Developmental Biology - Hematopoietic Stem Cells|
Waves of Stem Cells Replenish Blood
Waves of hematopoietic stem cells in the late fetus and again in young adults produce blood cells...
Hematopoietic stem cells (HSCs) are responsible for the constant replenishment of all blood cells throughout life. One of the major challenges in medicine is to produce tailor-made HSCs to replace defective blood cells in patients suffering from blood related diseases, circumventing the shortage of donor HSCs available from clinics. So, to achieve controlled production of HSCs in a petri dish, a better understanding is required of where, when and how HSCs are physiologically produced in a living body.
Now, researchers from the groups of Catherine Robin (Hubrecht Institute, Utrecht, The Netherlands) and Thierry Jaffredo (UPMC, LBD IBPS, Paris, France) have found a previously unappreciated hematopoietic wave taking place in bone marrow of late fetuses and young adults. These HSCs are in the existing hemogenic endothelial cells of somites.
This transient hematopoietic wave fills in the gap between completion of embryonic blood and the beginning of adult bone marrow blood production in both chicken and mice. The results of this research were published on the fourth of November, 2019, in Nature Cell Biology.
Endothelial origin of hematopoietic stem cells
The constant production of short-lived blood cells, needed for proper oxygenation of tissues and protection against pathogens throughout life, relies on a small cohort of HSCs. The first HSCs derive from specialized endothelial cells, named hemogenic endothelial (HE) cells, via an endothelial to hematopoietic transition (EHT).
EHT transiently occurs in the main arteries, such as the aorta, during the embryonic development of vertebrates.
The pool of HSCs is then amplified before migrating to the bone marrow where HSCs will reside during adult life. Whether EHT occurs past the embryonic stage and in other organs, such as the bone marrow, was unknown until now.
Hemogenic endothelial cells in the bone marrow
To find out whether EHT occurs past the embryonic stage and into bone marrow, researchers used a combination of experimental embryology, genetic, transcriptomic and functional approaches on chicken and mouse models - tracing bone marrow-forming endothelial cells through fluorescent genetic labelling and live imaging analyses.
They found that the entire vascular network of bone marrow is derived from somites.
Somites are segments of the body that will progressively form tissues of the organism as the embryo develops, these include bones, muscles and skin.
Unexpectedly, researchers found that some somite-derived endothelial cells produce HSCs and multipotent progenitor cells in late fetus and young adult bone marrow through the same EHT process that was thus far only seen in the embryo.
These cells are molecularly very similar to the cells undergoing EHT or recently emerged HSCs in the embryonic aorta, with a prominent Notch pathway, endothelial-specific genes and transcription factors involved in EHT. The results therefore demonstrate that HSCs are newly generated past embryonic stages, from hemogenic endothelial cells from somitic origin and via EHT, the same mechanism that occurs in the embryo.
A new wave of blood cell production
The yolk sac of the embryo produces two partially overlapping waves of hematopoiesis.
• The first (primitive) wave gives rise to hematopoietic cells that last only during embryonic development:
• The second (definitive) wave produces various progenitors that migrate to the fetal liver to produce the immediate needed blood cells.
These progenitor cells are sufficient for the embryo to survive until birth, when the aorta-derived HSC-dependent wave will take over. The transient hematopoietic production discovered in the present study fills the gap between the end of the yolk sac hematopoiesis and the bone marrow HSC-dependent production of blood cells. Indeed, the pool of HSCs that expand in the fetal liver starts to colonize the bone marrow only just before birth.
HSCs are present in very low numbers and time is most likely required before they find their final adult-type niches and start to differentiate andproliferate into more committed progenitor cells and mature blood cells.
The transient hematopoietic wave that researchers describe in the late fetal and young adult stages might also prepare bone marrow niches for HSCs coming from the fetal liver.
Stem cell therapies
Defects in HSCs lead to various blood-related disorders and cancers that are partly treated by HSC transplantations. The controlled production of bona fide HSCs from pluripotent precursor cells remains very difficult to achieve in vitro in a petri dish, and therefore requires a better understanding of HSC physiologically as it occurs in the living body.
in the future, identifying all the steps of hematopoietic production and all molecular events controlling this process is fundamental to devising innovative stem cell therapies for hematopoietic disorders.
It is well established that haematopoietic stem and progenitor cells (HSPCs) are generated from a transient subset of specialized endothelial cells termed haemogenic, present in the yolk sac, placenta and aorta, through an endothelial-to-haematopoietic transition (EHT). HSPC generation via EHT is thought to be restricted to the early stages of development. By using experimental embryology and genetic approaches in birds and mice, respectively, we document here the discovery of a bone marrow haemogenic endothelium in the late fetus/young adult. These cells are capable of de novo producing a cohort of HSPCs in situ that harbour a very specific molecular signature close to that of aortic endothelial cells undergoing EHT or their immediate progenies, i.e., recently emerged HSPCs. Taken together, our results reveal that HSPCs can be generated de novo past embryonic stages. Understanding the molecular events controlling this production will be critical for devising innovative therapies.
Laurent Yvernogeau, Rodolphe Gautier, Laurence Petit, Hanane Khoury, Frédéric Relaix, Vanessa Ribes, Helen Sang, Pierre Charbord, Michèle Souyri, Catherine Robin & Thierry Jaffredo.
The authors apologize to those investigators whose important work we were unable to cite or describe due to space constraints. We thank D. Traver for critical reading of the manuscript and S. Gournet for help in image preparation. We are indebted to R. Adams for his sharing of the Tg(Cdh5Cre/ERT2) transgenic mouse line and to S. Germain for providing us with the founders. We thank the Cell Imaging and Flow Cytometry facility of the IBPS (Paris, France) for access and technical support in confocal image acquisition and the Genom’IC platform at Cochin Institute, Paris for their invaluable help with transcriptomic samples treatment. This work was supported by CNRS, UPMC, Fondation Les Treilles (L.Y.), an EMBO short-term fellowship (L.Y.), MERI and FRM PhD fellowships (H.K.) and grants from FRM (DEQ20100318258) and an ANR/CIRM joint grant (ANR/CIRM 0001–02) in T.J.’s laboratory. The production of the GFP+ chicken embryos was supported by grants from BBSRC and the Wellcome Trust. Part of the work and L.Y. were supported by a European Research Council grant (ERC, project no. 220-H75001EU/HSCOrigin-309361) and a TOP subsidy from NWO/ZonMw (912.15.017) in C.R.’s laboratory.
Return to top of page.
Dec 19 2019 Fetal Timeline Maternal Timeline News
The yolk sac of the embryo produces two partially overlapping waves of hematopoiesis. The first (primitive
) wave gives rise to hematopoietic cells that last only during embryonic development. The second (definitive
) wave produces various progenitors that migrate to the fetal liver to produce the immediately needed blood cells. CREDIT Hubrecht Institute.