Independent origins of fetal liver haematopoietic stem and progenitor cells

Yokomizo, Tomomasa; Ideue, Takako; Morino-Koga, Saori; Tham, Cheng Yong; Sato, Tomohiko; Takeda, Nobuo; Kubota, Yoshiaki; Kurokawa, Mineo; Komatsu, Norio; Ogawa, Michio; Araki, Kimi; Osato, Motomi; Suda, Toshio

doi:10.1038/s41586-022-05203-0

Cited by 88 publications

(82 citation statements)

References 60 publications

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“…Our findings support the notion that embryos show a sequential emergence of hematopoietic waves to ensure the abundance of macrophages required for tissue homeostasis and regeneration during a crucial developmental time window. In line with our results, it has been recently reported in mice (Gomez Perdiguero et al, 2015; Patel et al, 2022; Yokomizo et al, 2022; Fanti et al, 2023) and in zebrafish (Tian et al, 2017; Ulloa et al, 2021) that embryonic and adult HSCs do not give rise to several blood subtypes at steady state, upon ablation of mature blood cells, and in response to immune challenge. These observations indicate that ensuring a rapid response to stress to maintain tissue homeostasis in an HSC-independent manner might be a conserved mechanism between species throughout their life.…”

Section: Resultssupporting

confidence: 93%

Homogenic endothelium-independent hematopoiesis ensures the abundance of erythrocytes and macrophages during zebrafish development.

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Mikdache

Diabangouaya

et al. 2023

Preprint

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In all organisms studied, from flies to humans, blood cells emerge in several sequential waves and from distinct hematopoietic origins. However, the relative contribution of these ontogenetically distinct hematopoietic waves to embryonic blood lineages and to tissue regeneration during development is yet elusive. Here, using a lineage-specific switch and trace strategy in the zebrafish embryo, we report that the definitive hematopoietic progeny barely contributes to erythrocytes and macrophages during early development. Lineage tracing further show that ontogenetically distinct macrophages exhibit differential recruitment to the site of injury based on the developmental stage of the organism. We further demonstrate that primitive macrophages can solely maintain tissue regeneration during early larval developmental stages after selective ablation of definitive macrophages. Our findings highlight that the sequential emergence of hematopoietic waves in embryos ensures the abundance of blood cells required for tissue homeostasis and integrity during development.

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Section: Resultssupporting

confidence: 93%

Homogenic endothelium-independent hematopoiesis ensures the abundance of erythrocytes and macrophages during zebrafish development.

Elsaid

Mikdache

Diabangouaya

et al. 2023

Preprint

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“…It has recently been shown that in early embryonic development Evi1-high cells are predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs(Yokomizo et al, 2022). Based on this report and the prediction of LSM model, we proposed that Evi1-high precursors in adult murine BM are true functional HSCs.…”

Section: Resultsmentioning

confidence: 99%

“…It has recently been shown that in early embryonic development Evi1-high cells are predominantly localized to intra-embryonic arteries and preferentially giving rise to HSCs (22).…”

Section: Cellular Features Extracted By Lsm Model Are Intrinsic To Hscsmentioning

confidence: 99%

Deep learning-based predictive identification of functional subpopulations of hematopoietic stem cells and multipotent progenitors

Wang

Han

Huang

et al. 2022

Preprint

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Hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) are crucial for maintaining lifelong hematopoiesis. Developing methods to distinguish stem cells from other progenitors and evaluate stem cell functions has been a central task in stem cell research. Deep learning has been demonstrated as a powerful tool in cell image analysis and classification. In this study, we explored the possibility of using deep learning to differentiate HSCs and MPPs based on their light microscopy (DIC) images. After extensive training and validation with large image data sets, we successfully develop a three-class classifier (we named it LSM model) that reliably differentiate long-term HSCs (LT-HSCs), short-term HSCs (ST-HSCs), and MPPs. Importantly, we demonstrated that our LSM model achieved its differentiating capability by learning the intrinsic morphological features from cell images. Furthermore, we showed that the performance of our LSM model was not affected by how these cells were identified and isolated, i.e., sorted by surface markers or intracellular GFP markers. Prospective identification of HSCs and MPPs in Evi1GFP transgenic mice by our LSM model suggested that the cells with the highest GFP expression were LT-HSCs, and this prediction was substantiated later by a long-term competitive reconstitution assay. Moreover, based on DIC image data sets, we also successfully built another two-class classifier that can effectively distinguish aged HSCs from young HSCs, which both express same surface markers but functionally different. This finding is of particular interest since it may provide a novel quick and efficient approach, obviating the need for a time-consuming transplantation experiment, to evaluate functional states of HSCs. Together, our study provides evidence for the first time that HSCs and MPPs can be differentiated by deep learning based on cell morphology. This novel and robust deep-learning-based platform will provide a basis for the future development of a new-generation stem cell identification and separation system. It may also provide new insight into molecular mechanism underlying self-renewal feature of stem cell.

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“…From the AGM, the first HSCs migrate to the FL by E12.5 to amplify and acquire an adult HSCs phenotype (Mahony and Bertrand, 2019). Recent studies indicate that (LT) HSC and HPCs fate is already segregated in the AGM, and that the fetal liver merely serves as a niche for their modest amplification as separate populations (Patel et al, 2022;Yokomizo et al, 2022;Ganuza et al, 2022). Within this context, LT-HSCs are generated as a safeguard pool of cells from the first stages of development, but signaling pathways that allow this segregation and how these LT-HSCs preprint (which was not certified by peer review) is the author/funder.…”

Section: Introductionmentioning

confidence: 99%

IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid

Thambyrajah

Fadlullah

Proffitt

et al. 2022

Preprint

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Recent findings are challenging the classical hematopoietic model in which long-term hematopoietic stem cells (LT-HSC) are the base of the hematopoietic system. Clonal dynamics analysis of the hematopoietic system indicate that LT-HSC are not the main contributors of normal hemapoiesis in physiological conditions and the hematopoietic system is mainly maintained by multipotent progenitors (MPPs, hereafter HPC) and LT-HSCs are mostly in a non-active state. The first HSCs emerge from the aorta-gonad and mesonephros (AGM) region along with hematopoietic progenitors (HPC) within hematopoietic clusters. Molecular pathways that determine the HSC fate instead of HPC are still unknown, although inflammatory signaling, including NF-ΚB has been implicated in the development of HSCs. Here, we identify a chromatin binding function for IΚBα (also known as the inhibitor of NF-ΚB) that is Polycomb repression complex 2 (PRC2)- dependent and specifically determines dormant vs proliferating HSCs from the onset of their emergence in the AGM. We find a specific reduction of LT-HSCs in the IΚBα knockout new-born pups. This defect is manifested at the FL stage already, and traceable to the first emerging HSCs in the E11.5 AGM, without affecting the general HPC population. IΚBα-deficient LT-HSCs express dormancy signature genes, are less proliferative and can robustly respond to activation stimuli such asin vitroculture and serial transplantation. At the molecular level, we find decreased PRC2-dependent H3K27me3 at the promoters of several retinoic acid signaling elements in the IΚBα- deficient aortic endothelium and E14.5 FL LT-HSCs. Additionally, IΚBα binding itself is found in the promoters of retinoic acid receptors rarα in the AGM, and rarγ in the LT-HSC of FL. Overall, we demonstrate that the retinoic acid pathway is over-activated in the hematopoietic clusters of IΚBα-deficient AGMs leading to premature dormancy of LT- HSCs that persists in the FL LT-HSCs.

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Independent origins of fetal liver haematopoietic stem and progenitor cells

Cited by 88 publications

References 60 publications

Homogenic endothelium-independent hematopoiesis ensures the abundance of erythrocytes and macrophages during zebrafish development.

Homogenic endothelium-independent hematopoiesis ensures the abundance of erythrocytes and macrophages during zebrafish development.

Deep learning-based predictive identification of functional subpopulations of hematopoietic stem cells and multipotent progenitors

IκBα controls dormancy induction in Hematopoietic stem cell development via retinoic acid

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