<TITLE: Regeneration of the Pancreatic Beta Cells
ACADEMIC DOMAIN: medicine
DISCIPLINE: neurology
EVENT TYPE: lecture discussion
FILE ID: ULECD080
NOTES: continued in and continuation of ULEC150

RECORDING DURATION: 9 min 49 sec

RECORDING DATE: 8.3.2007

NUMBER OF PARTICIPANTS: 15

NUMBER OF SPEAKERS: 4

S1: NATIVE-SPEAKER STATUS: Finnish; ACADEMIC ROLE: junior staff; GENDER: male; AGE: 51-over

S2: NATIVE-SPEAKER STATUS: Dutch; ACADEMIC ROLE: senior staff; GENDER: male; AGE: 31-50

S3: NATIVE-SPEAKER STATUS: Finnish; ACADEMIC ROLE: junior staff; GENDER: female; AGE: 31-50

S4: NATIVE-SPEAKER STATUS: Chinese; ACADEMIC ROLE: research student; GENDER: female; AGE: 31-50>


<S1> special reason not only this special seminar but another special reason to come to helsinki at this time so that that is naturally <NAME S4>'s <NAME S4>'s dissertation which will be tomorrow in the in the small lecture hall at the haartman institute . and er now we have an an excellent ch- chance to to get prepared for for give give more of the background for <NAME S4>'s thesis and and also hear about the latest developments in in the brussels lab on panc- beta cell regeneration so with these </S1>
<LECTURE ULEC150 by S2>
<S1> er thanks <NAME S2> a lot . er if i may start by er just to again er admiring and and wondering about your your rat acinar trans-differentiation model which is so so beautiful and clear-cut results that you have so so we know and and you have shown and others have shown that that when you put acinar cells in culture you you very easily can see er acinar acinar-to-ductal metaplacia trans-differentiation er so but i- in this model you you don't think that there is any ra- not even a rapid change of phenotype to to to er er a duct-like phenotype er on the way <S2> [(no)] </S2> [to] to either differentiation or is it that [just you have (xx)] </S1>
<S2> [yes] no no there is in fact s- in the first er four or five days where we need to er have de-differentiation of the cells er but this occurs spontaneously not only the acinar markers are lost but there is er expression of some duct cell markers like cytokeratin 20 but th- pr- the problem is er to find er good duct cell markers i mean er erm the cells will not start to express functional markers like carbon (xx) do in this model , so they are in kind of de-differentiated state er and in in these de-differentiated states , markers are expressed which you normally only find in in in duct cells <S1>  mhm </S1> so this is really a ductal phenotype </S2>
<S1> but in in in vivo if you translate these observations to the in vivo situation of neogenesis in the duct ligated pancreas for example don't don't you think that the correlate of your observations in in vivo is that that actually those those acinar cells they they er go through this duct- ductular complexes <S2> mhm-hm </S2> before <S2> [yes] </S2> [differentiating] into islets and so so that the- we we cannot say that they are fully mature functional duct cells but at least morphologically they have a <S2> [yes] </S2> [an] intermediate phase of a er <S2> [yes] </S2> [that] resembles of duct (xx) </S1>
<S2> mhm there are many similarities that's true yeah </S2>
<S1> so there is no discrepancy in the way in er this whole picture , <NAME S3> </S1>
<S3> can you replace EGF with the other er ligands i i didn't see that in your scheme like with with beta cell and (xx) alpha </S3>
<S2> erm you mean in the in the mouse or in the in in vitro </S2>
<S3> er in both </S3>
<S2> well in the mouse we certainly didn't try because EGF is er rather cheap <S3> [yes i thought] </S3> [but the others] are very expensive <S3> [yeah] </S3> [so] that's a way er the reason why we did not do it erm yeah that's a good it's a good question in fact for for LIF we have compared with all the related factors like CNTL (xx) six <S3> [mhm-hm] </S3> [and so on] but er EGF we have not er really tried so far to to repla- i think (xx) alpha works but for the others er <S3> mhm </S3> we we didn't try </S2>
<S1> that's it's so naturally quite er surprising this this very clear-cut thing in your screening of factors that that this clear-cut effect that you see with just the combination of EGF and LIF is is so potent and er and and it's the obvious question of course is that er what what really is the special signalling pathway that you trigger with these <S2> [mhm-hm] </S2> [combinations] do you have any any insight [into] </S1>
<S2> [well] in vitro clearly what we find is that with er inhibitors of jak-two phosphorylation or inhibitors of er er stat-three phosphorylation it completely inhibits beta [cells] </S2>
<S1> [but] but you can stimulate jak-two and stat-three with with various other <S2> yeah </S2> but so why why is it just EGF plus LIF that has this effect [er] </S1>
<S2> [well] LIF can be replaced by CNDF which works via er similar receptors and also we have the same signalling pathway <S1> [but if] </S1> [EGF] is another er question but we believe that EGF also works via the jak-two st- er stat-three pathway in this model and we are now actually w- it is known that it can er act via this pathway and we have now we are now trying er altering inhibitors of the other EGF driven pathways and er this seems to er to confirm this story <S1> [(also)] </S1> [so] i- i- it is possible even by adding other agents to switch the EGF to to another pathway and then again it inhibits i- it inhibits this er neogenesis , so we we believe that EGF er reinforce the the the effect from the from LIF on on the same pathway </S2>
<P:04>
<S1> so so that </S1>
<S2> and even gastrin can work th- this has been demonstrated er recently by er daniel fourmy's er catherine seva's er group in erm france they er found that the er gastrin receptor can also activate a j- jak-two-stat-three pathway </S2>
<P:07>
<S1> so so this er probably suggests that that er also pharmacological activators of this pathway would be interesting to [to study] </S1>
<S2> [i think so] at least in a rat </S2>
<S1> mhm one one possible ques- issue of course is that tha- that is it true that that that is what even if this works so nicely in the in the rat it does not work in the mouse <S2> [mhm yes] </S2> [or does it] have you been [able to] <S2> [yeah] yeah </S2> [do it] </S1>
<S2> [we have] tried erm mouse of course we have not wha- often it's dangerous to say oh we're going to do it in mouse and because we have much le- we have er no experience we have no experience with isolation and culture of of mouse pancreatic cells so you say wow he's going to do that <SU-1> [mhm] </SU-1> [then] i- it didn't work but maybe it is because we have no experience and (there) can be so many small things that er have to be adapted from model to model so we are going to further try to do it but erm there is another er group you know in in in japan who er , also er found er trans-differentiation of acinar cells to beta cells (even in lineage) genetic tracing to demonstrate that with a combination of EGF plus (xx) er but that doesn't work in rat </S2>
<S1> mhm </S1>
<P:05>
<S4> so have you tried er in human acinar er [cells (xx) with this (combination)] </S4>
<S2> [yes of course we are trying hard] the problem is that er in the rats there is no doubt that a significant proportion of acinar cells remain in the culture state they change their phenotype very rapidly but they remain present we can keep them in culture for at least eight days with human cells <S4> die @@ </S4> they seem to to to disappear to die and we have no indication whatsoever that any of these cells or a s- significant proportion of these cells can survive in there [(xx)] </S2>
<S1> [that that's a] that's a big problem in approaching this as as we know very well an- and continue to discuss @probably@ tomorrow but if you want to do this with human and depending on the situation of course it may vary but in our situation w- we cannot directly take the cells freshly and start studying them i- if we have a lag of of some days <S2> yes </S2> and they have been in c- in vitro for some days then when we get them we have a lot of er sort of duct like cells and and probably o- i i i suppose you you would agree with me that the quite a big part of those are probably may may have been derived from acinar cells that are all detectable as as clearly acinar cells <S2> i don't know </S2> but it's it's er it's it's quite possible that that would be the case and and that just makes it hard to study this </S1>
<S2> yes but it is also possible that that acinar cells and i think that is the case are much more sensitive to er for instance the (ischemia or profusion) <S1> mhm-hm [yes yes] </S1> [to er] to (apoxia) and to to other manipulations in that they're just dying before you can do anything with them in the case of human cells </S2>
<S1> yeah , okay but i'm sure we will and you will continue the discussion tomorrow hopefully a lively discussion er tomorrow n- at noon so thanks a lot </S1>
