ISAL 2025 | Mitochondrial metabolism as a druggable driver of hematopoietic stem cell fate

My background is very much in basic stem cell biology. So what we observed previously is that when hematopoietic stem cells age, collectively the stem cell pool becomes dysfunctional and biased, and we could see that this coincides with a drop in mitochondrial activity. First, we kind of explored if this was a causal relationship. So when we see the functional defects in the stem cells, meaning they have lower repopulation capacity, they are biased towards the myeloid lineage at the expense of erythroid and lymphoid production, whether this was a causal relationship with the drop in mitochondrial parameters. So we looked at sequencing, RNA sequencing of these stem cells. And indeed, we could find that a lot of these transcriptional programs that relate to the aging phenotype are actually correlated with a lower metabolic state of these stem cells. So when we found that out, we tried to treat these aged mice with mitoquinol. This is a mitochondrial-targeted antioxidant, broadly speaking, discovered by Mike Murphy in his lab. And we could actually see that five consecutive injections of this drug could alleviate some aspects of this. And it did occur through a shift in more cells having a higher mitochondrial metabolism. This was very promising. The blood in these mice started to look a little bit better. So the lymphoid output came back a little bit. The myeloid output was reduced. When we gave this in a drinking water-soluble form over a longer time, we could also see that the anemia wasn’t that strong. But importantly, we wanted to see if there was rescue in the stem cells. So first looking again at these transcriptomes, we could see that there was a shift towards a younger transcriptome. And when we transplanted these cells, they indeed performed a bit better after they had MitoQ treatment in the original aged mice compared to the untreated aged mice. So this was super promising. And this is all published work. What we’ve tried to do with that recently is look at other contexts of premature aging, so not chronological aging, and one of those is hematopoietic aging after chemotherapy treatment. So, of course, chemotherapy is still very commonly used in the clinic, and the biggest focus, of course, is on disease eradication, but we also see that it has significant long-term impact on the normal hematopoietic system. So herein we see that even young mice with chemotherapy treatment really show exactly the same signs as normal chronological aging in the blood and in the bone marrow and in the stem cells. So again, in this context of 5-FU treatment, which is not commonly used in liquid malignancies, but of course in solid tumors, we could see that the hematopoietic system really ages quite rapidly and if you give MitoQ treatment to these mice again we can rescue some aspects of this so this is still unpublished we’re trying to see what the mechanism is behind this but we think it’s a promising work.

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