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SCRA > 12. regenerative biology 2 > Flashcards

12. regenerative biology 2 Flashcards

1
Q

what was discovered in 2001?

A

that there soluble factors in serum that are important for muscle regernation - particularly in re-entry to the cell cycle

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2
Q

how do you get more proliferation when growing muscle cells in culture?

A

plate them at low density - this way they are not contact inhibited

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3
Q

what is required for de-differentiation regeneration of myofibres in vivo in newts? and why is this?

A

direct clipping - cutting off the end of fibres
- they need to be physically damaged to trigger cell cycle re-entry
>need to trigger start of programmed cell death in order to regenerate

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4
Q

what happens when newt skeletal muscle is fragmented (breaking up of multinuclear structure)?

A

programmed cell death response - involves caspase response, this may act on cells or be released from cell (they are not sure)
>from this, this paper were able to get terminally differentiated skeletal muscle cells into regernative progenitors

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5
Q

what happens when skeletal muscle cells are injured?

A

most of them will die

>some don’t die and re-enter cell cycle and de-differentiate and contribute to regenerating muscle

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6
Q

what two things do axolotl regernating limbs need to do in order for there to be cell cycle re-entry by differentiated cells ?

A

> trigger a programmed cell death response

>down regulate TS p53

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7
Q

if p53 is not down regulated what happens?

A

cell cycle re-entry cannot be triggered = no regeneration/impaired regeneration

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8
Q

why do we not want to interfere with p53 in humans?

A

it is regarded as the ‘guardian of the genome’ - interfering with this will lead to cancer
>this may be one of the reason why we cannot regenerate

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9
Q

a paper want to see what pushed myotubules to divide, what did they do? what protein did they identify?

A

screened blastema secreted proteins for effects on division of cultures myotubes
- to see how salamanders re-enter the cell cycle safely
>MLP (MARKS-like protein)

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10
Q

what did they do to show that MLP is important during regernation?

A
  • did a big cloning screen
  • saw the effect on dissociated cells
  • purified active protein
  • made antibodies to see where it was
  • KO
  • added it ectopically
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11
Q

MLP is very good at inducing the blastema. what can it induce?

A

significant increase in length of blastema

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12
Q

what was seen when anti-MLP was used to block it affect in a wide range of regernating tissues?

A

blocking it has an affect on dividing nuclei - MLP upregulates division
>this shows it is widely used in axolotl to regenerate tissue

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13
Q

what is it proposed that the ‘serum factor’ may do?

A

this might P Rb allowing it to release E2F and drive proliferation

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14
Q

what do we know about the S phase re-entry factor in serum?

A

it is being cleaved by thrombin - serum and thrombin can trigger cell cycle re-entry

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15
Q

is thrombin cleaving a factor in the serum or on the cells? and how was this determined?

A

thrombin cleaves something in the serum
>pre-incubate the serum with thrombin, inhibit thrombin then treat cells with the serum - this was shown to trigger cell cycle re-entry

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16
Q

what can the S phase re-entry factor also stimulate cell cycle in?

A

newt iris pigmented epithelial cells

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17
Q

what might being able to identify this S-phase cell cycle re-entry factor determine?

A

why salamanders can re-grow limbs and we cannot

>may also allow for us to do mammalian regernation

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18
Q

mouse muscle cell line was treated with serum or newt blastema extract, what happened?

A

cells immediately upregulated genes like fos and c-myc, left G0 and entered G1
>they resist entry into cell cycle and do not enter S phase

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19
Q

some people are born without limbs, what might we want to be able to do?

A

kick start embryonic development in that part of the body again

20
Q

how does embryonic development in salamander differ from regeneration?

A

> embryonic development doesn’t need nerves

>blastema division and growths needs nerves (depends on nerve derived factors)

21
Q

what can be used to induce ectopic limbs in salamanders?

A

re-direct the nerve, damage the tissue and the nerve will generate a limb to grow in a ectopic position

22
Q

what are some of the nerve derived factors? and what implication does this have on humans?

A

BMP and FGF drive blastema cell proliferation

>we will need to think about nerve derived factors if we ever get to this stage in humans.

23
Q

what protein sets up a proximodistal gradient and what is this set up by?

A

Prod1 - this is set up by MEIS

24
Q

where is Prod1 found?

A

only in salamanders not in humans

25
Q

what does Prod1 do?

A
  • it binds nAG and can interact with EGFR
  • this stimulates S cell entry
  • and induces MMP9
26
Q

what natural regernation occurs in mammals?

A

very limited ability to regenerate lost/damaged tissue or heal without scarring

27
Q

what do mammals do that Urodeles don’t?

A

scar

28
Q

why might we not regenerate? (4)

A
  • don’t want to down regulate TS
  • our circulation is under high pressure and so want strong healing response
  • we have a very mature immune system
  • we have a scarring response
29
Q

what might it be hard to introduce a bioscaffold into?

A

the hostile environment of regeneration

30
Q

name two types of animals that have lots of division in their brain postnatally

A

fish and salamanders - can regernate lots of their brain

31
Q

what is seen in the brain of zebrafish?

A

self-renew neural precursor cells throughout brain - these use different TF from embryonic development

32
Q

which neurones die is Parkinsons?

A

DN - these neurons die and drive the shaking and inability to move

33
Q

what happens when of midbrain dopamine neurons in newts are ablated? and what is a key component in this? and how does this compare to embryonic development?

A

this induces NSC in the normally quiescent midbrain to proliferate and undertake full DN regulation
>Shh signalling
>this is similar to embryonic development

34
Q

even injury is not enough to re-activate neuogenic genes that are epigentically switches off. describe why most of the mammalian brain cant regenerate?

A

> injury induced to the brain
proliferation and recruitment of glia around injury but no neurogenesis
glia induces olig2 expression
this supresses neurogenesis

35
Q

what can be inhibited to allow neurogenesis in mice the brain? and what implication may this have on therapy?

A

olig2
>when people have a stroke you can get into the area and safely get cells to make new neurones (currently v restricted by epigenetics)

36
Q

describe Deer antler regeneration

A 
every year the males generate antlers
>this is stem cell based 
>they don't get cancer 
>doesn't need nerves
>the large casting wounds don't scar
37
Q

what type of mice have amazing skin regernation, and what could this be applied to?

A

African spiny mouse
>these mice can loose chucks of their skin and regrow them (most other mice would scar/die)
>this includes regernation of hair follicles, sebaceous glands, dermis and cartilage
>in dorsal and ear
>this could be applied to burns victims

38
Q

what is the only part of mature mammalian limb to regenerate? and what does this require?

A

fingertip

>the nail be needs to be intact

39
Q

describe new fingertips that are made in mammals

A

they are shorter but have minimal scaring

>this process does not always work perfectly

40
Q

does the regeneration come from stem cells/already committed progenitors after fingertip amputation in mice?

A

lineage restricted and not pluripotent stem cell activity (cells are not completely de-differentiated)
>ectoderm contributes to epidermis, nail and sweat glands and not to mesoderm tissue

41
Q

the activation of what in the nail epithelium couples nail growth to digit regernation? and what happens when this is KO?

A

Wnt signalling

>don’t get fingertip regeneration

42
Q

why do we need the nail bed for fingertip regernation?

A

Wnt responsive stem cells are present

43
Q

in addition to stem cells which respond to Wnt, what else is there in the fingertip blastema?

A

some committed progenitors

44
Q

what can we learn from natural regernation? (6)

A
  • understand the wound healing regernation switch
  • how to prevent scars
  • understand how to control endogenous cells division and de-differentiation, and their re-differentiation
  • including positional identify
  • nerve dependency
  • understand how to make the local environment permissive for regeneration
45
Q

in order to allow regernation in humans what will we need to do in this 24 hours period after wound?

A

remove factors that are blocking regeneration

46
Q

what is the argument that challenges the want for humans tissue regernation?

A

we will be able to develop better prosthetics to challenge regeneration anyways so why bother with further regenerative research.

SCRA (19 decks)

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