Lecture 4 - Intro To Hemopoiesis And Stem Cells

Question 1

Three stem cell lineage

Answer 1

• Myeloid - give WCC
• Megakaryocyte - give rise to platelet
• erythoiud - give rise to RBC
• cytokines, growth factors, chemokines are responsible for this pathway of differentiation

Question 2

Neutropenia and infection

Answer 2

• severity neutropenia increases the risk of severe infection almost linearly

Question 3

Hemopoietic cell maturation
- stem cell -> progenitor cell -> effector cell

1) proliferative potential
2) lineage commitment
3) maturation induction
4) self renewal

Answer 3

1) proliferative potential decreases over the compartments
2) lineage commitment is non existent in stem cells and then increases as differentiation progresses
3) maturation induction is absent ins tem cell and then increases as differentiation progresses
4) self renewal: only stem cell capable of self renewal and then decreases rapidly as you move down compartments

Question 4

2 features of HSC

Answer 4

• multipotentiality
• self renewal
• hemopoietic reconstituyting ability (wherther it is transplantable or not) determines whether the cell is a stem cell or not

Question 5

HSC vs commited progenitor

• morphology
• responsibveness
• frequency
• cycle
• in vivo markers
• engrafment

Answer 5

• morphology: stem cell smaller
• responsiveness: HSC more
• Frequency: 10-5 vs >10-4
• cycle: GO vs cycling
• in vivo marker: pre-CFU-S vs CFU-S
• engrafment: long term vs early, transitory

Question 6

Lineage restricted stem cells from HSC

Answer 6

• some self renewing cells have a restricted differentiation potential, arising directly from asymmetric divisions of HSC
• normal stem cell self renewal is assymetrical

Question 7

HSC

Answer 7

• ease of collection
• alternative sources available: bone marrow, peripheral blood, cord blood
• utility as gene transfer target
• ability to maintain and manipulate ex vivo
• inexhaustible

Question 8

Induced pluripotent stem cells

Answer 8

• pluripotent stem cells in embryogenesis give rise to HSC

- these cells come back up differentiation tree to give rise to HSC in the bone marrow

Question 9

Hemapoietic cell differentiation and maturation are regulated by cell intrinsic and cell-extrinsic factors

Answer 9

• cell intrinsic: proteins, RNA, micro RNA, lipids, stochastic factors, organelles
• cell extrinsic: hemapoietic growth factors, cytokines, chemokines, small peptides, microvesicles.

Question 10

Regulation of erythoid lineage (RBC)

Answer 10

• via INDIRECT FEEDBACK LOOP
• HSC -> BFU-E -> CFU-E -> erythroblast -> erythrocyte (red cell mass)
• negative feedback loop via O2 sensor -> kidney/Liver -> EPO -> promotes differentiation

Question 11

Human myeloid Colony Stimulating Factors (CSF)

Answer 11

• Multi lineage: IL3, GMCSF

- Lineage restricted: 
GCSF - Neutrophil
MCSF - Macrophage
EPO - erythrocyte
TPO - Megakaryocyte

Question 12

Actions of haemoapoietic regulators

Answer 12

• proliferation
• linage commitment
• maturation
• functional stimulation
• promotion of survival
• induction of apoptosis

Question 13

Regulation of Myelopoiesis - WCC

Answer 13

Via DIRECT negative feedback loop

• HSC -> multi-CFC -> GM-CFC -> G-CFC -> mature effector cell
• mature efefctor cell negatively regulate GM/G-CSF (measure WCC mass and promote differentiation)
• inflammation positively GM/G-CSF

Question 14

EPO and TPO

Answer 14

• very similar DNA, escept TP has a very large carboxy terminus

Question 15

The stem cell niche

Answer 15

• cytokines/receptors
• chemolkines/ receptor
• extracellular matrix
• cells
• physical microenvironment: different elasticities in tissues
• blood stem and progenitor cells respond to substrate elasticity