Link between Immune System function and Hematopoietic Stem Cells – Journal Club Online v.1

by Alexey Bersenev on April 15, 2008 · 0 comments

in Journal club

Blogging on Peer-Reviewed ResearchWe are so busy in the lab sometimes that we can’t find time to get together and discuss the last exciting papers that other researchers in the field have published.
So, we decided to find an alternative form to classical journal club, which could turn out to be even better than the original, because it could be done at a convenient time for everybody and could be updated.
The first idea was just a simple chat. Example is below.

The paper what we’re discussing is here
The p47 GTPase Lrg-47 (Irgm1) Links Host Defense and Hematopoietic Stem Cell Proliferation. Cell Stem Cell 2008;2:83 by Carl G. Feng et al. from Margaret Goodell group

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me: let’s start journal club
Joanna: ok
Jae-Won: so as I always ask to myself and others, what is the point of the paper?
8:50 PM Joanna: links the immune response to hematopoiesis
through the IFN gamma induced Irgm1
me: will you give the short intro to the paper?
Joanna: sure
me: go ahead
8:51 PM Jae-Won: yeah, go ahead.
Joanna: this is a paper about interferon-inducible GTPase 1 (Irgm1), which was discovered through a microarray of genes activated during HSC activation
8:52 PM Irgm1 is a GTPase that is important in defense against certain microbial infections
8:54 PM and though the mechanism of its action is not fully characterized in the immune system, it is linked to phagocytosis
8:55 PM this paper is the first to link it to the induction of hematopoiesis
me: It seems to be a second one
Joanna: first to show a concrete protein

Jae-Won: yeah
8:56 PM I know of another paper
Joanna: several that imply a link
Jae-Won: it’s published in cell
me: in terms of link between activation of HSC by immune system activation
Joanna: what does that paper publish?
me: http://www.immunity.com/content/article/abstract?uid=PIIS1074761306002664
Jae-Won: remember when von Andrian group published about circulating HSCs and their functional role in immunosurveilence?
8:57 PM me: Toll-like R & HSC was first story in the series
von Andrian a bit different I guess
Jae-Won: http://celltrials.info/2007/12/02/the-sentinel-stem-cell/
I wrote an article..
Joanna: right this paper was mentioned in the intro to the article
it just links the two systems
me: but could be considered
8:58 PM Joanna: but it doesn’t not provide how
and taht was in the immune system, this is in the HSC
Jae-Won: the paper implicated SIP1 receptor..
8:59 PM me: Yea, Goodell paper shows the mechanism
Joanna: yes, so they have four main points
9:00 PM Jae-Won: anyways, here is my version of the whole story: did microarray –> found a gene significantly changed –> did lit review and found implication in immune system –> knock this gene out –> see what happens..
okay…
me: how HSC get activated to produce more killers when immune system challenged
Joanna: yeah and the KO shows impaired reconstitution
me: good scenario, many groups doing that
9:01 PM Jae-Won: interesting thing is that how HSCs, which are multipotent, are ‘directed’ to produce more killers upon challenge?
Joanna: i am confused
that is not in this paper?
me: I meant “killers”
Jae-Won: okay,, I think I went too fast..
we went too fast…
me: mean we don’t know what kind of cells HSC going to produce
9:02 PM Jae-Won: go ahead and make important points about the paper Joanna
Joanna: hmm ok
me: paper show that they just getting activated by this mechanism
Jae-Won: you wanted to make 4 points.. go ahead.
Joanna: well KO HSC’s are outcompeted by WT HSC’s, leading to the conclusion that they suck at engraftment (though this is not because of adhesion)
9:03 PM KO HSC’s hyperproliferate
and the dont-know-what-to-call-it (kinetics?) of HSC response to chemical or microbial challenge are slower and weaker
9:04 PM me: in KO they do not response to microbe at all
according picture
9:05 PM Joanna: yaeh, ok
me: 1% LSK before –> 1% LSK after
Jae-Won: so sounds to me that hyperproliferation of HSCs impairs the ability of HSCs to differentiate..
me: this is the best part of paper to me
good assay
Joanna: impairs ability to engraft, no?
9:06 PM Jae-Won: yeah engraft.. so reconstitution is bad.. hence.. not giving rise to different cells properly
9:07 PM Joanna: i guess so, but couldn’t you have a perfectly healthy stem cell in terms of differentiation that just couldn’t engraft?
Jae-Won: how would HSCs give rise to different cells without differentiation?
Joanna: huh?
me: they engraft but very few compare to WT
9:08 PM they are engraft and able to differentiate
but much much less then WT
Joanna: so jae you were saying something about killer cells?
Jae-Won: that’s what I’m saying..
9:09 PM yeah…by linking two mechanisms, the paper implies that upon immune response, HSCs differentiate rapidly into killer cells..
9:10 PM Joanna: why killer cells?
me: we actually DO NOT know where they differentiate
Joanna: yeah
me: they just got activated
Jae-Won: so nothing to do with killer cells specifically..
could be just general response..
me: i used term “killers” because theoretically (we don’t know ) we need them to “kill” microbe
9:11 PM Jae-Won: but doesn’t mean specifically killers.. could be overall blood count, etc…
me: so theoretically HSC shoud give common lymphoid progenior and then “lytic” T-cells
Jae-Won: or does it?
me: or NK
Joanna: yeah well since this GTPase is involved in phagocytosis
it is implicated in macrophages
9:12 PM and actually, it is preferentially expressed in the lung and primary macrophages
(this is information from UniProt)
me: and linked to interferon system in innate immunity
Joanna: (see alexey, this is what I meant about molecular data giing you clues about bigger things)
Jae-Won: that’s why I suggested, if differentiation response of HSCs is specific upon microbe stimulation or general..
9:13 PM the only problem with molecular data giving one clues about bigger things is that one eventually needs to validate it anyway..
validation takes time
Joanna: yeah, but it’s a pointer.
Jae-Won: and it comes down to really what the point of validation is..
9:14 PM Joanna: anyway, i think the cue what to differentiate into is a different signal from this one, no?
Jae-Won: that’s probably why Alexey was frustrated to see molecular things sometimes..
Joanna: but that is a good question
me: :) sometimes is ok if it’s give an idea
Joanna: what are the HSC’s stimulated to differentiate into
9:15 PM or are they just stimulated to proliferate (that’s what I thought) and then throuhg a second signal told what to become
me: maybe they are gonna check next
Jae-Won: yeah.. under that microbial challenge..
good, interesting… do you see the utility of this work?
Alexey might know…
9:16 PM Any genetic condition that doesn’t give rise to innate immunity yet HSC is ”normal’?
or something like that..
me: it’s more basic biology i guess
Joanna: the utility for me is that it links what we’re wokring on to a topic that’s very interesting to me
9:17 PM well they did say an SNP in this gene in humans is found in chron’s disease
me: its could be interesting
9:19 PM Jae-Won: Anyway, linking a primitive form of cells with mature cells in terms of functions is interesting and has a broad application.
Joanna: good theory
Jae-Won: -ve… too basic..
but you know that’s science.
9:23 PM me: so do you like a paper Jae?
Joanna: i never think this level is too basic, but that’s just what i like
Jae-Won: Good example of a ‘simple’ paper..
me: kool
Joanna, can you conclude
Jae-Won: simple but good concept
Joanna: simple but important
me: + & –
9:24 PM Joanna: sure
me: significance and how we can benefit
Joanna: well Jae did a good job of writing the pluses, though, i would say this paper doesn’t go far enough to characterize what happens
9:26 PM i’m actually not even sure what exactly irgm does
me: me too :(
but they told that in introduction actually
9:27 PM Joanna: we can find that out
me: i’ll give my conclusion then
Joanna: i don’t know that they’ve identified irgm’s targets and control mechanisms
interesting thing i found out is that there is a natural varient expressed taht is missing the NT-most portion
let me think a minute about my conclusion
me: So I like paper, because It’s kind of new area – link between function of immune system and HSC – How does it works
9:28 PM I like that figure what we were discuss before
LSK after microbe stimulation
9:29 PM Joanna: which one?
cool
can you tell us a little more about that, actually
me: wt = 1–>15, KO = 1–>1
9:30 PM Jae-Won: kool..
me: they give a microbe iv to mice then 4 weeks after kill mice and check LSK in BM
simple
WT before infection 1% LSK, after -15
KO 1 – 1
me: I’ll leave only this picture in the paper
all of others go to supplements
Jae-Won: kool
me: all other pictures needs just for reviewers
Jae-Won: good discussion..
9:32 PM me: because they discribed a new gene
HSC regulator
so they have to show all of standart assays
me: serial transplant is missing so they can’t conclude about self-renewal
me: we can def learn methodology
it’s simple and rapid
me: but very new stuff
me: I like that idea came up from microarray data
what was made in FEW labs

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This is a picture what I like a lot – progenitors/stem fraction of bone marrow got activated (15 fold) in wild type mice, compared with “no activation at all” in knockout mice (by gene what was studied):

So it’s was first pilot version of “Journal Club Online” concept, we are going to try more, using different tools,
any suggestions about better realization of concept will be appreciated.

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