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1. HUMAN & ANIMAL PHYSIOLOGY > kevin (L5) > Flashcards

kevin (L5) Flashcards

1
Q

haematopoiesis

A

Haematopoiesis

  • highly organised differentiation process
  • ordered expression of different sets of genes

Controlled by factors in the environment of the developing blood cell – the bone marrow in adults

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2
Q

haematopoietic stem cell

A

Mature blood cells in healthy individuals mostly have short lifetimes (exception: lymphocytes) and are constantly regenerated in the bone marrow.
we make 5 x 1011 blood cells daily

This is accelerated when there is haematological stress

e. g. infection, need more leukocytes
e. g. high altitude, need more red cells.

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3
Q

haematopoiesis in embryo (per week)

A

Haematopoiesis begins at a very early stage in embryonic development, at about 3 weeks in the human.

At that time the cells in the embryo separate into 2 sets, one generating the embryo proper & all the tissues of the adult, the other forming the YOLK SAC (aka vitelline sac) which is the site where blood cells and blood vessels are first formed.

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4
Q

yolk sac

A

DIAGRAMS IN L5-S6

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5
Q

5 week foetus

A

The yolk sac joined to the embryo by a stalk.
Contains mesoderm derived cells
“haemangioblasts”
Differentiate to form (nucleated) red blood cells and endothelial cells which generate a capillary system (“plexus”) within the yolk sac.

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6
Q

what starts forming at 5 weeks

A

Heart is fully formed - liver started forming too
Mesoderms cells make up the stork - have a set of stem cells that from red blood cells which have nuclei (for first month)
Generate a capillary system in yolk sac
Heart pumps blood through the yolk sac

At the same time the heart and aorta start to form: these join up with the capillary plexus and the erythrocytes start to circulate.

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7
Q

where does the late stage occur?

A

At a later stage of embryogenesis haematopoiesis occurs mainly in the liver and at birth shifts to the bone marrow (BM).

Described as definitive unlike the early primitive haematopoiesis occurring in the yolk sac.

Now, the entire range of blood cells found in the adult are produced.

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8
Q

Bone Marrow

A

The BM is in effect a highly specialised tissue comprising a range of cells

  • some of which (haematopoietic cells) form blood cells
  • others (stromal cells) provide support functions for the haematopoietic cells, providing the specialised environment needed for haematopoiesis to occur.
  • Yet other cells (osteoblasts and osteoclasts) are concerned with producing the bone itself.
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9
Q

what happens during an immune response?

A

(Bear in mind that cells of the immune system undergo further proliferation and differentiation in the periphery – especially in secondary lymphoid tissue – during immune responses: one of the purposes of haematopoiesis is to generate cells which are capable of responding to pathogens.)

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10
Q

where does haematopoiesis occur?

A 
haematopoiesis occurs in bones
bones are:
- a source of skeletal rigidity
- reservoir of Ca2+ and PO4 3-
- haematopoietic organs

Adults made mostly in the bone marrow of the vertebrae (the bones that make up the spine), ribs, pelvis, skull, sternum (the breastbone), and parts of the humerus (the upper arm bone) and femur (the thigh bone).

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11
Q

major sites of blood

A

Major sites of the blood come from the vertebrae, ribcage, sternum, pelvis, parts of the femur, and parts of the ilium bones

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12
Q

bones

A

(Bone marrow is made in epiphyseal of the femur)

Bone is a specialised form of connective tissue (mesodermal/mesenchymal origin) with an extracellular matrix (ECM) which is rigid

Rigid outer layer of dense compact (aka cortical) bone, 70% hydroxyapatite (hydrated calcium phosphate)

Inner core of much less dense spongy bone (aka cancellous, trabecular).

Diaphysis is largely made of fat - as soon as the fat grows and over proliferates in medullary cavity, the stem cell stop dividing

Endosteum → exists in both the diaphysis and the epiphysis
There is a niche for the homeopathic stem cells on the endosteum that is in lining of the bone cavity

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13
Q

osteon

A

The osteon is the unit structure of compact bone made up of concentric mineralised lamellae around a central (Haversian) canal.

Unit of bone is osteon - made up of canaliculi
Holes in bone are blood vessels
Permeated through the outer coat, the periosteum, and they invaginate into the spongy bone area
We have vertical tracts - called haversian canal
We have horizontal tracts - called volkmann’s canal

DIAGRAM IN L5 S14

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14
Q

structure of bones cnotrolled by?

A

Structures are controlled by osteoblasts and osteoclasts
They are adding cells
When the cells are there they excrete a mineral salt (calcium appetite)
This makes the solidity and strength of the bones

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15
Q

bone marrow

A

The bone marrow (BM) is within the medullary cavity & spongy bone.
It is intensely cellular because that is where blood cells are produced.

Two kinds, red and yellow

  • red in flat bones and at the epiphyses of long bones
  • yellow in the shafts of long bones.

(Yellow marrow contains lots of fat, especially in older
individuals, & that is why roast BM is so yummy.)

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16
Q

histology of red bone marrow

A

trabecular bone
granulocytes
megakarocytes
erythroid island

Platelets formed from megakaryocyte cells
These are massive cells that excrude their membrane through the blood vessels and get washed away to form the platelets
Platelets can be activated to form a clot
Diff cell types are so packed together in bone - difficult to differentiate them
There is a niche around the edge

DIAGRAM IN L5 S17

17
Q

discovery of hematopoietic stem cell

A

The understanding of the haematopoietic role of bone marrow (BM) started to develop in the 1960s with research on the effects of radiation in animals.

The main cause of death after exposure to ionising radiation is haematological failure.

Transfusion of blood or most lymphoid tissues does not save the animal

Transfusion of BM does.

18
Q

serial transplants

A

Repeated serial transplants can be done.

So the HSC is capable of self renewal

  • but not for ever: eventually the transplant does not work, indicating that the stem cell is not immortal
  • Probably true of all adult stem cells
  • cf “Hayflick limit”
  • “end replication problem” & telomeres
19
Q

use of hematopoietic stem cell

A

all blood cell types could be derived from single BM cells.

haematopoietic stem cells (HSCs) are the multipotent parental cell type for ALL blood cells and probably also endothelium.

20
Q

experiments demonstrating multipotency

A

The experiments demonstrating multipotency depended on irradiating the BM cells used to reconstitute the mice with SMALL doses of radiation, not enough to kill the cells but enough to cause minor chromosome alterations (“chromosomal markers”) in rare cells

21
Q

results of experiment

A

In some individual transplanted mice there could be found cells of all leukocyte types bearing the same marker
In other mice, ALL myeloid but NOT lymphoid cells had the same marker
And in yet others ALL lymphoid but NOT myeloid cells had the same marker

22
Q

conclusion of experiment

A

This implied that there were also stem cells of more restricted potency
capable of producing EITHER myeloid OR lymphoid cells
these are now known as common lymphoid progenitor or common myeloid progenitor cells
CLP & CMP.
These can be thought of as transit amplifying cells.

23
Q

HSC used as marker

A

Each marker is unique;
all descendants of a marked cell (a CLONE) have the same maker.
Hence if particular cells in a mouse all heave the same marker they are all descended from the same stem cell.

24
Q

so what can the HSC turn into

A

HSC:

  • Common Lymphoid Progenitor –> lymphocytes
  • Common Myeloid Progenitor –> granulocytes / erythrocytes / thrombocytes
  • transit amplifying cells –> end cells (differentiated)
25
Q

what is the HSC

A

A rare (<0.1%) cell present in bone marrow expressing the antigen CD34.

We now know that CD34+ cells are the essential cell type for BONE MARROW TRANSPLANTATION.

Other cells express CD34 (e.g. endothelial cells) so it us not a unique marker for HSCs

26
Q

what is CD34+ HSC used as

A

CD34+ HSC is used as gene therapy tools

To treat diseases like adrenoleukodystrophy (ALD) - IT S WORKING - CAN MYELATE CELLS IN THEIR BRAINS

27
Q

stem cell niche

A

HSCs are found in two locations in BM:

  • the endosteum (boundary between solid bone & marrow) associated with osteoblasts;
  • the perivascular region around vascular sinusoids (large blood vessels with thin-walls comprised of fenestrated endothelium).
28
Q

do they have different roles to other niches?

A

“endosteal” and “vascular” niches.

Do they have different roles?
It has been suggested that the endosteal niche contains long-term, slowly dividing HSCs which maintain the vascular niche HSCs.
In the vascular niche the HSCs are more actively dividing and progenitor cells are produced.

29
Q

define niche

A

Microenvironment around stem cells that provides support and signals regulating self-renewal and differentiation

The niche can act on a stem cell by various mechanisms:

  • Direct contact between the stem cell and the niche cells
  • Soluble factors released by the niche that travel to the stem cell
  • Intermediate cells that ‘communicate’ between the niche and the stem cell
30
Q

define juxtacrine signalling

A

CONTROL CAN BE DIRECT - JUXTACRINE SIGNALLING
Cells have to physically touching and associating
Soluble factors make up the signal and have to transverse space and be in direct contact
Stromal cells that receive the signal and send another signal
You can direct the niche into 3 ways of interacting to control differentiation and self renewal

31
Q

growth and differentiation

A

As the HSC divides, one cell leaves the niche and becomes a progenitor cell, the other stays put
- asymmetric division in space as well as in kind

DIAGRAM IN L5 S37

Evidently the progenitor cell is now in a different environment.

  • Growth factors drive its growth and then differentiation.
  • (Perhaps the job of the stem cell niche is to slow cell division and block differentiation.)
  • The different phases of differentiation and the growth factors required have been largely worked out by cell culture experiments.
32
Q

In vitro culture of bone marrow cells

A

culture of BM cells is often done suspended in semi-solid media so that the progeny of a single cell can be seen as a colony.

added growth factors & cytokines are needed to drive both proliferation and differentiation of cells

33
Q

specificity of those cells

A

There are many of these, some more-or-less specific for different cell types

  • eg Granulocyte/monocyte colony colony stimulating factor (GM-CSF), erythropoietin (EPO)
  • NB the term CSF.

Others with much broader activities
- eg. IL-3 which will stimulate growth of most haematopoietic cell types

34
Q

action mechanisms

A

Growth factors/cytokines act both in a paracrine fashion
- they diffuse from the producer cell to the responder cell

and in a juxtacrine fashion
- they remain on the cell surface of the producer cell and so the responder cell must be juxtaposed – touching.

35
Q

control inputs

A

And they are produced both within the BM and from sources outside the BM
- e.g. GM-CSF from lymphocytes, EPO from kidney.

Infection can massively increase the amount of growth factors present because of activation of a range of leukocytes at the site of infection
- hence increased haematopoiesis.

36
Q

erythrocytes and platelets

A

The early stages for production of both these cells pass through a common pathway generating a “megakaryocyte/erthrocyte precursor” (MEP) from the CMP: they then split.

37
Q

erythropoiesis

A

DIAGRAM IN L5 S44

38
Q

generation of platelets (thrombopoiesis

A

Generation of platelets (thrombopoiesis):

  • stimulated by thrombopoietin (TPO) & other non-specific growth factors.
  • TPO produced constitutively mostly by liver.
  • Inflammation can double production by liver via cytokine IL-6.
  • In thrombocytopenia (reduced platelets) BM stromal cells also produce TPO.
  • Platelets have TPO receptors and so remove TPO from circulation (-ve feedback).

1. HUMAN & ANIMAL PHYSIOLOGY (8 decks)

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