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Hematopoietic Stem Cells in Health, Aging and Malignancy: Focus on Metabolism (EHA2024) · EHA Unplugged

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  In this episode of EHA Unplugged, we will revisit a
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  spotlight talk from EHA 2024. Doctor Christoph Shadda from the
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  Yagilonian University in Krakow discusses hematopoietic stem
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  cells in health, aging and malignancy, with a focus on
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  metabolism. During my last years of research
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  during PhD post docs and I was when starting my own lab, we
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  focus on hematopathic stem cells, HSCS especially we look
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  at the heterogeneity and how they age and they age in quite
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  specific way. So the first thing with time
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  this reconstitution potential of HS CS is decreasing.
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  But actually the numbers of HS CS expands and what is very
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  typical for them they show so-called myeloid bias.
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  So they are prone to deficit more to myeloid cells.
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  So there are different models that explain this.
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  One assumes that this is just the epigenetic shift and and
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  driven gene expression. The author says this is the
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  kernel selection model. So assume that there is like a
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  sub clones that are interestingly have this myeloid
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  bias deprecation program and they just are selected in aging
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  and you end up with the the myeloid bias.
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  Of course you can think of about the composite model of these two
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  and we'll get back to it today. So I want to summarize our
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  results or our findings in three different settings of HSC aging
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  and and highlight the, the, the metabolic context of it.
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  So first, the stress induced aging.
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  So we know that under pressure and stress conditions age
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  faster. This is the same with HS CS,
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  yes, the second law is called physiological aging.
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  So you, you may live in comfortable conditions, but you
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  won't escape aging. And finally, I want to, I want
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  to show how at least in short, how the HSC looks when there is
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  a malignancy in the system. So let's start with this
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  premature aging. It happens that I studied an
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  enzyme called heme oxygenase one age 1.
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  So age 1 degrades peroxidated him into the anti-inflammatory
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  products and generally thought to be cytoprotective enzymes.
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  So they look on H1 knockout mice and actually say that the in
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  already in the young animals there is expansion of the HSC
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  pool. So then when you look on
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  peripheral that you already see a general myeloid bias there.
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  And finally when we transplanted the purified HSCS we observed
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  there was the constitution there are the main symptoms of HSC
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  aging visibly already in young age 1 mice.
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  So we thought that this represents some kind of
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  premature HSC aging model. And it seems that it is really
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  even at broad transcriptional level.
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  The young HCS from knockout animals cluster together with
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  all the wild type HCS. The HC from young age of 1
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  deficient my soul already premature aging.
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  So what about the metabolism here when we do generatement
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  analysis on this young HO1 knockouts among HSCS, one of the
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  first hit was pyruvate metabolic processes.
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  So there was a beautiful paper by Tasha Sudalap showing
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  actually there is so-called glycolytic metabolic stemless
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  signature and this this depends on pyruvate crossing.
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  So pyruvate can be put to the mitohondria by PDH for the
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  Oxford respiration or by transfer by LDH to lactate in
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  glycolysis. And this glycolytic score, this
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  glycolytic path here defines this metabolic stem that they
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  show, but it's also important that the PDK's.
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  So PDK's can inhibit PDH by phosphorylation and by this
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  suppress the glycolytic metabolism influx into the
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  mitohondria. And in fact this is the PDK
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  explosion regulated really much in transcription level.
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  So it gives you opportunity to see so-called pyruvate crossol
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  gene signature. So we so we check how it looks
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  in this HO1 deficient HSCS and in fact this is the case.
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  So they don't regulate LDH and PDK 2.
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  And it seems like this pure weight in this HO1 local HSCS
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  goes more to the OXX. But actually you are able to
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  measure the ATP production among the strictly defined populations
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  and you observe that they don't use this Oxford because there's
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  actually lower, lower level of the ATP inside this H1 different
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  HSCS. This glycolytic metabolic
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  standards that is dependent on this pirate crossroad is
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  disturbed in this premature aging model of HSCS in this H1
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  local dynamics. So the next question was, is
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  that the case also during the physiological aging, But at the
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  time people already knew that this there is some heterogeneity
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  among HS CS, but there was no prospective marker to dissect
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  the central duty and study it in during aging.
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  So first thing what we did, we screen frame markers that are
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  very specific only to HS CS and among these markers to find the
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  genes that are differentially degraded during the aging.
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  And this is how we found the Neogenine 1.
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  So majority of HS CS in all the mice expands and majority of
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  them are new one positive actually the new one negative
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  HSCS in not expanded aging. So then we see what is the
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  difference between this new one plus and one negative HSCS.
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  The new one plus regulates some sort of cycle genes.
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  But the most important for us was that they do express genes
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  that are typical for mature myeloid and platelet cells.
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  We have the hinge of this clonal selection model, myeloid bias
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  that can prospectively study this.
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  So, but of course the function is the most important here.
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  When we transplant 10 cells, HSCS, new one negative or
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  positive and indeed the new one positive HSCS mostly produce
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  ground loss sites while this new one negative HSCS provide more
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  balanced output. But there was one more question
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  to say if this is really the cloud selection model here.
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  So the question was, is there any hierarchy dependencies
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  between neo one negative and positive or relief independently
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  one of each other? The proper answer would be this
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  is the composite model because we have both clonality here, but
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  also a hierarchy and genetic shift with neo one negative HSC
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  standing in the apex of this hierarchy differentiated and
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  giving rise to new one positive biased HSCS.
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  So the, the question was how the glycolytic metabolic stemness
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  look here with the within this tension between young and old.
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  To do so, we make an Atlas of aging HSC people.
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  So very, very early stages of this HSC differentiation.
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  So generally you see the clones, you see also the epigenetic
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  model and how the whole system looks regarding the pyruvate.
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  So in fact, there's no much difference between aging or neon
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  plus and negative subpopulation. So at the end, and I just want
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  to show you the last models of the old model of HSC malignancy.
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  So this is a very hot topic right now.
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  Then the prelocating HSCS and the common hematopoiesis is
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  mainly studied in context of MD's or or AML in elderly
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  people. So we did a bit different thing.
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  And so I want to show you our recent observation about HSCS.
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  But in pediatric ALS, we observed a very strange aberrant
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  basal differentiation program. But generally it's typical for
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  only for basal progenitals. But we observed that the part of
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  HSC already expressed the signature of basal
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  differentiation. And what was interesting for us
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  this, this part of HSC also expressed high glycolysis call.
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  So this I want to end. I would like to thanks all all
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  of my lab members.