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Lecture 5 - Mesenchymal stem cells (MSCs) Flashcards

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1
Q

What are mesenchymal stem cells (MSCs)?

A

MSCs are multipotential cells that can differentiate into various cell types such as bone, cartilage, and fat.

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2
Q

Who first isolated MSCs from bone marrow?

A

Friedenstein and co-workers in 1970.

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3
Q

What are the key properties of MSCs?

A
  • Adherence to plastic in culture
  • Expression of CD105, CD73, and CD90 in ≥95% of culture
  • Lack of expression of CD34, CD45, CD14, or CD11b, CD79α, CD19, and HLA-DR (≤2% of culture)
  • Ability to differentiate into bone, cartilage, and fat.
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4
Q

What is the significance of the MSC niche?

A

The MSC niche influences MSC heterogeneity and affects their properties and functions.

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5
Q

Fill in the blank: MSCs can differentiate into _______.

A

[bone, cartilage, fat]

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6
Q

What regulatory signals are involved in MSC differentiation?

A
  • 1-Methyl-3-isobutylxanthine (IBMX)
  • Dexamethasone
  • Insulin
  • Indomethacin
  • TGF-β3
  • β-glycerol phosphate
  • Ascorbate
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7
Q

What are some common positive stains used to identify differentiated MSCs?

A
  • Oil Red O
  • Collagen II
  • Toluidine blue
  • Alkaline phosphatase
  • Alizarin Red
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8
Q

What is the role of MSCs in cancer therapy?

A

MSCs may be used in cancer therapy due to their ability to interact with tumor microenvironments.

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9
Q

True or False: There is a definitive MSC-specific marker.

A

False.

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10
Q

What is MSC heterogeneity?

A

MSC heterogeneity refers to the variability in surface marker expression, proliferation, and differentiation among MSCs from different sources.

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11
Q

What are some sources of MSCs?

A
  • Bone marrow
  • Adipose tissue
  • Skeletal muscle
  • Umbilical cord
  • Synovium
  • Circulatory system
  • Spleen
  • Kidney
  • Lung
  • Dental pulp
  • Conjunctiva
  • Thymus
  • Amniotic fluid
  • Foetal tissues (liver, lung, marrow, blood)
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12
Q

What is the minimal criteria for MSCs defined by the International Society for Cellular Therapy?

A
  • Adherence to plastic
  • Expression of specific surface markers
  • Differentiation potential
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13
Q

Fill in the blank: MSCs from different sources may yield cells with similar _______ characteristics.

A

phenotypic

But differences in surface markers, proliferation and differentiation.

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14
Q

What are some key markers that MSCs lack?

A
  • CD34
  • CD45
  • CD14
  • CD11b
  • CD79α
  • CD19
  • HLA-DR
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15
Q

What is the importance of surface markers in MSCs?

A

Surface markers help in identifying and characterizing MSCs, although they are not exclusive to them.

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16
Q

What is the typical morphology of MSCs in culture?

A

Adherent, spindle-shaped, fibroblastic colonies.

In culture (CFU-F)

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17
Q

What are the three sources of therapeutic cells mentioned?

A

Bone marrow, Adipose, Umbilical cord blood

These sources are commonly used for mesenchymal stem cell (MSC) therapies.

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18
Q

What is the isolation efficacy of bone marrow and adipose tissue?

A

100% for both

This indicates that both sources have a complete success rate in isolating the desired cells.

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19
Q

What is the maximum expansion capacity of umbilical cord blood?

A

Highest

This suggests that umbilical cord blood can proliferate more than the other sources.

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20
Q

What is the differentiation potential of umbilical cord blood-derived MSCs?

A

Osteo- & chondrogenic, NOT adipogenic

Indicates that these cells can differentiate into bone and cartilage but not fat.

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21
Q

What does MSC heterogeneity refer to?

A

Variability in the properties and behavior of mesenchymal stem cells

This variability can impact their effectiveness in therapies.

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22
Q

What roles do MSCs play in tissue homeostasis and repair?

A
  1. Providing daughter cells that differentiate and participate in repair
  2. Homing to distant sites of injury
  3. Secretion of paracrine factors that support wound repair

These mechanisms are crucial for tissue regeneration.

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23
Q

True or False: The mechanisms of MSCs in tissue repair are fully understood.

A

False

Most understanding is based on in vitro data, and the complexities in vivo remain largely unclear.

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24
Q

What does the MSC niche refer to?

A

The specific environment where MSCs reside and function

This includes factors that influence their behavior and differentiation.

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25
What is the significance of extracellular vesicles (EVs) in MSC functions?
They transport proteins, lipids & nucleic acids, and may 'educate' target cells ## Footnote This suggests that EVs play a vital role in MSC paracrine signaling.
26
Fill in the blank: The MSC niche is important for _______.
Tissue homeostasis, formation, and regeneration ## Footnote These processes are essential for maintaining tissue integrity.
27
What are the implications of tissue-specific cues on MSCs?
They cause a gradual transition from undifferentiated cells to progenitors then mature phenotypes ## Footnote This transition is critical for proper tissue repair and function.
28
What does α-Smooth muscle actin expression in MSCs indicate?
Indicates MSCs exist in a perivascular niche and may reside in the basement membrane
29
What are the possible roles of MSCs in tissue homeostasis and repair?
* Providing daughter cells that differentiate and participate in repair * Homing to distant sites of injury * Secretion of factors that support wound repair by recruiting other cell types and modulating the immune response
30
True or False: MSCs are generally regarded as hypoimmunogenic.
True
31
What therapeutic applications are associated with MSCs?
* Treatment or prevention of GVHD * Potential therapy following stroke, heart attack, or other injury * Delivery of therapeutic proteins * Cell-free exosomal therapeutics * Tissue engineering
32
What is MSC priming?
Applying external stimuli, including growth factors, small molecules, hypoxia, and 3D culture to improve therapeutic outcomes
33
What signaling pathways are important for MSC migration to the ischemic heart?
* SDF-1/CXCR4 * HGF/c-MET
34
List some chemotactic factors associated with glioma MSCs.
* IL-8 * CXCL1 * CXCL2 * PDGF-BB * EGF * SDF-1α * TGF-β1 * Neurotrophin * VEGF
35
What factors influence the signaling complexity of MSCs in cancer?
* Hypoxia * ECM composition * Extracellular acidity * Inflammatory component of the stroma
36
What are the two types of MSCs based on their inflammatory effects?
* Pro-inflammatory MSC1 * Anti-inflammatory MSC2
37
What is the function of Toll-like receptors (TLRs)?
Activate immune cells via binding of pathogen-derived molecules
38
Fill in the blank: Mesenchymal stem cells can differentiate into a number of cell types, predominantly _______.
bone, cartilage and fat
39
What is a key characteristic of MSCs in terms of their immunogenicity?
Hypoimmunogenic and immunomodulatory
40
What is the significance of MSCs being described as 'Trojan Horses' in cancer treatment?
Ability to home to tumours and delivery therapeutic agents directly into tumour environment, often without detection or rejection by the immune system.
41
What is the importance of MSCs in the context of tissue engineering?
They have great potential in regenerative medicine and therapeutic applications
42
What is the overarching conclusion about MSCs based on the information provided?
MSCs have diverse roles in tissue repair, homeostasis, and potential therapeutic applications, but their mechanisms and effects in vivo are not fully understood
43
How are MSCs cultured?
Collection from bone marrow at top of pelvis. Density gradient centrifugation to isolate and placed in cell culture.
44
What do early cultures express?
Multiple mesenchymal lineage markers, therefore suggests a lack of commitment.
45
What are the three differentiation routes of MSCs?
1. Adipogenesis 2. Chondrogenesis 3. Osteogenesis
46
What are the regulatory signals in adipogenesis?
* 1-methyl-3-isobutylxanthine (IBMX) * Dezamethasone * Insulin * Indomethacin (PPAR gamma agonist) * PPAR gamma
47
What is the stain for adipocytes?
Oil Red O
48
What are the regulatory signals for chondrogenesis?
* High density (hypoxic) * TGF-b3 * IGF-1 (insulin-like growth factor 1) * BMPs 2/4/6/7 (with Sox9)
49
What are the stain for cartilage (chondrogenesis)?
* Collagen II * Toluidine blue
50
What are the regulatory signals of osteogenesis?
* Dexamethasone * b-glycerol phosphate * Ascorbate
51
What are the stains for osteoblasts?
* Alkaline phosphatase * Alizarin Red
52
What does dexamethasone and b-glycerol phosphate activate?
Runx2 which aides differentiation of MSCs into osteoblasts
53
What does insulin, indomethacin and IBMX activate?
PPAR gamma which aides MSC differentiation into adipocytes
54
What pathway do BMPs activate?
BMPs activate Dlx5 and SMAD1/5 which both activate Runx2 aiding osteogenesis
55
How is Sox9 activated?
TGF-b3 activates Smad3 activating Sox9 inducing chondrogenic differentiation
56
When is Sox9 expression increased in chondrogenesis?
During MSC differentiation into pre-hypertrophic chondrocytes
57
When is Sox9 expression decreased in chondrogenesis?
During pre-hypertrophic chondrocyte differentiation into hypertrophic chondrocytes
58
MSC differentiation pathway in osteogenesis
1. Progenitor - transitory osteoblast 2. Mature cell - osteoblast 3. Terminal differentiation - bone osteocytes
59
MSC differentiation in chondrogenesis
1. Progenitor - transitory chondrocyte 2. Mature cell - chondroblast 3. Terminal differentiation - cartilage chondrocytes
60
MSC differentiation in adipogenesis
1. No progenitor stage 2. Mature cell/terminal differentiation - adipocyte
61
Examples of MSC positive markers
* CD29 - b1-integrin * CD90 - thymocyte differentiation antigen 1 (Thy-1) * CD105 - TGF-b receptor * STrO-1 - Stro1- cells have no CFU-Fs
62
Examples of MSC negative markers
* CD11 - leukocyte integrin * CD43 - primitive HSC marker * HLA-DR - human leukocyte antigen DR * Glycophorin-A - erthyroid marker
63
What are the difinitive markers for MSCs?
No definitive markers. Selection based on markers can give a very mixed population of cells.
64
Are MSCs (or MSC-like cells) functionally equivalent?
No, similar phenotypic characterisitics but differences in surface markers, proliferation and differentiation.
65
What is the best source of MSCs for therapeutic applications?
Adiopose tissue. Isolates highest number of cells with 100% efficiency, expansion capacity medium and differentiation potential into osteo-, chondro- and adipogenic.
66
How does MSC niche affect differentiation?
MSC niche affects transcription and therefore gene expression changing cell type production which results in heterogeneity.
67
Where does MSC niche reside?
In a perivascular niche.
68
How can phenotype be regulated?
By the substrate stiffness. Stiffness of surface affects the differentiation. E.g. collagenous bone forms on 100 kPa whereas brain and neurite-like projections on 1 kPa.
69
How can cisplatin damage/toxicity be residued in MSCs?
IL-10 can resuce toxicity.
69
How could MSCs be therapeutically used for mycardial infarction?
MSC transplantation could result in vasculogenesis and cardiomyogenesis promoting CPC (chondroprogenitor cell) and CSC recruitment, respectively.
70
What responses are MSC-secreted molecules involved in?
* Inflmmation * Immune response * Cell migration * Angiogenesis
71
How can BM-MSCs impact cancer?
Can be both positive and negative effect. E.g. positive factors = CCL5, TG-b, VEGF via motility, proliferation, invasion, etc E.g. negative factors = oncostatin-M via tumour growth inhibition, antiangiogenic effect, endothelial cell apoptosis.
72
Role of TRAIL?
Can induced apoptosis, e.g. in lung tumours, hUC-MSC caused prolonged survival and increased tumour apoptosis.

Regenerative Medicine (14 decks)

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