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SCRA > 13. regenerative biology 3 > Flashcards

13. regenerative biology 3 Flashcards

1
Q

what is there a hunt for in the heart?

A

stem cells - there still isn’t a consensus for this

>but there is a possibility to use endogenous stem cells/iPSCs

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2
Q

during embryonic development ……. cells releases factors to stimulate local cell division in …….

A

epicardium

cardiomyocytes

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3
Q

name a target cells for regernative therapy in the heart?

A

epicardium cells - maybe we could make them behave like embryonic sheath and make it release factors to help cardiomyocytes to divide

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4
Q

name the type of cells (of which there are many in the heart) that people have succeeded in pushing to become cardiomyocytes? what have they then been able to do?

A

fibroblasts

>help these integrate into damaged tissue

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5
Q

what is it called when inadequate blood supply to organs in the body, especially to the heart muscle?

A

isechmia

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6
Q

name 4 things that can cause heart damage?

A
  • isechema
  • hypertensions - high blood pressure
  • mutations
  • chemotherapy
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7
Q

what is very toxic to heart muscle?

A

chemotherapy - even though there is not much division in this tissue

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8
Q

how many non-fatal infarctions are there in the US every year?

A

1 million

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9
Q

what does infarction lead to?

A

massive cardiomyocyte death, about 1 billion per hour

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10
Q

describe a potential therapeutic for when people have a heart attack?

A

noto kick start division in the heart - will need to generate a huge number of cells, may not be possible to replace them all but will reduce damage

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11
Q

what does massive cardiomyocytes death after a heart attack trigger? (3)

A
  • inflammation due to immigration of migratory immune cells
  • fibroblast accumulation
  • ECM production and scaring
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12
Q

when fibroblast are activated they lay down ECM material, why might this be a good thing? and why might this be a bad thing?

A

give some strength to the damaged area
>it might get in the way of and interfere with the contracting muscle
>also makes the environment very hard for regeration to occur

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13
Q

why might injecting stem cells into a heart post heart attack be difficult?

A

the muscle is very tough
>it will be inflamed
>it will be beginning to scar
>cells may not be able to survive in this environment

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14
Q

in what animal can cardiac regeneration occur, and why might this be the case?

A

zebrafish and newts

>their circulation is not as high pressure as ours, heart can keep going while regerantion takes place

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15
Q

describe zebrafish heart

A

simple double chamber, blood flows into atrial chamber and out ventricle chamber

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16
Q

describe zebrafish heart regeneration

A
  • can cut off large chunks of heart

- cells will reprogram to progenitor like cells and migrate to rebuild tissue

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17
Q

you can wound embryos quite severely and the wound will heal without making a scar in the womb, soon after they are born what does this response switch to?

A

a scaring response

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18
Q

embryonic mouse heart can be damaged (describe how) and what can be seen?

A
  • cutting off parts
  • freezing
  • tying up blood vessels to stop oxygen flow
    >quickly regenerates with no scarring or inflammation
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19
Q

why might the embryonic mouse heart quick regernate with no scarring or inflammation? (3)

A
  • immature immunoinflammatory response
  • limited fibroblasts
  • low oxygen environment
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20
Q

how many days after birth do mice cardiomyocytes withdraw from the cell cycle?

A

7 days
after this they can not be induced to proliferate
>mice will scar over regenerating

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21
Q

what does the epicardium release to stimulate cardiomyocytes to divide? and what is a potential therapeutic application of this?

A

TGFβ and fibronectin

>generate patches that release this

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22
Q

name three other things that are seen in heart that can regenerate

A
  • macrophages and monocytes that release cytokines
  • nerves
  • angiogenesis
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23
Q

what have macrophages been seen to be key in?

A

reducing the damaging inflammation

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24
Q

what two things do we also want to encourage to grow along with epicardium?

A

nerves (so it will be contractile) and vasculature

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25
Q

what has our biology made very hard to do in terms of cardiomyocytes?

A

re-enter the cell cycle

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26
Q

what implication does cytoskeleton and adhesion molecules have on mammalian heart ability to regenerate? but what has show us that this is possible?

A

physically cells are stuck together in a matt of tissue - this would be difficult to disassemble
>this occurs in skeletal muscle

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27
Q

describe cardiomyocytes

A

they are binuclear

28
Q

why did some people think that they saw some myocytes entering the cell cycle after damage?

A

cells took up DNA labels - this was only because cells were undergoing DNA repair

29
Q

one study showed cardiomyocytes are turned over in humans, at what rate?

A

~1% per year at 20 years, declining to 0.4% per year at 75 years

30
Q

the study also showed at the age of 50 what % of cardiomyocytes are from birth?

A

55%

45% were generated afterward

31
Q

this study was through to be controversial, why?

A

people though that they were just seeing artefacts - even if this is there case it seems that there are a small number of cardiomyocytes that can divide put potential for division seems minor

32
Q

what needs to be down regulated in order to induce mammalian cardiomyocyte division experimentally?

A

down regulation of tumour suppressers like Rb

33
Q

what might explain why explain why tumours in myocardium as so rare?

A

their inability to reactivate cell cycle

34
Q

what was over expressed and what was KO in mammalian cardiomyocytes to induce cell cycle entry? and what did this show in an infarction model? why might this be unsafe in clinics?

A

cyclin D
Rb
>improved cardiac function
>KO Rb might lead to cancer - evolution has made way to control cell cycle and prevent cancer

35
Q

describe the structure of cardiac muscle

and what is there a hunt for in terms of this?

A

fibres, some of which are branched, thick specialised adhesive link between branches of the fibres
>hunt for drugs that can disassemble and reassemble contractile structures and work with binuclear cells

36
Q

to induce regeneration in the heart what do we need to do?

A

find a way to unstick these cells and get them to re-enter the cell cycle

37
Q

name two types stem cell based cardiac therapy (even through none have been very successful)

A
  1. exogenous stem cells

2. endogenous stem cells

38
Q

what was seen when skeletal myoblasts were added to mammalian hearts?

A

they didn’t integrate well and they sometimes interfered with contractions

39
Q

what are the advantages of using mesenchymal stem cells? (5)

A

good at homing to injured sites, modulate immune response, inflammation and secrete survival factors
>they transiently hang around and support the damaged tissue to improve the local environment for regerantion

40
Q

how was the dogma about stem cells in the heart overturned?

A

> study followed markers of cardiac lineages from embryo to adult rodent and human
lsl1+ cells contribute to many regions of the heart
lsl2+ cells remain in adult heart
these may be cardiogenic stem and progenitors

41
Q

what made reader sceptical of the findings of heart stem cells?

A

the paper was published in nature, theyd also filed a patent application but did not declare their financial interest
>additionally, why don’t these repair the heart?

42
Q

there has not been a definitive study identify a stem cell population in the human heart, although some have been suggested, describe these

A

they have not shown classic stem cell properties or the ability to generate large number of cells

43
Q

what were c-kit+ cells?

A

self-renewing, clonogenic, multipotent, giving rise to monocytes, smooth muscle and endothelial cells

44
Q

what happens when c-kit+ cells were infected into mouse myocardium?

A

them/their progeny form well-differentiated myocardium, including myocytes and blood
>they survive and integrated
>vessels formed round them

45
Q

what was controversial about these c-kit+ cells? and what implication did this have on therapy?

A

they were not as pure as they claimed - mixture of cells was added
>some cells died quickly - for SC therapy we want cell that will survive long time especially as it is an invasive and stressful procedure

46
Q

in order to show that you have generated a cardiomyocytes what will you need to show?

A
  • cell markers
  • genes
  • electrophysiology
  • contractions
47
Q

describe a clinical trial that is currently going on

A

> MSC isolated from BM and expanded in culture
genetically engineered to secrete factors
pushed to differentiate to cardiac cells
put into patients and tract progress
no patients got worse
some had improve left ventricle function

48
Q

why was the field of stem cells in the heart confused put until recently?

A

one of the key researchers was making things up

49
Q

define the epicardium

A

epithelial sheath that surrounds the heart

50
Q

what was seen when the epicardium was induce to express key embryonic epicardial genes?

A

reactivation of the embryonic state of the epicardium they could get local cell division
>myocardocyte that divided could integrate into the heart muscle

51
Q

what does the epicardium down regulate after an infarction?

A

Follistatin 1

52
Q

what can patches of follistatin 1 do? and what were the patches made of?

A

increase vascularisation and induce cell division locally

>bioengineering scaffolds that don’t trigger and immune response

53
Q

follistatin 1 increases vascularisation, what affect might this have?

A

the blood can deliver growth and survival factors to help this tissue regenerate more efficiently

54
Q

what affect does inducing the myocardia to produce follistatin 1?

A

it did not have the same effect
>it seems key that this FST1 is from epicardium and not from the heart muscle itself
>maybe proteins are processed differently e.g. glycans

55
Q

what was seen when mice were given these patches after infarction?

A

patch increased local cell division and maybe has a role in reducing scar tissue

56
Q

what type of cell makes up >50% of the heart? and how might they be used therapeutically?

A

cardiac fibroblasts

- Transdifferentiation into cardiomyocytes

57
Q

what did they make from fibroblasts? and how did they do this?

A

induce cardio myocytes

>they did this by adding three TFs

58
Q

what properties did these iCM have? (7, last 4 in vivo)

A
  • cardiomyocytes-like gene expression prolife
  • contracted spontaneously in vitro
  • showed spontaneous Ca2+ oscillations with varying frequencies, similar to neonatal cardiomyocytes
  • differentiated to cardiomyocytes in vitro
  • integrate with heart tissue
  • survived
  • didn’t cause problems
59
Q

in 2010, what was made in regard to iCM?

A

criteria for these iCMs. you need to satisfy criteria to show that you have made iCMs
- all need to be satisfied to get cells into clinic, prove they are safe and safely differentiated, and able to integrate into tissue safely

60
Q

what has a paper in Nature has shown about iCMs?

A

they have been successfully incorporated into non-human primate hearts and had beneficial effects
>they increased arrhythmia and so this will need to be adjusted

61
Q

define 4 cell-based cardiac regenerative medicine

A
  1. injecting cardiomyocytes
  2. cardiomyocytes progenitor cells given differentiation signals and injected
  3. signal injected into the heart that mimic epicardium signalling
  4. fibroblasts reprogrammed to cardiomyocytes and injected
62
Q

for what application have iPSC been used for in terms of heart regerantion?

A

used to produce sheet of cardiomyocytes and vascular cells
>these were transplanted into rats and an improvement in function was observed
>this will stick and support the damaged heart
>will also contribute to contraction and strength of heart

63
Q

what properties of bioscaffolds can be altered? (6)

A
  • porosity
  • high surface area to volume ratio
  • appropriate mechanical properties
  • biodegradable
  • material - collagen, fibrins, peptides
  • patches/hydrogels
64
Q

give a therapeutic application of bioscaffolds

A

can increase strength of the muscle – if one bit of the heart dies, the rest of the heart might need to be strengthened to compensate

65
Q

what was seen when iCM were plated on tissue culture plastic and what else? and what was concluded from this?

A

> they were randomly arranged and had no particular cardiomyocytes structure
when you print grooves onto the plastic you can direct these cells into much more cardiac muscle like sheets
on grooves, substrates have less proliferative ability
- this might be what we need in order to efficiently put cells back into patient

66
Q

what does the substrate that cells are grown on affect?

A

cytoskeleton
cell-cell adhesion
gene expression

SCRA (19 decks)

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