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Molecular Basis of Disease > Stem Cells And Regenerative Medicine > Flashcards

Stem Cells And Regenerative Medicine Flashcards

1
Q

What are stem cells?

A

Undifferentiated cells that can differentiate into many different types of cells depending on the signal they receive.

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2
Q

What is the purpose of stem cells?

A

They provide new cells as an organism grows and can replace damaged cells to some degree

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3
Q

What are the 3 types of stem cells?

A

Adult stem cell, embyronic stem cell and induced pluripotent stem cell

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4
Q

Why are stem cells useful? + examples

A

Stem cells can be used by researchers for therapeutic research

Model in studies / disease modelling / 3D organoid model
Cell replacement therapy
Drug screening

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5
Q

Give examples of disease stem cells are used in?

A

Blindness, wound healing, myocardial infarction, cancers and spinal cord injury

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6
Q

What is the purpose of ASCs?

A

Supply new cells as organisms grow and replace damaged cells.

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7
Q

How do ASCs behave?

A

Reproducing ability varies and are tissue specific (more in skin than heart).

They are multipotent.

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8
Q

What is multipotent?

A

Only subset of cells linked to location can form.

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9
Q

Why might scientists use adult stem cells?

A

Extract them and manipulate them in vitro.

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10
Q

Where do embryonic stem cells arise from?

A

Cells are supplied from the embryo in the blastocyst stage before implantation from the inner cell mass (the part that will give rise to all other cells0

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11
Q

How do ESCs behave?

A

Pluripotent - can differentiate into any cell

The cells proliferate multiple rounds before differentiating

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12
Q

What are the different ESCs + what do they give rise to?

A

Each germline gives rise to different specific tissues.

Ectoderm - nervous, epithelial and sensory tissues
Mesoderm - skeletal, cardiac, muscle, blood and connective tissues
Endoderm - lungs, pancreas, stomach, liver and germ cells

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13
Q

How are iPSCs made?

A

In the lab by taking differentiated tissues from a biops and reprogramme the cell with a specific set of pluripotency factors producing pluripotent stem cells similair to embryonic stem cells.

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14
Q

What is the main use of iPSCs?

A

Usually used for cell therapy and reparing mutations by gene editing techniques e.g. CRISPR and then differentiate back into healthy cell in vitro

This is then transplanted back into specific patient

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15
Q

Give other examples of iPSCs use?

A

Models for basic + translational research, cell differentiate studies, disease modelling , drug screening and cell replacement therapy

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16
Q

What is the advantage of iPSC being transplanted back into specific patient?

A

Reduces risk of graft rejection

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17
Q

At which stage are ESCs totipotent and which stage is pluripotent?

A

Before germ line established its totipotent, after is pluripotent

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18
Q

What are stem cell niches?

A

Supportive environments where tissue specific stem cells are maintained.

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19
Q

What is the purpose of a stem cell niche?

A

The niche interacts with stem cells to regulate cell fate + protects them from depletion and excessive proliferation

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20
Q

What is a stem cell niche made up of?

A

Extracellular matrix (contains molecules e.g. collagen, fibrinogen)
Secreted soluble signalling factors (e.g. WnT, growth factors, cytokines)
Physical factors (e.g. shear stress, tissue stiffness and topography)
Interaction with surrounding cells + neighbouring niche cells
Environmental signals (metabolites, inflammation = T cells and macrophages)

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21
Q

Compare potency between all 3 types of stem cells

A

ESC - Pluripotent - almost unlimited growth and can differentiate into any type of cell
ASC - oligopotent/unipotent - limited cell potency
iPSC - Less growth potential than ESC

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22
Q

Compare tumour risk between all 3 types of stem cells

A

ESC - high risk (unregulated stem cell growth)
ASC - Lower risk of tumour formation
iPSC - lower risk of tumour formation

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23
Q

Compare compatibility to recipient between all 3 types of stem cells

A

ESC - Higher risk of rejection (genetically different from recipient’s cells)
ASC - Compatible with recipients cells so lower risk of rejection
iPSC - Compatible with recipients cells so lower risk of rejection

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24
Q

Compare number of stem cells made between all 3 types of stem cells

A

ESC - Unlimited number of cells produced
ASC - limited numbers
iPSc - limited numbers

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25
Q

Compare probability of mutations occuring between all 3 types of stem cells

A

ESC - Very low probability of mutation induced damage in DNA
ASC - Higher probability mutation induced damage in DNA and risk of disease
iPSC - Higher probability mutation induced damage in DNA and risk of disease

26
Q

What ethical issues are there in stem cell research?

A

Obtaining cells from embryos

27
Q

What are the pluripotency factors?

A

Transcription factors

4 specific ones in Yamanaka’s cocktail to reprogramme differentiated cells into iPSCs

28
Q

What are the specific pluripotency factors used in iPSCs?

A

Oct3/4, Sox 2 and Klf 4

29
Q

What are the steps to generate iPSCs?

A

1) c-Myc promotes DNA replicates and relaxes chromatin structure so Oct3/4 can access target genes
2) Sox2 and Klf4 cooperate with Oct3/4 to activate target genes
3) Target genes encode for transcription factors which causes epigenetic changes - open chromatin configuration = pluripotent epigenome

30
Q

Which form must DNA be in to make the cell pluripotent?

A

Chromatin must be in an open configuration as is in ESCs.

31
Q

How do we track stem cells?

A

Stem cells are manipulated in vitro by inserting reporter gene e.g. fluoroscent

32
Q

What is in vivo stem cell imaging used for?

A

In vivo imaging allows developmental and clinical translation of cell based therapeutics without being invasive

33
Q

What is in vitro stem cell imaging used for?

A

Long term cell tracking in pre-clinical and clinical trials

34
Q

How does a heart attack lead to heat failure?

A

Blood supply to heart muscle is lost.
Cardiac muscle dies and not replaced (low level of endogenous regenerative ability)
Fibrosis and scarring occurs = decreased cardiac function leading to cardiac failure

35
Q

What use are stem cells after heart attacks?

A

Stem cells can be used to replace lost cardiomyocytes and improve blood supply to the affected region.

Mainly aim to directly stimulate endogenous cardiomyocyte production.

36
Q

What is neurovascularisation and how does it help improve cardiac function?

A

Stem cells differentiate into coronary vessels so improves circulation to affected areas. Paracrine effects improve cardiomyocyte replacement.

37
Q

What other heart conditions are stem cells used in?

A

Other conditions include cardiomyopathies/conduction defects - electrical regulation defects

38
Q

What is different in the genetics of animal models that regenerate cardiac tissues compared to humans?

A

There is re-expression of developmental gene programmes (including Raldh2 and Wt2) early after injury

39
Q

What steps occur of developmental gene re-expression in cardiac tissue?

A

Epicardium (surface layer of heart) first re-activated as it is the sources of coronary vessel cells. It also promotes cardiomyocyte proliferation.

Endocardium re-activation then occurs so when fibrin clot forms, it degrades and cardiomyocyte proliferation regenerates the heart.

40
Q

What happens in large models like pigs when a fibrin clot forms in the heart?

A

The clot doesn’t resolve leading to scarring affecting cardiac function.

41
Q

Why is lymphatics and immune response needed for cardiac regeneration - in small animal models?

A

Lymphatics clear excess inflammatory immune cells resulting in less inflammation improving cardiac function.

Immune response contains correct cells that allow revascularisation and proliferation.

42
Q

What is the immune response in neonatal mice compared to adult mice during a heart attack?

A

Neonatal mice - infiltration of injury by embryonic macrophages, revascularisation and global cardiomyocyte proliferation

Adult mice - infiltration by monocyte derived macrophages, limited vascularisation + no cardiomyocyte proliferation.

43
Q

What is the lymphatic response humans during a heart attack?

A

In humans, the lymphatic system does not clear excess tissue fluid and inflammatory immune cells efficiently leading to oedema and inflammation which reduces cardiac repair and function.

44
Q

If the lymphatic system is stimulated, what affects would it have on the heart after a heart attack?

A

An increased lymphatic response improves tissue fluid and inflammatory cell clearance so reduces oedema and inflammation. This improves cardiac repair and function

45
Q

What are the steps to make cardiac lineage cells from iPSCs?

A

1) Somatic cell reprogrammed using Yamanaka’s cocktail for pluripotency.
2) iPSCs specified towards pre-cardiac mesoderm by INHIBITING GLYCOGEN SYNTHASE KINASE 3B.
3) This acts as a switch and inhibits Wnt signalling leading to differentiation of cardiac progenitor cells.
4) Use specific signalling molecules to differentiate cells towards specialised cardiac niches e.g. epicardium, cardiomyocyte, smooth muscle etc…

46
Q

What is the benefit of using iPSC derived cardiomyocytes?

A

Benefits regarding immune rejection.

47
Q

How are iPSC derived cardiomyocytes implanted?

A

Direct intra-myocardiac injection of iPSC cardiomyocytes after myocardial infarction

48
Q

What are the effects of transplanting iPSC derived cardiomyocytes to regenerate primate hearts?

A

No evidence of rejection and cells incorporated into tissue.

- Electrical coupling and improved cardiac contractile function BUT VENTRICULAR TACHYCARDIA INCREASED.

49
Q

What causes increased ventricular tachycardia in cardiomyocyte stem cell transplantation?

A

Some cells contract faster than others.

50
Q

What are the effects of transplanting human ESC derived cardiomyocytes to regenerate primate hearts?

A

Enhanced cardiac function but graft association ventricular arrhythmias in some animals.
Remuscularisation was successful.

51
Q

How is developmental gene reactivation different from cell transplantation as treatment after Mi?

A

Uses pararine effects by adding myocardial thymyosin beta 4 which causes developmental gene reexpression.

It is cell free and stimulates de novo cardiomyocyte formation and neovascularisation.

52
Q

How is developmental gene re-activation used for cardiac regeneration after MI?

A

Re-expression of a key embryonic epicardial gene Wt1 by priming Tb4 in vivo. Cardiac progenitors form which differentiate into de-novo cardiomyocytes.

53
Q

What is myocardial thymosin beta 4 ad what is it used in?

A

It is a molecule produced by cardiomyocytes needed for epicardial migration, coronary vasculature and cardiomyocyte survival.

54
Q

What effect does adding Tb4 (thymyosin beta 4) have on the heart?

A

Stimulate epicardial outgrowth and neovascularisation + re-expression of epicardial gene Wt1.

55
Q

What other transplantation methods can be used for cardiac regeneration? - how does it help

A

Graft sheets of cardiomyocytes can improve function but does not integrate into heart tissue.

Instead they release paracrine factors to regenerate damaged muscle.

56
Q

What is epicardial FSTL1? + function

A

A secreted factors normally expressed in epicardium that promotes cardiomyocyte proliferation but is lost after MI.

57
Q

What other paracrine signalling based methods can be used for cardiac regeneration?

A

Epicardial FSTL1 promotes regeneration of cardiomyocytes.

58
Q

Summarise all the methods that can be used for cardiac regeneration?

A

Stem cell therapy
Direct integration of grafted cells
Re-expression of developmental gene programmes (thymyosin)
Paracrine signals helping host tissue to regenerate (thymyosin and FTSL1 and grafting sheets)

59
Q

Why is stem cell therapy used in cancer patients after recovery? + example

A

Chemo and radiotherapy kills cancerous cells.
Stem cell transplantation allows healthy cell production.

e.g. haematopoietic stem cell for blood cells after lymphoma/leukemia

60
Q

Which type of stem cell is used for healthy cell regeneration in cancer patients?

A

iPSCs and ESCs

61
Q

How is stem cell therapy used as a treatment for cancer itself?

A

Production of anti-cancer vaccines.

62
Q

How do anti-cancer vaccines work?

A

Stem cells deliver genes, nanoparticles and oncolytic niruses to tumour niche. Prime cells for drugs to target and extract exosomes.
Correct mutation in vitro and drug test before replacement.

Molecular Basis of Disease (29 decks)

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