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Regenerative Medicine > Lecture 4 - Haematopoietic stem cells > Flashcards

Lecture 4 - Haematopoietic stem cells Flashcards

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1
Q

What are haematopoietic stem cells (HSCs)?

A

The most studied and best characterized adult stem cells, involved in the production of blood cells.

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2
Q

How many nucleated cells are there in total human bone marrow?

A

~1 x 10^12 nucleated cells.

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3
Q

What is the estimated number of active HSCs in adult humans?

A

50,000 to 200,000 active HSCs.

1/10,000,000 nucleated cells in bone marrow are HSCs

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4
Q

How often do HSCs divide?

A

Once every ~40 weeks.

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5
Q

What is haematopoiesis?

A

The production of haematopoietic (blood) cells.

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6
Q

What is the daily production rate of blood cells in a healthy adult?

A

Approximately 4-5 x 10^11 cells per day.

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7
Q

Where does haematopoiesis predominantly occur?

A

In red bone marrow (medullary).

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8
Q

What is the capacity of a single HSC?

A

Capable of reconstituting the whole haematopoietic system.

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9
Q

What are the two types of haematopoietic stem cells?

A
  • Long-Term Haematopoietic Stem Cells (LT-HSCs) * Short-Term Haematopoietic Stem Cells (ST-HSCs)
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10
Q

What characterizes Long-Term Haematopoietic Stem Cells (LT-HSCs)?

A

Self-renewal over a long period, able to differentiate into all blood cell types, divide infrequently.

Maintain quiescent state more (long-term maintenance and stability of the haematopoietic system)

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11
Q

What characterizes Short-Term Haematopoietic Stem Cells (ST-HSCs)?

A

Limited self-renewal, actively involved in haematopoietic progenitor cells, contribute for a shorter duration.

More immediate response to body’s need for blood cells, e.g. infection

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12
Q

What are HSC markers used for?

A

To identify haematopoietic stem cells through combinations of surface markers.

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13
Q

What is the significance of the HSC niche?

A

Regulates HSC function and fate through signaling.

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14
Q

What is quiescence in HSCs?

A

A dormant phase that protects HSCs from exhaustion and maintains regenerative capacity.

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15
Q

What does proliferation in HSCs refer to?

A

HSCs dividing and multiplying to produce more stem cells or differentiate into different lineage of blood cells.

Essential for replenishing blood cells, responding to changes, including injury or infection.

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16
Q

What is the role of maintenance in HSCs?

A

Processes that preserve the long-term HSC pool. Includes mechanisms which balance quiescence, proliferation, repair DNA damage, protein HSCs from stress and aging.

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17
Q

What is retention in the context of HSCs?

A

Mechanisms that enable HSCs to remain in their niche, promoting quiescence, proliferation, and differentiation.

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18
Q

Where do HSCs primarily reside in the bone?

A

Epiphysis and metaphysis, espcially in trabecular bone regions.

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19
Q

What is the location of non-dividing HSCs compared to dividing HSCs?

A

Non-dividing HSCs are enriched in central marrow; dividing HSCs are enriched in the endosteal region.

Endossteal region has greater in vivo homing, lodgement and reconstitution potential than HSCs in central marrow.

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20
Q

Which factors regulate HSC fate?

A

Both cell intrinsic and cell-extrinsic factors.

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21
Q

What are two important factors secreted by perivascular stromal cells that promote HSC maintenance?

A
  • CXCL12 (SDF1) * SCF (KIT ligand)
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22
Q

True or False: HSCs are capable of self-renewal.

A

True.

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23
Q

Fill in the blank: HSCs divide infrequently to maintain _______.

A

long-term regenerative capacity.

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24
Q

What do Leptin receptor positive (Lepr+) perivascular stromal cells, endothelial cells and NG2+ pericytes secrete?

A

Factors that promote HSC maintenance

Includes CXCL12 and SCF

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25
Which factors are particularly important for HSC maintenance?
* CXCL12 (SDF1) * SCF (KIT ligand) ## Footnote These factors are secreted by specific cells in the HSC niche.
26
What is responsible for HSC mobilisation from the bone marrow to blood?
Circadian release of noradrenaline via downregulation of CXCL12
27
What are the key components of the HSC niche signaling? ## Footnote Extrinsic factors.
* Quiescence * Self-renewal * Differentiation ## Footnote Includes signals like Ang1, CXCL12, SCF, TGFβ1, CXCL4, IL7, EPO, Notch ligands, TPO. CXCL12, SCF - perivascular MSCs Notch ligands, SCF - endothelial cells
28
How are LT-HSCs and MPPs located in relation to blood vessels?
Both cell types are found <10 µm from a blood vessel
29
What happens to LT-HSC motility when stimulated with cyclophosphamide/GCSF?
LT-HSC became more motile, and their number increased 10-fold ## Footnote LT-HSCs typically have low motility under steady state conditions. Cyclophosphamide response depends on environment.
30
What niche condition is associated with maintaining HSC quiescence?
Hypoxic niche
31
What influences the expansion of LT-HSCs and MPPs?
Extent of bone remodelling
32
What are the effects of HSC ageing?
* Reduced DDR * Accumulation of ROS * Shift in polarity of cytoskeletal proteins & epigenetic markers * Epigenetic drift ## Footnote DDR = DNA damage repair
33
What regulatory effect does OPN have on HSC pool size? ## Footnote OPN = osteopontin
Negative regulatory effect
34
What is the relationship between CHIP and blood cancers?
Many mutations found in CHIP are drivers of AML and other blood cancers
35
What is the difference between autologous and allogeneic HSC transplantation?
Autologous uses the patient's own cells, while allogeneic uses donor cells
36
What is myeloablative conditioning in HSCT?
Total body irradiation and/or chemotherapeutics that prevent recovery of the haematopoietic system
37
What are possible complications of HSCT?
* Infections * Graft versus host disease (GvHD) ## Footnote GvHD mainly affects skin, liver, and GI tract.
38
What is the average number of mutations in HSC pool by age 70?
350,000 to 1.4 million protein coding mutations
39
Which genes are commonly mutated in CHIP?
* DNMT3A * JAK2 * TP53
40
What are the therapeutic uses of HSCs mentioned?
* Transplantation * Gene therapy * Gene editing * Differentiation into blood cells
41
What are the main cell surface markers to identify HSCs?
CD34+ and CD38-
41
What is HSC differentiation lineage?
HSCs differentiate into either common lymphoid progenitor cells (IL-7) or common myeloid progenitor cells (IL-3, GM-CSF, M-CSF).
42
How is HSC differentiation regulated?
HSC differentiation regulated by the niche. Combinations of markers can be used to identify the differentiation lineage.
43
What are the physical signals of the stem cell niche?
* Fibronectin * Vitronectin * Laminin * Collagen
44
What are the cell fate processes?
* Replication * Differentiation * Migration * Apoptosis
45
How does the mouse haemapoietic system differ to humans?
Mice have different anatomies. The long bones of mice have a greater contribution to haemapoiesis than those of humans.
45
Why is identifying the exact niche of HSCs difficult?
Difficult due to rarity of HSCs and their location.
46
How has identifying the location of HSCs and progeny been improved?
Advances in marker identification and combinations of transgenics and advanced imaging techniques. E.g. Acar et al optically cleared murine tibiae to image HSCs in situ. ## Footnote Comapred Laminin, c-Kit, a-cat-GFP in arteriole, sinusoid and TZ vessel.
47
Where do most HSCs reside?
~80% of HSCs exist in perivascular niche ## Footnote ~20% in the endosteal niche (maintain quiescence)
48
What are the intrinsic and extrinsic factors regulating cell cycle entry?
Intrinsic factors: * Transcription factors * Cell cycle regulators Extrinsic factors: * ROS * Hypoxia * TPO * SCF
49
What are the intrinsic and extrinsic factors regulating quiescence entry?
Intrinsic factors: * Transcription factors - FoxO family regulates oxidative stress and cell cycle inhibitors * Cell cycle regulators - p21, p27 arrest cell cycle Extrinsic factors: * Niche cell types * TGFb * SCF * Hypoxia
50
How do adipocytes affect HSCs?
Adipocytes are inhibitory to haemapoiesis. Generally less supportive of HSC maintenance and function. Especially evident after aging, radiation or chemotherapy where adipocytes expand and correlate with reduced HSC activity.
51
What affect dpes mixed remodelling have on HSC expansion? ## Footnote Mixed remodelling describes bone turnover, i.e. the blance between bone formation and bone resorption. Mixed remodelling suggests disruption of bone homeostasis.
Mixed remodelling areas promote expansion upon stimulation. ## Footnote HSCs expand clonally in restricted physical domains.
52
What factors promote HSC retention and maintenace?
CXCL12 and SCF
53
What affect aging have on Jagged 1?
There is reduced Jagged 1 which results in less Notch signaling, therefore less proliferation
54
How does aging affect adrenergic nerve fibres?
Reduced numbers of adrenergic nerve fibres.
55
How does aging affect the niche factors?
Reduced CXCL12 Reduced SCF Reduced Jagged 1 Reduced OPN Increased CCL5
56
What does CHIP mean? ## Footnote In HSCs, CHIP may occur
Clonal haemapoiesis of indeterminate potential
57
What genes are most affected by mutations?
Genes involved in epigenetic regulation
58
What age is clonal haemapoiesis most prevelent?
In the elderly.
58
How many protein coding mutations in HSC pool by age 70? ## Footnote Average person without a haematological cancer
~350,000 to 1,400,000 ## Footnote Myeloid cells can have increased malignancy. Lymphoid also possible.
58
How does size of clone relate to maligancy? (CHIP)
Size of clone directly related to risk of malignancy. ## Footnote Common mutations found in CHIP also drivers of AML and other blood cancers. CHIP also related to non-malignant diseases such as CHD.
58
How do mutations affect protein coding genes?
* Cytosine deamination * Double strand break repair * Polymerase error * Structural rearrangment of chromosomes
58
What are possible side effecs of HSCT?
Infections and graft vs host disease ## Footnote GvHD mainly affects skin, liver and GI tract
58
What is the process for autologous HSCT for cancer treatment?
1. Pre-treatment with GCSF prior to HSC collection in blood (mobilisation) 2. Collection of stem cells (G-PBMNCs) from either the blood of bone marrow 3. Processing to remove the stem cells and blood is returned to patient 4. Conditioning and chemotherapy with or without radiotherapy to kill cancer cells and remove blood-producing cells left in the bone marrow 5. Reinfusion of stem cells into patient to begin produing new blood cells
58
What is the only current established stem cell therapy?
HSC transplantation (HSCT) ## Footnote Has been carried out since 1957.
59
How might GvHD be reduced?
Enrichment of CD34+ HSCs, e.g. CliniMACs by Mitenyi which attack exisiting cells

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