Platelets or thrombocytes are small fragments of cytoplasm in the blood that derive from megakaryocytes and are vital for coagulation and innate immune protection. The ability to quickly replenish the platelet pool is crucial during an ongoing infection to minimize the risk of thrombocytopenia.
Our new paper – of which I am so proud – explores how emergency megakaryocyte output by hematopoietic stem cells (HSCs) is developmentally established. The subject of this work is uncharacteristic of our lab to say the least since we mostly work on B cells. But we have always had an interest in hematopoiesis and the fetal to adult switch in HSC behavior. Our findings identify the acquisition of megakaryocyte-specific lineage signatures as a ubiquitous trait of HSCs undergoing the fetal to adult developmental transition. In addition to being scripted at the chromatin level, this lineage priming translates into a gain of emergency megakaryopoiesis capacity in postnatal HSCs.
Mechanistically, we demonstrate that the expression of the fetal RNA binding protein Lin28b is responsible for maintaining a lineage naive HSC state. We propose that the termination of Lin28b in HSCs after birth controls a hematopoietic gear shift from prioritizing self-renewal in the fetus to increased host protection in postnatal life.
Behind the scenes, the making of this paper was challenging. In following the ATACseq data we had gone down an unfamiliar path (which to be fair is anything outside of the B cell realm for me). This was scary but greatly mitigated by Trine Kristiansen’s (postdoc and first author pictured below) independence and perseverance and her close collaboration with Jonas Ungerbäck (postdoc in collaborating Sigvardsson lab) who led the bioinformatics efforts. Not long before Trine departed from our lab for a postdoc, we were devastated to find out that our manuscript had been rejected after a long review process. After the initial letdown, we could see that we had received highly constructive feedback from the reviewers which had the potential to substantially improve the paper. Trine dusted herself off and managed to address all of the reviewers’ concerns and put together a new and improved manuscript remotely.
After many Sunday zoom meetings across time zones, I am so happy that this work has found a good home where it will contribute to the fast-evolving field of inflammation and hematopoiesis. The single cell ATACseq data on fetal and adult HSCs is beautiful and I hope people will download it to find their favorite developmentally regulated HSC signatures.
In the end, the whole experience was really rewarding. With Trine and Jonas at the helm, it chartered new territories for our lab both conceptually and technically. Ultimately, we achieved a better understanding of the maturation of the hematopoietic system and how it adapts to prepare for the threats of infections outside of the womb.
As per tradition, I have also asked the first author, Trine Kristiansen, to pen down a few thoughts on this work.
How would you explain the take home message of the paper to your grandmother?
- Blood stem cells, like us, have different behavior depending on their age. Developmentally timed cues teach blood stem cells to be ready for platelet output upon inflammation. These teachings are stored not in the code but in the configuration of the cell’s DNA.
In ten years time, which aspect of your findings do you think that peers will cite this paper for?
- That megakaryocyte priming of the HSC compartment is part of the fetal to adult developmental switch.
What is your personal favourite figure panel and why?
- I like figure 4 – linking Lin28b expression to an insulation of the stem cell compartment against inflammation induced differentiation.
Looking back at the paper and all the work that went into it, what part was your proudest accomplishment?
- I am the proudest of how the lab and our close collaborator and bioinformatics extraordinaire Jonas Ungerbäck made the single cell ATACseq experiment possible. We needed a lot of cells from different ages, and it was really a team effort to get enough material collected in a short time. (I would add that Trines coordination of this, for us, pioneering effort, was nothing but awe inspiring for me)
The project took a long time and did not at all develop as we initially envisioned. What did you learn from the whole process?
- We thought the project would take us down a lymphoid differentiation path. Instead, we followed the data, and I learned a lot about the platelet lineage that I didn’t anticipate. Pursuing phenotypes in less familiar directions brought me out of my comfort zone – which is a great opportunity to gain new perspectives.
What are you doing now?
- I am in the Scadden lab (Harvard medical school) now on a Swedish Research Council (VR) international postdoc grant. From megakaryocyte primed HSCs, I’m now starting to explore the bone marrow niche.
We miss you here at the Yuanlab, what do you miss the most about life in Lund?
- I miss the people, in the lab and department and around BMC… also the chocolate croissants from Broder Jacobs. They are perfect after a morning swim in Högevall 🙂