Download lecture08-blood

Blood and
Body Defenses
Jim Pierce
Bi 145a
Lecture 8, 2009-10
Blood

Blood is a connective tissue
Cells
 Extracellular Matrix

Blood
Hematopoeisis in utero
Hematopoeisis in utero
Hematopoiesis
Bi 214 –
Hematopoiesis
Great model of:
A Developmental System
Cell Differentiation
Cell Signaling
Epigenesis
Hematopoietic Systems

Reticuloendothelial System

Comprised of

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Endothelial Cells
Monocyte Derivatives
Hepatocytes
Located

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
Bone Marrow
Liver
Spleen
Blood Vessels
Hematopoietic Systems

Reticuloendothelial System

Roles
 Making
new hematopoietic cells
 Making new connective tissue cells (??)
 Cleaning up old circulating cells
 Control
of iron metabolism
Bone Marrow

The “classic” location
of Hematopoiesis
Thymus
Child Thymus
(in adult it’s mostly fat)
Spleen
Spleen
Spleen
Liver
We’ll talk more
about the liver
next term
Hematopoietic Systems

Mononuclear Phagocyte System

Comprised of
 Monocyte

derived cells
Located in
 Every
part of the body
Hematopoietic Systems

Mononuclear Phagocyte System examples:
 Kupffer
cell in the liver
 Alveolar macrophages in the lung
 Professional antigen presenting cells like the
dendrititc cell in the lymph node
 Peritoneal macrophages in the abdomen
 Osteoclasts on the bone
 Microglia in the nervous system
 Histiocytes in the connective tissues
 Giant cells at the site of a granulomatous infection
 Macrophages in a maturing scar
Hematopoietic System

We’ll talk more about these monocyte
derived cells in each organ system

For further discussion of immune function
check out Bi 114 - Immunology
Hematopoetic Cells
Red Blood Cells
 White Blood Cells
 Platelets

Megakaryocytes
 Pluripotent Stem Cells
 Multipotent Stem Cells

Bone Marrow Aspiration
Bone Marrow Biopsy
Peripheral Blood Smear
Lymphocyte
Monocyte
Neutrophils
Eosinophil
Basophil
Megakaryocyte
Erythrocytes
Erythrocytes

Erythrocyte population
is in steady state equilibrium

Erythrocytes are
constantly produced
Erythrocytes

Interestingly, the bone marrow churns out
huge numbers of committed progenitors
who would become erythrocytes

Most of these
undergo apoptosis

Erythropoietin is
the “survival factor”
Hematopoiesis

Hematopoiesis, in general,
is a wonderful model system
for considering positive and
negative factors controlling
cell proliferation and differentiation
Circulating Progenitors

The first model of hematopoiesis
kept the Stem Cells in the bone marrow
and the Adult Cells in the circulation

After looking at enough peripheral blood,
hematologists realized this might be wrong
Circulating Progenitors

Every once in a
while, you can
find …

a megakaryocyte

in the peripheral
blood smear
Circulating Progenitors

The hunt was on…

And with improved cell sorting techniques,
it was found that there were…
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Circulating Progenitor Hematopoietic Cells
Circulating Progenitors

Not surprisingly, scientists studying
angiogenesis and vascular disease
wondered about endothelial cells…

There are circulating endothelial progenitors,
too!
Circulating Progenitors

Over time, scientists began to wonder if other
“progenitor cells” were circulating

… perhaps as a source of stem cells
… perhaps to explain where
“wound healing cells” come from
… perhaps just to see if something’s there!


Circulating Progenitors
May 12, 2005
Circulating Progenitors

Flow Cytometry
with FACS

Their secret…

Better primary
antibodies.
Circulating Progenitors

in vitro culture
Produced
Hydroxyapatite
Nodules
(bone)
Circulating Progenitors

in vivo

Bone!
Circulating Progenitors
Osteoclasts remove bone
 Osteoblasts make bone matrix
and become osteoclasts as bone forms.

Circulating Progenitors

The “old” hypothesis:
Osteoclasts produce a “positive signal”
 This signal induces osteoblasts to arrive
 Osteoblasts arrive and differentiate
 Bone is formed

Circulating Progenitors

A “new” hypothesis:
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Osteoblasts are always circulating
Osteoblast adhesion is
“constituatively inhibitied”
Local Signals (bony injury, bone resorption)
remove inhibition
This permits osteoblasts to adhere
Adherent osteoblasts differentiate
Bone is formed
Circulating Progenitors
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This new model supports several
(previously unexplained) observations

Injury to tissue can lead to
ectopic bone formation
Growth spurts change magnitude
of bone formation – not location
Osteopetrosis
Osteophytes



Circulating Progenitors
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If circulating bone progenitors exist…

Perhaps other circulating connective
tissue progenitors exist.
Circulating Progenitors

Consider the current arguments:

Healing wounds have a “special” cell –
the myofibroblast
acts like a fibroblast – i.e. ECM maker
 It acts like a myocyte – i.e. contracts (tension
maker)
 No one knows where it comes from
 It
Circulating Progenitors

Consider the current arguments:

Healing wounds have a “special” cell –
the myofibroblast
 “De-differentiate
 Migrate
In?
Re-Differentiate”
Circulating Progenitors

Consider the current arguments:

Tissue culture can “beat up” connective tissue

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The fibroblast can be made to re-differentiate
into adipocytes, myocytes, and chondrocytes
Progenitor cells may have been found in the
connective tissue – though not well identified
Local Proliferation and Differentiation
Migrate in (like bone)?
Circulating Progenitors

The hot hypothesis:

There are a population of progenitor cells
derived from the mesoderm

These cells are able to circulate

They prefer positive signals from certain
locations (bone marrow, liver, spleen?)
where they remain dormant.
Circulating Progenitors

Their proliferation is controlled by systemic
controls (i.e. neurohormonal and endocrine)

Their differentiation is inhibited by
“normal tissue” and negative controls

Injury or Stress frees these cells
to respond by differentiating to a phenotype
Circulating Progenitors

… sounds a lot like the immune system

… sounds a lot like erythrocyte generation
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… sounds a lot like the nervous system
… sounds a lot like the endocrine system

Wound Healing

This sets the stage for wound healing

Injury


Inflammation
Proliferation
Remodeling

… a bit later

Cells and Cell Functions

Red Blood Cell

Transport
 Oxygen
 Carbon
Dioxide
 Protons
 Large
Proteins by Cell Surface Receptors
Cells and Cell Functions

Red Blood Cell

Metabolism
 Acid-Base
Metabolism
 Repair of Oxidative Stress
 Repair of Reductive Stress
 Catabolism of neurohormones
Cells and Cell Functions

White Blood Cells

Body Defense
 Self
versus Non-self
 Self versus Damaged-self
 Innate versus “thinking”
Cells and Cell Functions

White Blood Cells

Body Repair
 Wound
Healing
 Scar Maturation

Metabolism
 Control
of blood ECM (regular, acute inflammatory,
chronic inflammatory)
 Control of body Iron stores
Cells and Cell Functions

Platelets
Coagulation
 Anticoagulation
 Thrombolysis
 Inflammation
 Wound Healing

Extracellular Matrix

Plasma versus Serum

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Clotting Factors, Fibrinogen
Serum Protein Electrophoresis
Albumin
 Globulins

 Alpha-1,
Alpha-2, Beta-1, Beta-2
 “Gamma”-globulins (immunoglobulins)
SPEP
Serum
Protein
Electrophoresis
SPEP band intensity
Gamma Globulins
Extracellular Matrix
Proteins and their bound water
 Small covalent compounds

Some bound to protein (lipophilic)
 Some with bound water

Lipoproteins
 Salts and their bound water

Sodium, Chlorine
 Bicarbonate

Extracellular Matrix

The source of the ECM is wide spread.
Proteins often come from the liver
 Salt is often regulated by the kidneys
 Acid / Base balance is regulated by the
kidneys and the lungs
 Hormones are produced and consumed
everywhere.

Plasma Functions
Coagulation and Inflammation
 Transport

The ECM that does not rely just on diffusion
 Nutrients and Wastes
 Signals (Endocrine, Neuroendocrine, Immune)
 Cells


Metabolism
Blood and Body Defenses
Questions?