Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors

Ganuza, Miguel; Hall, Trent; Myers, Jacquelyn; Nevitt, Chris; Sánchez-Lanzas, Raúl; Chabot, Ashley; Ding, Juan; Kooienga, Emilia; Caprio, Claire; Finkelstein, David; Kang, Guolian; Obeng, Esther A.; McKinney‐Freeman, Shannon

doi:10.1038/s41556-022-00999-5

Cited by 40 publications

(39 citation statements)

References 68 publications

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“…It has long been thought that HSCs expand considerably (>20‐fold in mice) during mid‐gestation, 28–30 ultimately giving rise to postnatal HSCs that sustain adult hematopoiesis 31–33 . However, a recent paper challenges this model and indicates that a majority of fetal HSCs are fated to differentiate, rather than contribute to adult hematopoiesis 34 . Short‐term engrafting MPPs have been shown to arise from hemogenic endothelium in parallel to fetal HSCs, rather than as direct descendants of HSCs 34–36 .…”

Section: Pediatric Leukemia Initiation Occurs Against a Backdrop Of N...mentioning

confidence: 99%

“…[31][32][33] However, a recent paper challenges this model and indicates that a majority of fetal HSCs are fated to differentiate, rather than contribute to adult hematopoiesis. 34 Short-term engrafting MPPs have been shown to arise from hemogenic endothelium in parallel to fetal HSCs, rather than as direct descendants of HSCs. [34][35][36] Lineage tracing experiments have shown that these MPPs can contribute to postnatal hematopoiesis.…”

Section: Intrinsic Ontological Changes In Fetal Blood Progenitors And...mentioning

confidence: 99%

“…34 Short-term engrafting MPPs have been shown to arise from hemogenic endothelium in parallel to fetal HSCs, rather than as direct descendants of HSCs. [34][35][36] Lineage tracing experiments have shown that these MPPs can contribute to postnatal hematopoiesis. 34 Thus, fetal hematopoiesis does not fully conform to a stem cell hierarchy, and several independently derived progenitor populations could potentially give rise to postnatal leukemias (Figure 1).…”

Section: Intrinsic Ontological Changes In Fetal Blood Progenitors And...mentioning

confidence: 99%

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Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

Mendoza-Castrejon

Magee

2023

Immunological Reviews

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Leukemia is the most common childhood cancer, accounting for more deaths due to disease in developed nations than any other illness. 1 While leukemias can occur at any age, the mutations that cause childhood leukemias often differ from those that cause adult leukemias. 2 Some types of leukemia, such as juvenile myelomonocytic leukemia, present almost exclusively in early childhood. 3 These observations suggest that for several leukemogenic mutations, transformation efficiency changes with age. Alternatively, age-restricted leukemias might arise from cells of origin that emerge, and then disappear, through the course of normal ontogeny. In either case, transcriptional programs that direct normal ontogeny of the immune system can substantially influence leukemogenesis.

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Section: Pediatric Leukemia Initiation Occurs Against a Backdrop Of N...mentioning

confidence: 99%

Section: Intrinsic Ontological Changes In Fetal Blood Progenitors And...mentioning

confidence: 99%

Section: Intrinsic Ontological Changes In Fetal Blood Progenitors And...mentioning

confidence: 99%

See 1 more Smart Citation

Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

Mendoza-Castrejon

Magee

2023

Immunological Reviews

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“…VECs, Vascular endothelial cells; HSCs, Hematopoietic stem cells; SCF, Stem cell factor; PTN, pleiotrophin; MDK, Midkine recent lineage tracing study suggests that many HSCs in fetal liver are biased to differentiate rather than self-renew. [49] In addition to Ng2-Cre labelled perivascular cells, VECs promote HSCs expansion in fetal liver by secreting SCF, which is regulated by a critical component of the polycomb repressive complex 2 (Ezh2). [50] Recent spatial transcriptomics analysis suggests that hepatoblasts, stromal cells, endothelial cells, and macrophages form 'pocket-like' units to constitute the fetal liver niche for HSCs.…”

Section: The Extramedullary Niche Of Hscs In Fetal and Adultmentioning

confidence: 99%

Dynamic crosstalk between hematopoietic stem cells and their niche from emergence to aging

Deng

Chen

et al. 2023

BioEssays

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The behavior of somatic stem cells is regulated by their niche. Interaction between hematopoietic stem cells (HSCs) and their niches are a representative model to understand stem cell‐niche interplay. Here, we provide an overview of crosstalk between HSCs and their niches in bone marrow and extramedullary organs following the life journey of HSCs from emergence, development, maturation until aging. We highlight the unique differences of HSC niches in different life stages within various organs focusing on recent literature to propose new speculations and hypotheses.

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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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Murine foetal liver supports limited detectable expansion of life-long haematopoietic progenitors

Cited by 40 publications

References 68 publications

Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

Layered immunity and layered leukemogenicity: Developmentally restricted mechanisms of pediatric leukemia initiation

Dynamic crosstalk between hematopoietic stem cells and their niche from emergence to aging

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

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