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SCRA > 4. stem cells and regenerative medicine in the pancreas > Flashcards

4. stem cells and regenerative medicine in the pancreas Flashcards

1
Q

the biliary tree is a system of vessels that directs secretions from which three organs into what system?

A

secretions from the liver, pancreas and gallbladder are directed to the duodenum (the small intestine)

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2
Q

secretions exit the biliary tree through a hole into the duodenum, what is this hole called?

A

Ampulla or Vater

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3
Q

what type of organ is the pancreas?

A

a secretory organ

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4
Q

what are acinar cells and what do they do?

A

they are exocrine ducts which secrete digestive enzymes

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5
Q

what and where do pancreatic islets secrete?

A

hormones into the blood

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6
Q

what are the two main hormones produced by these islets?

A

insulin and glucagon

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7
Q

what do alpha cells produce?

A

glucagon

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8
Q

what do beta cells produce?

A

insulin

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9
Q

what is the function of the islets of Langerhans?

A

to regulate blood glucose homeostasis

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10
Q

which cell type makes up 60-70% of the islets?

A

beta cells

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11
Q

what is the function of insulin?

A

insulin lower blood glucose levels

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12
Q

name three ways in which insulin functions?

A

stimulates the body cells to absorb glucose, the liver stores glucose as glycogen and fat cells convert glucose into fatty acids

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13
Q

what is the function of glucagon?

A

raises blood glucose levels

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14
Q

how does glucagon function?

A

stimulates the break down of glycogen stores in liver and muscle cells

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15
Q

what is the range of normal blood glucose levels that needs to be maintained?

A

70-110mg/dL

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16
Q

what happens when normal blood glucose levels are disturbed?

A

the pancreas will react in order to restore normal blood glucose levels

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17
Q

what is type 1 diabetes classed as?

A

a chronic autoimmune disease

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18
Q

what occurs in T1D?

A

T cells attack insulin secreting beta cells, this results in beta cells becoming unresponsive

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19
Q

when does T1D manifest?

A

it usually manifest during childhood

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20
Q

in terms of stem cell therapy, why will T1D be harder to treat than T2D?

A

a way to prevent T cells from attacking any new beta cells will need to be developed

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21
Q

how many of the total cases of diabetes are T2D?

A

85-90%

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22
Q

what is T2D?

A

a chronic, progressive disease characterised by an abnormal insulin action and secretion

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23
Q

what is the initial problem seen in the development of T2D, which if controlled can prevent the development of T2D?

A

insulin resistance

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24
Q

what is insulin resistance?

A

when key target tissues have diminished response to insulin

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25
Q

what percentage of the pancreas is normally comprised for islet cells?

A

1-2%

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26
Q

during insulin resistance, what happens to the islet?

A

beta cells increase in both size and number

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27
Q

why do islet cells respond in this way to insulin resistance?

A

cells of the body aren’t responding to insulin efficiently, and so the body is overcome the lack of responsiveness by producing more insulin

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28
Q

what is glucose tolerance?

A

when blood glucose can be maintained during insulin resistance due to the increase in insulin production

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29
Q

what happens after islet compensation in insulin resistance?

A
  • there is impaired islet compensation/glucose tolerance
  • islets are overwhelmed and so beta cells begin to apoptose
  • number of islets decrease
  • reduction in number of beta cells per islet
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30
Q

what is the result of insulin resistance and impaired islet compensation?

A

cells are less responsive to insulin in addition to the pancreas producing less insulin and type 2 diabetes manifests

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31
Q

give three risk factors for T2D

A
  • genetics
  • obesity
  • age
32
Q

during insulin compensation what percentage of the islets do beta cells make up?

A

90%

33
Q

what does the world heath organisation predict in relation to T2D? and what does this mean for pancreatic research?

A
  • diabetes will be the 7th leading cause of death by 2030

- the is a potential large financial for T2D research

34
Q

the liver, pancreas and biliary tree development starts at what day after fertilisation?

A

day 35

35
Q

describe the pancreas at day 35 after fertilisation?

A

their is a ventral pancreatic bud and a dorsal pancreatic bud

36
Q

how does the biliary system initially develop?

A

it develops as a tubular structure from the elongation and moulding of the posterior portion of hepatic diverticulum

37
Q

organs linked by the biliary tree are also linked during… ? and what does this tell us?

A
  • development

- all of these cells are derived from a single multipotent population of cells

38
Q

what happens 40 days after fertilisation?

A

dorsal and ventral pancreatic bud rotate clockwise and fuse

39
Q

what forms at day 45 post fertilisation?

A

the biliary tree

40
Q

where is it common to find stem cells niches in this system?

A

associated with the biliary ducts

41
Q

where are stem cells found in the liver?

A

canal of hering at the tip of the biliary tree

42
Q

if the liver is damaged and hepatocytes are unable to respond, what may occur?

A

there may be streaming of stem cells from other regions

43
Q

what is the marker for biliary tree stem cells and their progeny (hepatic and pancreatic lineage)? and what can be put under control of this promoter for lineage tracing?

A

Sox9

CreER

44
Q

what is the marker for cells of pancreatic lineage?

A

PDX1

45
Q

in linage tracing, what is floxed upstream of a reporter gene? and give an example of a reporter gene?

A
  • stop codon

- lacZ

46
Q

when LacZ is expressed how can it be detected?

A
  • addition of XGAL

- beta-galactosidase will hydrolyse the glycosidic bond and give rise to galactose and a blue product

47
Q

what cells will be marked by this lineage tracing? and what does this tell us?

A
  • cells of the intestine, pancreas, liver and biliary tree

- sox9 marks a progenitor population within the biliary tree

48
Q

where are the multipotent progenitors of biliary tree?

A

peribiliary glands

49
Q

when these multi-potent progenitors decide to become pancreatic, what is their first fate decision?

A

whether to be ventral or dorsal

50
Q

what cell type becomes endocrine?

A

ventral progenitors

51
Q

these progenitors may become endocrine cells or…?

A

acinar cells

52
Q

give three possible fates of the multipotent progenitors of the biliary tree?

A

hepatic cells
extra-hepatic cells
pancreatic cells

53
Q

what two transcription factors determine where pluripotent stem cells will be endoderm?

A

sox17 and foxA2

54
Q

what two transcription factors drive endoderm cells to become pancreatic endoderm?

A

sox9 and pdx1

55
Q

which three cells types can the pancreatic endoderm then become? and what does this depend on?

A
  • ducts cells, acinar cells, endocrine cells

- this depends on their gene expression

56
Q

in order to give rise to beta cells what do we need to drive cells to become?

A

endocrine progenitors

57
Q

altering what type of signalling in the body can change the fate between hepatic and pancreatic lineages?

A

non-carconical Wnt signalling

58
Q

how was this type of signalling that can change cells fate between hepatic and pancreatic lineages identified?

A
  • hepatic and pancreatic progenitors were isolated by flow cytometry
  • RNAseq was used to define molecular identify of cells
59
Q

what is trans-differentiation?

A

when one committed cells gives rise to a different type of committed cell

60
Q

what is de-differentiation?

A

when a committed cells goes back to a less differentiated state

61
Q

how has acinar cells plasticity been shown in model animals?

A

following pancreatic duct ligation - where a ligature is made in the pancreas and a pancreatic duct is tied off - acinar cells can convert to embryonic type multipotent cells and give rise to acinar cells, duct cells and endocrine cells

62
Q

what does this animal model acinar cellular plasticity suggest?

A

that it is possible to take acinar cells and manipulate them to become beta cells

63
Q

under what conditions have interconversion between cells of the islet been observed?

A

experimental and pathological

64
Q

what is special about this interconversion between islet cells?

A

it does not require the manipulation of very many genes

65
Q

the over expression of what can make beta cells from alpha cells?

A

Pax4

66
Q

what are three ways to make functional beta cells?

A
  1. directed differentiation of ESC/iPSC
  2. reprogramming of islets cells/acinar cells/hepatocytes
  3. inducing replication of beta cells
67
Q

what does directed differentiation try to mimic?

A

normal development

68
Q

what does directed differentiation currently involve?

A

an in vivo transplantation step

69
Q

why do we need to be careful about injected beta cells derived from directed differentiation?

A

need to be sure that they have been fully reprogrammed so that they will not give rise to cancer

70
Q

what is a downside of using alpha cells for reprogramming?

A

they do not proliferate very well and so will need to obtain lots of them

71
Q

how is the co-scientific director of the Harvard stem cell institute? and what field is he now at the forefront of?

A

professor Doug Melton

the field of generating and reprogramming beta cells

72
Q

when and what was the first evidence that beta cells could be generated in vitro? and what were they then showed to do?

A
  • in 2014, Professor Doug Melton helped define a differentiation protocol for hPSC in vitro
  • when transplanted into diabetic mice they restored glucose regulation
73
Q

what was the second strategy for generating beta cells was Doug Melton also involved in defining?

A

generating beta cells through the reprogramming of adult exocrine cells in vivo

74
Q

how were the specific transcription factors delivered to the exocrine cells in order to reprogram them and what was the downside of this?

A

retroviral delivery

would not want to give patient cells made by this method as it might lead to cancer

75
Q

when adult exocrine cells were reprogrammed in vivo what was observed?

A

beta cells were not confined to the islets and were distributed throughout the pancreas

76
Q

what needs to be determined about location of beta cells in the pancreas?

A

whether their localisation in the islets are necessary for their function

77
Q

what did a third study do to overcome the problem of Doug Meltons second study?

A

they used small molecules facilitate the reprogramming of mouse fibroblasts into pancreatic lineage

SCRA (19 decks)

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