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Pharmacology of Regenerative Medicine > Mesenchymal Stem Cells > Flashcards

Mesenchymal Stem Cells Flashcards

1
Q

What is the history of MSCs?

A

1970: Adherent, fibroplastic cells extracted from bone marrow.
1980s: Multipotential nature of these cells established.
1999: Multipotentiality of hMSCs fully found.
Now: The future

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2
Q

Where in the bone marrow do MSCs reside?

A

They reside in the stromal space.

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3
Q

How can MSCs be isolated and grown?

A

Painful - bone marrow from hip, spin cells down over a density gradient in centrifuge. MSCs will stick to plastic - need to wash a couple of times.

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4
Q

How would MSCs in culture appear after ten days?

A

Adherent, spindle-shaped, fibroblastic colonies in culture (CFU-F).
Lack of commitment shown.

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5
Q

MSCs will readily differentiate into

A

Fat cells (Adipogenesis)
Cartilage (Chondrogenesis)
Bone (Osteogenesis)

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6
Q

Adipogenesis can be stained for using

A

Oil Red O - fat droplets

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7
Q

Chondrogenesis can be stained for using

A

Toluidine blue - collage type II

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8
Q

Osteogenesis can be stained for using

A

Alkaline phosphatase / Alizarin Red - binds to calcium rich deposits.

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9
Q

What are the regulatory signals which induce MSCs into differentiating into fat cells?

A

1-Methyl-3-isobutyxanthine
Dexamethasone
Insulin
Indomethacin

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10
Q

How does chondrogenesis of MSCs occur?

A

High density
TGF-Beta3
Serum-free conditions.

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11
Q

How does osteogenesis occur?

A

Dexamethasone
B-glycerol phosphate
Ascorbate
10% v/v FBS

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12
Q

Wnt signalling is involved with what aspect of MSCs? (more than one)

A

Self-renewal.
Inhibition of PPARgamma and hence adipogenesis.
Stimulation of Runx2 and hence osteogenesis.

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13
Q

Chondrogenesis (meaning)

A

Formation of cartilage.

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14
Q

What role does PPARgamma play in MSCs differentiation?

A

It inhibts osteogenesis.

Promotes adipogenesis.

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15
Q

What role does Runx2 play in MSCs differentiation?

A

Wnt promotes Runx2 which promotes osteogenesis.
Runx2 is promoted by the actions of BMP also.

Although Runx2 inhibits chondrogenesis, it promotes the differentiation of pre-hypertrophic chondrocytes into hypertrophic chondrocytes.

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16
Q

Osteogenesis (meaning)

A

Bone formation

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17
Q

What role does Runx2 have in Chondrogenesis?

A

Inhibits initially but promotes the formation of hypertrophic chondrocytes from pre-hypertrophic chondrocytes. (Under the action of Wnt)

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18
Q

What is the role of BMP in MSCs differentiation?

A

IT promotes Runx2 which promotes osteogenesis.

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19
Q

What role does Ihh (indian hedgehog) have in MSCs differentiation?

A

It promotes differentiation into hypertrophic chondrocytes from pre-hypertrophic chondrocytes.

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20
Q

Adipogenesis (meaning)

A

Fat cell formation

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21
Q

What role does Shh have in MSCs differentiation?

A

Inhibits chondrocyte formation.

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22
Q

Adiogenesis (regulatory signals) [4]

A

1-methyl-3-isobutylxanthine
Dexamethasone
Insuline
Indomethacin

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23
Q

Chondrogenesis (regulatory signals)

A

High desnsity of cells.
TGF-Beta3
Serum-free

Bonus: IGF-1, BMPs 2, 4, 6, 12 & 13.

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24
Q

Osteogenesis (regulatory signals)

A

Dexamathasone
B-glycerol phosphate
Ascorbate
10% v/v FBS

(BMP-2 and bFGF not always needed, the small molecules above are normally sufficient)

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25
Q

What other cells will MSCs differentiate into?

A

Muscle myoblasts
Stromal cells
Tendon tenocytes

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26
Q

What are some positive markers for MSCs?

A

CD105
CD73
CD90

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27
Q

What are some negative markers for MSCs?

A

CD11b
CD14
CD45
CD34

28
Q

What are the key characteristics of MSCs? [4]

A
  1. Adherence to plastic in culture
  2. Expression of CD105, CD73 and CD90 in >95% of culture.
  3. Lack of expression of CD34, CD45, CD14 ot CD11b, CD79a or CD19 and HLA-DR
  4. Differentiation in to bone, cartilage and fat.
29
Q

What type of term is MSCs?

A

Umbrella term - different sources of cells may yield cells with similar phenotypic characteristics but differences in surface markers, proliferation and differentiation.

30
Q

There is heterogeneity with regard to the replication potential of MSCs, what is the evidence for this?

A

MSCs from different sources differ in the surface marker expression and proliferation and differentiation.

31
Q

CD29 is expressed by MSCs from

A

Bone marrow + Spleen + Muscle

32
Q

CD44 is expressed by MSCs from

A

Muscle,
Somewhat in spleen,
Not at all for bone marrow.

33
Q

CD49 is expressed by MSCs from

A

Not bone marrow,

Somewhat partial expression in those from muscle and spleen sources.

34
Q

When is the heterogeneity of MSCs important?

A

Selecting the source of therapeutic cells - Bone marrow and adipose cells have Osteo-, Chondro- and Adipogenic potential whereas umbilical cord blood only has Osteo- and Chondro -, not adipogenic.

35
Q

Although cells from umbilical cord blood have the highest expansion capacity in terms of culturing them, why would they not always be the optimum source of MSCs?

A

They have only Osteo and Chondro potential,
Will not differentiate into fat cells.

Also not very frequent in umbilical cord blood, really low.

36
Q

How does age relate to the ability of a person to produce MSCs?

A

Drops off as they age.

37
Q

How does replication potential of MSCs differ between people?

A

Due to heterogeneity - there is a lot of variation.

38
Q

What physical signals may be present in the MSC niche? [4]

A
  1. Fibronectin
  2. Vitronectin
  3. Laminin
  4. Collagen
39
Q

What soluble signals may be present in the MSC niche? [3]

A
  1. Growth factors
  2. Cytokines
  3. Chemokines
40
Q

What cell-cell interactions may be important in the MSC niche?

A

Cadherins

CAMs

41
Q

What factors, other than cell-cell interactions, soluble signals and physical signals, may influence the MSC niche?

A

Different mechanical forces - elasticity.
Different oxygen potentials.
Different cell densities = chondrocytes.

42
Q

Microscopic evidence suggests that MSCs may exist where?

A

In a perivascular niche,
possibly in the basement membrane.

Tissue specific cues cause a gradual transition from undifferentiated cells to progenitors then mature phenotypes.

43
Q

How are MSCs linked to blood vessel formation?

A

High levels of alpha actin.

44
Q

What impact does the elasticity of the the substrate that MSCs are cultured on have?

A

Results in different differentiation.
1kPa = brain
10kPa = muscle
100kPa = Collagenous bone

45
Q

A culture of MSCs on a substrate with 10kPa elasticity would form

A

Muscle fibres

46
Q

A culture of MSCs on a substrate with 1kPA would form?

A

Neurones?

47
Q

What is the role of MSCs?

A

Tissue homeostasis and repair.

Secretion of factors that support wound repair by recruiting other cell types and modulating the immune response.

“Paracrine functions”

48
Q

Recent evidence regarding the role of MSCs and their paracrine functions involves what?

A

Involves EVs (extracellular vesicles), which can transport proteins, lipids and nucleic acids, and suggests that they may play a large role in the ability of MSCs to ‘educate’ target cells.

49
Q

What is important about the levels of different proteins, lipids etc within the EVs that MSCs are thought to be able to secrete?

A

Levels of IL10 and Il4 are high while others are not - the MSCs are able to actively select which molecules are sent in the EVs.

50
Q

Why is the potential of MSCs EVs to contain IL10/IL4 and target damaged cells important?

A

It can restore viability to damaged cells.

51
Q

What are the medical applications of MSCs?

A

Have immunomodulatory functions, may be useful in the treatment or prevention of GVHD.

Potential therapy following stroke, heart attack etc.

Potential to be used for the delivery of therapeutic proteins.

Tissue engineering.

52
Q

How would MSCs be useful in myocardial infarction treatment?

A

MSC transplantation.

Can be used for vasculogenesis or cardiomyogenesis.

53
Q

How are MSCs and cancer related?

A

The chemotactic responses of Bone Marrow MSCs resembles that of immune cells - inflammatory cytokines are strongly involved in the mobilisation of MSCs and then homing to tumours.

54
Q

Crucial mediators of MSC action in tumours

A

Hypoxia
ECM composition
Extracellular acidity.
Inflammatory component of the stroma.

55
Q

What are the ways in which MSC can cause cancer/promote tumour growth?

A 
They are motile cells that can proliferate and also invade cells. 
That can metastasise. 
Apoptosis inhibition. 
Angiogenesis. 
Immunosuppression.
56
Q

How can MSCs be used to treat cancer?

A

MSCs can be transfected with TRAIL gene (Tumour Necrosis Factor related Apoptosis-Inducing Ligand)

57
Q

The secretion pattern of LPS-treated MSCs favours

A

Pro-inflammatory mediators such as IL1B, IL6, TNFa (TLR4 activation).

58
Q

The secretion pattern of poly(I:C)-treated MSCs favours

A

Anti-inflammatory mediators such as IL10 and IL12 (TLR3 activation.)

59
Q

Toll like receptor 3 (TLR3) is associated with

A

anti-inflammatory MSCs

60
Q

Toll like receptor 4 (TLR4) is associated with

A

Pro-inflammatory MSCs

61
Q

TLR4 priming with ______ results in MSC number_____

A

TLR4 priming with LPS results in MSC1 which is pro-inflammatory and increases T cell activation, decreases tumours.

62
Q

TLR3 priming with _______ results in MSC number _____

A

TLR3 priming with poly(I:C) results in MSC2 which is anti-inflammatory and pro-cancer.

63
Q

What are the effects of the pro-inflmmatory MSC1?

A

Increased IL-6, IL-8.
Increased T-cell activation.
Increased inflammation in acute lung injury model
Increased inflammation and pain in diabetes model.
Decreased Tumours.

64
Q

What are the effects of the anti-inflammatory MSC2?

A

Increased growth factors an tumour/metastasis.
Decreased T cell activation.
Decreased inflammation.

65
Q

A single dose of MSC1 would have what effect on tumour growth?

A

Less growth than MSCs alone, and much less than MSC2.

66
Q

A single dose of MSC2 would have what effect on tumour growth?

A

More growth than just MSCs alone, much more than MSC2.

67
Q

Expression of what marker would differentiate MSCs from Muscle/Spleen with those from Bone marrow?

A

CD44 is expressed highly in Muscle, somewhat highly in Spleen but hardly at all in bone marrow derived MSCs.

Pharmacology of Regenerative Medicine (14 decks)

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