presence of oxygen.
! EPO is also (illegally) sometimes used as a blood doping agent in endurance sports such as bicycle racing.The # of RBCs in circulation is monitored and maintained by kidneyerythropoietin (EPO) which is synthesized and secreted by the kidney in response to decreased blood oxygen concentration. acts on receptors on surface of CFU-E
(specifically. triathlons and marathon running. known as hypoxiainducible factors (HIFs).!
. but you don’t have to remember this): Constitutively synthesized transcription factors for EPO.
Life Cycle of Red Blood Cells
There are two main points to this slide-1) Each stage of differentiation is modulated by a combination of cytokines and other growth factors. but by a different lineage than basophils
. 2) mast cells also come from CFU-GEMM.
eosinophils. and platelets all come from the same myeloid stem cell as RBCs
.Granulocytes (neutrophils. and basophils). monocytes.
. (e) Only lymphocytes arise via the lymphoid stem cell line. like granular leucocytes. are progeny of the myeloid stem cell and diverge from a myeloblast that can become either a neutrophil or a monocyte.Granulocytopoiesis
CFU-GEMM CFU-EO CFU-BA
Pluripotential stem cell (PPSC)
Leucocyte formation. Leucocytes arise from pluripotential stem cells PPSC (a-c) Granular leucocytes develop via a sequence involving myeloblasts. “Granulocytopoiesis” (d) Monocytes.
post-mitotic phase also takes ~ 1 week
Myeloblast Looks like lymphocytes. but often has 3-5 prominent nucleoli
Promyelocyte Azurophilic (nonspecific) granules appear
Myelocyte Oval or flat nucleus Specific granules appear.mitotic phase takes ~ 1 week. last stage at which cell division is possible
mainly band cells are immature neutrophils
Mature eosinophils.Metamyelocyte Specific granules continue to accumulate. nucleus indented. neutrophils. c or v shape
Band/stab cell eosinophil and basophil stab cells exist but are rarely found. basophils
the cell further differentiates.
**All granulocytes express non-specific granules. these are made first as the cell develops.Figure 13—11. Azurophilic granules are blue. Drawing illustrating the sequence of gene expression in the maturation of granulocytes. Then. not always in real life). specific granules are pink (in this picture. and then gains the ability to make the specific granules unique to that cell type
ratio of these neutrophils in bone marrow to bloodstream is ~5:1 This reserve pool can be released abruptly into the circulation in response to inflammation. *unlike erythrocytes. Called a “Shift to the left” **Indication of bacterial infection.Clinical correlations
Increased number of immature neutrophils in the bloodLarge number of band cells appear in the blood. infection. or strenuous exercise.
. mature and near-mature neutrophils are stored in bone marrow.
Jim Catroppo for pictures
.Origin of “shift to the left” referring to increase in immature neutrophils in blood
thanks to Dr.
. In addition to counting. measuring and analyzing red blood cells.TodayMost modern. automated hematology analyzers also measure the amount of hemoglobin in the blood and within each red blood cell. urban medical labs have an automated hematology analyzer
Counting chambers that hold a specified volume of diluted blood (as there are far too many cells if it is not diluted) are used to calculate the number of red and white cells per liter of blood. white blood cells and platelets.
-In these diseases.Clinical Correlation
Leukemias are malignant clones of leukocyte precursors. there is usually a release of large numbers of immature cells into the blood -Leads to a lack of some cell types and excessive production of others (which are often abnormal in function) -Patient is usually anemic and prone to infection -Usually diagnosed with bone marrow aspiration (can also see in peripheral blood)
. They occur in lymphoid tissue (lymphocytic leukemias) and in bone marrow (myelogenous and monocytic leukemias)
MonocytopoiesisNote that monocytes and neutrophils share the same progenitor (GFUGM)
the newly formed monocytes enter the connective tissue spaces of the body and transform into macrophages
Promonocyte -cytoplasm is bluish and houses numerous azurophilic (non-specific) granules (lysosomes) *Note that monocytes and neutrophils share the same progenitor (GFU-GM) Monocyte Every day. the average adult forms more than 1010 monocytes. most of which then enter the circulation Within a day or two.
Megakaryocytopoiesis (origin of platelets)
platelets originate in the red bone marrow by fragmentation of the cytoplasm of mature megakaryocytes which arise by differentiation of megakaryoblasts
Each megakaryocyte produces between 5.000 and 10.Megakaryocytopoiesis (Origin of platelets) -In adults.000 platelets
do contain granules that contain platelet-derived growth factor. it contains up to 30 times as much DNA as a normal cell (chromosomes replicate but the cell doesn’t divide) Giant cell. Platelets do not contain nuclei. invaginations of plasma membrane form demarcation membranes with platelet granules inside each These break off to form platelets. von Willebrand’s factor (which promotes adhesion of platelets to endothelial cells). fibroblast growth factor.Megakaryocytopoiesis
The nucleus become highly polyploid. and platelet factor IV (which stimulates blood coagulation)
Megakaryocytes form thin processes that cross the wall of the sinusoid and fragment at their tips. and platelets across a sinusoid capillary in red bone marrow.Platelets breaking off from megakaryocyte
Drawing showing the passage of erythrocytes.
. liberating the platelets. leukocytes.
In red bone marrow.
. cross the wall of the sinusoid by their own activity. creates pressure “suction” that “sucks” mature RBCs from stroma into capillary. veins leaving are smaller than arteries entering. after the action of releasing substances. they are believed to enter the sinusoid by a pressure gradient that exists across its wall.How RBCs and WBCs enter bloodstream from marrow
Because erythrocytes (unlike leukocytes) do not have sufficient motility to cross the wall of the sinusoid. Leukocytes.
In contrast. monocytes and lymphocytes have the potential for further division
.Note: Granulocytes never divide again.