Skip to main content

Advertisement

SpringerLink
Log in

The Fetal-to-Adult Hematopoietic Stem Cell Transition and its Role in Childhood Hematopoietic Malignancies

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Abstract

As with most organ systems that undergo continuous generation and maturation during the transition from fetal to adult life, the hematopoietic and immune systems also experience dynamic changes. Such changes lead to many unique features in blood cell function and immune responses in early childhood. The blood cells and immune cells in neonates are a mixture of fetal and adult origin due to the co-existence of both fetal and adult types of hematopoietic stem cells (HSCs) and progenitor cells (HPCs). Fetal blood and immune cells gradually diminish during maturation of the infant and are almost completely replaced by adult types of cells by 3 to 4 weeks after birth in mice. Such features in early childhood are associated with unique features of hematopoietic and immune diseases, such as leukemia, at these developmental stages. Therefore, understanding the cellular and molecular mechanisms by which hematopoietic and immune changes occur throughout ontogeny will provide useful information for the study and treatment of pediatric blood and immune diseases. In this review, we summarize the most recent studies on hematopoietic initiation during early embryonic development, the expansion of both fetal and adult types of HSCs and HPCs in the fetal liver and fetal bone marrow stages, and the shift from fetal to adult hematopoiesis/immunity during neonatal/infant development. We also discuss the contributions of fetal types of HSCs/HPCs to childhood leukemias.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AGM:

Aorta-gonad-mesonephros

Angptl2:

Angiopoietin-like 2

AMkL:

Acute megakaryocytic type

AML:

Acute myeloid leukemia

ALL:

Acute lymphoblastic type

BM:

Bone marrow

CSF1:

Colony-stimulating factor 1

CXCL12:

C-X-C Motif Chemokine Ligand 12

drHSCs:

Developmentally-restricted HSCs

DS:

Down Syndrome

E:

Embryonic day

ECs:

Endothelial cells

EPO:

Erythropoietin

EMPs:

Erythro-myeloid progenitors

ECM:

Extracellular matrix

FL:

Fetal liver

HSCs:

Hematopoietic stem cells

HPCs:

Hematopoietic progenitor cells

Hb:

Hemoglobin

imHSCs:

Immature HSC

IGF2:

Insulin-like growth factor 2

IL:

Interleukin

IFN:

Interferon

KITL:

KIT ligand

LMPs:

Lympho-myeloid progenitors

Mφs:

Macrophages

Mks:

Megakaryocytes

MLL:

Mixed lineage leukemia

ELPs:

Early lymphoid progenitors

PB:

Peripheral blood

PCW:

Post-conception weeks

pri-EPs:

Primitive erythroid progenitors

RBCs:

Red blood cells

THPO:

Thrombopoietin

TSLP:

Thymic stromal-derived lymphopoietin

TMD:

Transient myeloproliferative disorder

vWF:

von Willebrand factor

YS:

Yolk Sac

References

  1. Kikuchi, K., & Kondo, M. (2006). Developmental switch of mouse hematopoietic stem cells from fetal to adult type occurs in bone marrow after birth. Proceedings of the National Academy of Sciences, 103(47), 17852–17857.

    Article  CAS  Google Scholar 

  2. Bowie, M. B., Kent, D. G., Dykstra, B., McKnight, K. D., McCaffrey, L., Hoodless, P. A., & Eaves, C. J. (2007). Identification of a new intrinsically timed developmental checkpoint that reprograms key hematopoietic stem cell properties. Proceedings of the National Academy of Sciences, 104(14), 5878–5882.

    Article  CAS  Google Scholar 

  3. Bowie, M. B., McKnight, K. D., Kent, D. G., McCaffrey, L., Hoodless, P. A., & Eaves, C. J. (2006). Hematopoietic stem cells proliferate until after birth and show a reversible phase-specific engraftment defect. The Journal of Clinical Investigation, 116(10), 2808–2816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gothert, J. R., Gustin, S. E., Hall, M. A., Green, A. R., Gottgens, B., Izon, D. J., & Begley, C. G. (2005). In vivo fate-tracing studies using the Scl stem cell enhancer: Embryonic hematopoietic stem cells significantly contribute to adult hematopoiesis. Blood, 105(7), 2724–2732.

    Article  PubMed  CAS  Google Scholar 

  5. Morrison, S. J., Hemmati, H. D., Wandycz, A. M., & Weissman, I. L. (1995). The purification and characterization of fetal liver hematopoietic stem cells. Proceedings of the National Academy of Sciences, 92(22), 10302–10306.

    Article  CAS  Google Scholar 

  6. Yuan, J., Nguyen, C. K., Liu, X., Kanellopoulou, C., & Muljo, S. A. (2012). Lin28b reprograms adult bone marrow hematopoietic progenitors to mediate fetal-like lymphopoiesis. Science, 335(6073), 1195–1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Copley, M. R., Babovic, S., Benz, C., Knapp, D. J., Beer, P. A., Kent, D. G., Wohrer, S., Treloar, D. Q., Day, C., Rowe, K., et al. (2013). The Lin28b-let-7-Hmga2 axis determines the higher self-renewal potential of fetal haematopoietic stem cells. Nature Cell Biology, 15(8), 916–925.

    Article  CAS  PubMed  Google Scholar 

  8. Benz, C., Copley, M. R., Kent, D. G., Wohrer, S., Cortes, A., Aghaeepour, N., Ma, E., Mader, H., Rowe, K., Day, C., et al. (2012). Hematopoietic stem cell subtypes expand differentially during development and display distinct lymphopoietic programs. Cell Stem Cell, 10(3), 273–283.

    Article  CAS  PubMed  Google Scholar 

  9. Ghosn, E. E., Yamamoto, R., Hamanaka, S., Yang, Y., Herzenberg, L. A., Nakauchi, H., & Herzenberg, L. A. (2012). Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells. Proceedings of the National Academy of Sciences, 109(14), 5394–5398.

    Article  CAS  Google Scholar 

  10. Barber, C. L., Montecino-Rodriguez, E., & Dorshkind, K. (2011). Reduced production of B-1-specified common lymphoid progenitors results in diminished potential of adult marrow to generate B-1 cells. Proceedings of the National Academy of Science, 108(33), 13700–13704.

    Article  CAS  Google Scholar 

  11. Yan, H., Hale, J., Jaffray, J., Li, J., Wang, Y., Huang, Y., An, X., Hillyer, C., Wang, N., Kinet, S., et al. (2018). Developmental differences between neonatal and adult human erythropoiesis. American Journal of Hematology, 93(4), 494–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Birger, Y., Goldberg, L., Chlon, T. M., Goldenson, B., Muler, I., Schiby, G., Jacob-Hirsch, J., Rechavi, G., Crispino, J. D., & Izraeli, S. (2013). Perturbation of fetal hematopoiesis in a mouse model of Down syndrome’s transient myeloproliferative disorder. Blood, 122(6), 988–998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Okeyo-Owuor, T., Li, Y., Patel, R. M., Yang, W., Casey, E. B., Cluster, A. S., Porter, S. N., Bryder, D., & Magee, J. A. (2019). The efficiency of murine MLL-ENL-driven leukemia initiation changes with age and peaks during neonatal development. Blood advances, 3(15), 2388–2399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Porter, S. N., Cluster, A. S., Yang, W., Busken, K. A., Patel, R. M., Ryoo, J., & Magee, J. A. (2016). Fetal and neonatal hematopoietic progenitors are functionally and transcriptionally resistant to Flt3-ITD mutations. eLife, 5, e18882.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li, Y., Kong, W., Yang, W., Patel, R. M., Casey, E. B., Okeyo-Owuor, T., White, J. M., Porter, S. N., Morris, S. A., & Magee, J. A. (2020). Single-cell analysis of neonatal HSC ontogeny reveals gradual and uncoordinated transcriptional reprogramming that begins before birth. Cell Stem Cell, 27(5), 732-747 e737.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Parekh, C., & Crooks, G. M. (2013). Critical differences in hematopoiesis and lymphoid development between humans and mice. Journal of Clinical Immunology, 33(4), 711–715.

    Article  CAS  PubMed  Google Scholar 

  17. Ivanovs, A., Rybtsov, S., Ng, E. S., Stanley, E. G., Elefanty, A. G., & Medvinsky, A. (2017). Human haematopoietic stem cell development: From the embryo to the dish. Development, 144(13), 2323–2337.

    Article  CAS  PubMed  Google Scholar 

  18. Bertrand, J. Y., Jalil, A., Klaine, M., Jung, S., Cumano, A., & Godin, I. (2005). Three pathways to mature macrophages in the early mouse yolk sac. Blood, 106(9), 3004–3011.

    Article  CAS  PubMed  Google Scholar 

  19. McGrath, K. E., Frame, J. M., Fegan, K. H., Bowen, J. R., Conway, S. J., Catherman, S. C., Kingsley, P. D., Koniski, A. D., & Palis, J. (2015). Distinct sources of hematopoietic progenitors emerge before HSCs and provide functional blood cells in the mammalian embryo. Cell reports, 11(12), 1892–1904.

    Article  CAS  PubMed  Google Scholar 

  20. Palis, J., Robertson, S., Kennedy, M., Wall, C., & Keller, G. (1999). Development of erythroid and myeloid progenitors in the yolk sac and embryo proper of the mouse. Development, 126(22), 5073–5084.

    Article  CAS  PubMed  Google Scholar 

  21. Kingsley, P. D., Malik, J., Emerson, R. L., Bushnell, T. P., McGrath, K. E., Bloedorn, L. A., Bulger, M., & Palis, J. (2006). “Maturational” globin switching in primary primitive erythroid cells. Blood, 107(4), 1665–1672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tober, J., Koniski, A., McGrath, K. E., Vemishetti, R., Emerson, R., de Mesy-Bentley, K. K., Waugh, R., & Palis, J. (2007). The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood, 109(4), 1433–1441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Frame, J. M., Fegan, K. H., Conway, S. J., McGrath, K. E., & Palis, J. (2016). Definitive hematopoiesis in the yolk sac emerges from wnt-responsive hemogenic endothelium independently of circulation and arterial identity. Stem Cells, 34(2), 431–444.

    Article  CAS  PubMed  Google Scholar 

  24. Boiers, C., Carrelha, J., Lutteropp, M., Luc, S., Green, J. C., Azzoni, E., Woll, P. S., Mead, A. J., Hultquist, A., Swiers, G., et al. (2013). Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells. Cell Stem Cell, 13(5), 535–548.

    Article  PubMed  CAS  Google Scholar 

  25. Inlay, M. A., Serwold, T., Mosley, A., Fathman, J. W., Dimov, I. K., Seita, J., & Weissman, I. L. (2014). Identification of multipotent progenitors that emerge prior to hematopoietic stem cells in embryonic development. Stem cell reports, 2(4), 457–472.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Kasaai, B., Caolo, V., Peacock, H. M., Lehoux, S., Gomez-Perdiguero, E., Luttun, A., & Jones, E. A. (2017). Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling. Scientific Reports, 7, 43817.

    Article  PubMed  PubMed Central  Google Scholar 

  27. McGrath, K. E., Frame, J. M., & Palis, J. (2015). Early hematopoiesis and macrophage development. Seminars in Immunology, 27(6), 379–387.

    Article  CAS  PubMed  Google Scholar 

  28. Gentek, R., Ghigo, C., Hoeffel, G., Bulle, M. J., Msallam, R., Gautier, G., Launay, P., Chen, J., Ginhoux, F., & Bajenoff, M. (2018). Hemogenic endothelial fate mapping reveals dual developmental origin of mast cells. Immunity, 48(6), 1160-1171 e1165.

    Article  CAS  PubMed  Google Scholar 

  29. Dege, C., Fegan, K. H., Creamer, J. P., Berrien-Elliott, M. M., Luff, S. A., Kim, D., Wagner, J. A., Kingsley, P. D., McGrath, K. E., Fehniger, T. A., et al. (2020). Potently cytotoxic natural killer cells initially emerge from Erythro-Myeloid progenitors during mammalian development. Developmental Cell, 53(2), 229-239 e227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li, Z., Liu, S., Xu, J., Zhang, X., Han, D., Liu, J., Xia, M., Yi, L., Shen, Q., Xu, S., et al. (2018). Adult connective tissue-resident mast cells originate from late erythro-myeloid progenitors. Immunity, 49(4), 640-653 e645.

    Article  CAS  PubMed  Google Scholar 

  31. Schneider, C., Lee, J., Koga, S., Ricardo-Gonzalez, R. R., Nussbaum, J. C., Smith, L. K., Villeda, S. A., Liang, H. E., & Locksley, R. M. (2019). Tissue-Resident Group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming. Immunity, 50(6), 1425-1438 e1425.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gentek, R., Ghigo, C., Hoeffel, G., Jorquera, A., Msallam, R., Wienert, S., Klauschen, F., Ginhoux, F., & Bajenoff, M. (2018). Epidermal gammadelta T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult. Journal of Experimental Medicine, 215(12), 2994–3005.

    Article  CAS  Google Scholar 

  33. McGrath, K. E., Frame, J. M., Fromm, G. J., Koniski, A. D., Kingsley, P. D., Little, J., Bulger, M., & Palis, J. (2011). A transient definitive erythroid lineage with unique regulation of the beta-globin locus in the mammalian embryo. Blood, 117(17), 4600–4608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bian, Z., Gong, Y., Huang, T., Lee, C. Z. W., Bian, L., Bai, Z., Shi, H., Zeng, Y., Liu, C., He, J., et al. (2020). Deciphering human macrophage development at single-cell resolution. Nature, 582(7813), 571–576.

    Article  CAS  PubMed  Google Scholar 

  35. Popescu, D. M., Botting, R. A., Stephenson, E., Green, K., Webb, S., Jardine, L., Calderbank, E. F., Polanski, K., Goh, I., Efremova, M., et al. (2019). Decoding human fetal liver haematopoiesis. Nature, 574(7778), 365–371.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Werner, Y., Mass, E., Ashok Kumar, P., Ulas, T., Handler, K., Horne, A., Klee, K., Lupp, A., Schutz, D., Saaber, F., et al. (2020). Cxcr4 distinguishes HSC-derived monocytes from microglia and reveals monocyte immune responses to experimental stroke. Nature Neuroscience, 23(3), 351–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yoshimoto, M., Porayette, P., Glosson, N. L., Conway, S. J., Carlesso, N., Cardoso, A. A., Kaplan, M. H., & Yoder, M. C. (2012). Autonomous murine T-cell progenitor production in the extra-embryonic yolk sac before HSC emergence. Blood, 119(24), 5706–5714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lin, Y., Kobayashi, M., Azevedo Portilho, N., Mishra, A., Gao, H., Liu, Y., Wenzel, P., Davis, B., Yoder, M. C., & Yoshimoto, M. (2019). Long-term engraftment of ESC-Derived B-1 progenitor cells supports HSC-independent lymphopoiesis. Stem cell reports, 12(3), 572–583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Luis, T. C., Luc, S., Mizukami, T., Boukarabila, H., Thongjuea, S., Woll, P. S., Azzoni, E., Giustacchini, A., Lutteropp, M., Bouriez-Jones, T., et al. (2016). Initial seeding of the embryonic thymus by immune-restricted lympho-myeloid progenitors. Nature Immunology, 17(12), 1424–1435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Beaudin, A. E., Boyer, S. W., Perez-Cunningham, J., Hernandez, G. E., Derderian, S. C., Jujjavarapu, C., Aaserude, E., MacKenzie, T., & Forsberg, E. C. (2016). A transient developmental hematopoietic stem cell gives rise to innate-like B and T Cells. Cell Stem Cell, 19(6), 768–783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Adolfsson, J., Mansson, R., Buza-Vidas, N., Hultquist, A., Liuba, K., Jensen, C. T., Bryder, D., Yang, L., Borge, O. J., Thoren, L. A., et al. (2005). Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell, 121(2), 295–306.

    Article  CAS  PubMed  Google Scholar 

  42. Yamane, T., Hosen, N., Yamazaki, H., & Weissman, I. L. (2009). Expression of AA4.1 marks lymphohematopoietic progenitors in early mouse development. Proceedings of the National Academy of Sciences U S A, 106(22), 8953–8958.

    Article  CAS  Google Scholar 

  43. Ito, C., Yamazaki, H., & Yamane, T. (2013). Earliest hematopoietic progenitors at embryonic day 9 preferentially generate B-1 B cells rather than follicular B or marginal zone B cells. Biochemical and Biophysical Research Communications, 437(2), 307–313.

    Article  CAS  PubMed  Google Scholar 

  44. Yamane, T., Ito, C., Washino, A., Isono, K., & Yamazaki, H. (2017). Repression of primitive erythroid program is critical for the initiation of multi-lineage hematopoiesis in mouse development. Journal of Cellular Physiology, 232(2), 323–330.

    Article  CAS  PubMed  Google Scholar 

  45. Medvinsky, A., & Dzierzak, E. (1996). Definitive hematopoiesis is autonomously initiated by the AGM region. Cell, 86(6), 897–906.

    Article  CAS  PubMed  Google Scholar 

  46. North, T. E., de Bruijn, M. F., Stacy, T., Talebian, L., Lind, E., Robin, C., Binder, M., Dzierzak, E., & Speck, N. A. (2002). Runx1 expression marks long-term repopulating hematopoietic stem cells in the midgestation mouse embryo. Immunity, 16(5), 661–672.

    Article  CAS  PubMed  Google Scholar 

  47. Bertrand, J. Y., Chi, N. C., Santoso, B., Teng, S., Stainier, D. Y., & Traver, D. (2010). Haematopoietic stem cells derive directly from aortic endothelium during development. Nature, 464(7285), 108–111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Boisset, J. C., van Cappellen, W., Andrieu-Soler, C., Galjart, N., Dzierzak, E., & Robin, C. (2010). In vivo imaging of haematopoietic cells emerging from the mouse aortic endothelium. Nature, 464(7285), 116–120.

    Article  CAS  PubMed  Google Scholar 

  49. Chen, M. J., Yokomizo, T., Zeigler, B. M., Dzierzak, E., & Speck, N. A. (2009). Runx1 is required for the endothelial to haematopoietic cell transition but not thereafter. Nature, 457(7231), 887–891.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Eilken, H. M., Nishikawa, S., & Schroeder, T. (2009). Continuous single-cell imaging of blood generation from haemogenic endothelium. Nature, 457(7231), 896–900.

    Article  CAS  PubMed  Google Scholar 

  51. Lancrin, C., Sroczynska, P., Stephenson, C., Allen, T., Kouskoff, V., & Lacaud, G. (2009). The haemangioblast generates haematopoietic cells through a haemogenic endothelium stage. Nature, 457(7231), 892–895.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zovein, A. C., Hofmann, J. J., Lynch, M., French, W. J., Turlo, K. A., Yang, Y., Becker, M. S., Zanetta, L., Dejana, E., Gasson, J. C., et al. (2008). Fate tracing reveals the endothelial origin of hematopoietic stem cells. Cell Stem Cell, 3(6), 625–636.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Schulz, C., Gomez Perdiguero, E., Chorro, L., Szabo-Rogers, H., Cagnard, N., Kierdorf, K., Prinz, M., Wu, B., Jacobsen, S. E., Pollard, J. W., et al. (2012). A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science, 336(6077), 86–90.

    Article  CAS  PubMed  Google Scholar 

  54. Tober, J., McGrath, K. E., & Palis, J. (2008). Primitive erythropoiesis and megakaryopoiesis in the yolk sac are independent of c-myb. Blood, 111(5), 2636–2639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rybtsov, S., Sobiesiak, M., Taoudi, S., Souilhol, C., Senserrich, J., Liakhovitskaia, A., Ivanovs, A., Frampton, J., Zhao, S., & Medvinsky, A. (2011). Hierarchical organization and early hematopoietic specification of the developing HSC lineage in the AGM region. Journal of Experimental Medicine, 208(6), 1305–1315.

    Article  CAS  Google Scholar 

  56. Rybtsov, S., Batsivari, A., Bilotkach, K., Paruzina, D., Senserrich, J., Nerushev, O., & Medvinsky, A. (2014). Tracing the origin of the HSC hierarchy reveals an SCF-dependent, IL-3-independent CD43(-) embryonic precursor. Stem Cell Reports, 3(3), 489–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rybtsov, S., Ivanovs, A., Zhao, S., & Medvinsky, A. (2016). Concealed expansion of immature precursors underpins acute burst of adult HSC activity in foetal liver. Development, 143(8), 1284–1289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Ye, H., Wang, X., Li, Z., Zhou, F., Li, X., Ni, Y., Zhang, W., Tang, F., Liu, B., & Lan, Y. (2017). Clonal analysis reveals remarkable functional heterogeneity during hematopoietic stem cell emergence. Cell Research, 27(8), 1065–1068.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ganuza, M., Hall, T., Finkelstein, D., Chabot, A., Kang, G., & McKinney-Freeman, S. (2017). Lifelong haematopoiesis is established by hundreds of precursors throughout mammalian ontogeny. Nature Cell Biology, 19(10), 1153–1163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Henninger, J., Santoso, B., Hans, S., Durand, E., Moore, J., Mosimann, C., Brand, M., Traver, D., & Zon, L. (2017). Clonal fate mapping quantifies the number of haematopoietic stem cells that arise during development. Nature Cell Biology, 19(1), 17–27.

    Article  CAS  PubMed  Google Scholar 

  61. Pronk, C. J., Rossi, D. J., Mansson, R., Attema, J. L., Norddahl, G. L., Chan, C. K., Sigvardsson, M., Weissman, I. L., & Bryder, D. (2007). Elucidation of the phenotypic, functional, and molecular topography of a myeloerythroid progenitor cell hierarchy. Cell Stem Cell, 1(4), 428–442.

    Article  CAS  PubMed  Google Scholar 

  62. Gekas, C., Dieterlen-Lievre, F., Orkin, S. H., & Mikkola, H. K. (2005). The placenta is a niche for hematopoietic stem cells. Developmental Cell, 8, 365–375.

    Article  CAS  PubMed  Google Scholar 

  63. Robin, C., Bollerot, K., Mendes, S., Haak, E., Crisan, M., Cerisoli, F., Lauw, I., Kaimakis, P., Jorna, R., Vermeulen, M., et al. (2009). Human placenta is a potent hematopoietic niche containing hematopoietic stem and progenitor cells throughout development. Cell Stem Cell, 5(4), 385–395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ottersbach, K., & Dzierzak, E. (2005). The murine placenta contains hematopoietic stem cells within the vascular labyrinth region. Developmental Cell, 8(3), 377–387.

    Article  CAS  PubMed  Google Scholar 

  65. Barcena, A., Muench, M. O., Kapidzic, M., & Fisher, S. J. (2009). A new role for the human placenta as a hematopoietic site throughout gestation. Reproductive Sciences, 16(2), 178–187.

    Article  PubMed  Google Scholar 

  66. Barcena, A., Kapidzic, M., Muench, M. O., Gormley, M., Scott, M. A., Weier, J. F., Ferlatte, C., & Fisher, S. J. (2009). The human placenta is a hematopoietic organ during the embryonic and fetal periods of development. Developmental Biology, 327(1), 24–33.

    Article  CAS  PubMed  Google Scholar 

  67. Rhodes, K. E., Gekas, C., Wang, Y., Lux, C. T., Francis, C. S., Chan, D. N., Conway, S., Orkin, S. H., Yoder, M. C., & Mikkola, H. K. (2008). The emergence of hematopoietic stem cells is initiated in the placental vasculature in the absence of circulation. Cell Stem Cell, 2(3), 252–263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Mucenski, M. L., McLain, K., Kier, A. B., Swerdlow, S. H., Schreiner, C. M., Miller, T. A., Pietryga, D. W., Scott, W. J., Jr., & Potter, S. S. (1991). A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell, 65(4), 677–689.

    Article  CAS  PubMed  Google Scholar 

  69. Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S., Mehler, M. F., Conway, S. J., Ng, L. G., Stanley, E. R., et al. (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science, 330(6005), 841–845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sheng, J., Ruedl, C., & Karjalainen, K. (2015). Most tissue-resident macrophages except microglia are derived from fetal hematopoietic stem cells. Immunity, 43(2), 382–393.

    Article  CAS  PubMed  Google Scholar 

  71. Samokhvalov, I. M., Samokhvalova, N. I., & Nishikawa, S. (2007). Cell tracing shows the contribution of the yolk sac to adult haematopoiesis. Nature, 446(7139), 1056–1061.

    Article  CAS  PubMed  Google Scholar 

  72. Lux, C. T., Yoshimoto, M., McGrath, K., Conway, S. J., Palis, J., & Yoder, M. C. (2008). All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood, 111(7), 3435–3438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gomez Perdiguero, E., Klapproth, K., Schulz, C., Busch, K., Azzoni, E., Crozet, L., Garner, H., Trouillet, C., de Bruijn, M. F., Geissmann, F., et al. (2015). Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature, 518(7540), 547–551.

    Article  PubMed  CAS  Google Scholar 

  74. Kashem, S. W., Haniffa, M., & Kaplan, D. H. (2017). Antigen-Presenting Cells in the Skin. Annual Review of Immunology, 35, 469–499.

    Article  CAS  PubMed  Google Scholar 

  75. Ayres-Silva Jde, P., Manso, P. P., Madeira, M. R., Pelajo-Machado, M., & Lenzi, H. L. (2011). Sequential morphological characteristics of murine fetal liver hematopoietic microenvironment in Swiss Webster mice. Cell and Tissue Research, 344(3), 455–469.

    Article  PubMed  Google Scholar 

  76. Miles, C., Sanchez, M. J., Sinclair, A., & Dzierzak, E. (1997). Expression of the Ly-6.E1 (Sca-1) transgene in adult hematopoietic stem cells and the developing mouse embryo. Development, 124(2), 537–547.

    Article  CAS  PubMed  Google Scholar 

  77. Brouard, N., Jost, C., Matthias, N., Albrecht, C., Egard, S., Gandhi, P., Strassel, C., Inoue, T., Sugiyama, D., Simmons, P. J., et al. (2017). A unique microenvironment in the developing liver supports the expansion of megakaryocyte progenitors. Blood Advances, 1(21), 1854–1866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Soares-da-Silva F., Freyer L., Elsaid R., Burlen-Defranoux O., Iturri L., Sismeiro O., Pinto-do O. P., Gomez-Perdiguero E., Cumano A. (2021) Yolk sac, but not hematopoietic stem cell-derived progenitors, sustain erythropoiesis throughout murine embryonic life. Journal of Experimental Medicine, 218(4).

  79. Chen, M. J., Li, Y., De Obaldia, M. E., Yang, Q., Yzaguirre, A. D., Yamada-Inagawa, T., Vink, C. S., Bhandoola, A., Dzierzak, E., & Speck, N. A. (2011). Erythroid/myeloid progenitors and hematopoietic stem cells originate from distinct populations of endothelial cells. Cell Stem Cell, 9(6), 541–552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Travnickova, J., Tran Chau, V., Julien, E., Mateos-Langerak, J., Gonzalez, C., Lelievre, E., Lutfalla, G., Tavian, M., & Kissa, K. (2015). Primitive macrophages control HSPC mobilization and definitive haematopoiesis. Nature Communications, 6, 6227.

    Article  PubMed  CAS  Google Scholar 

  81. Stremmel, C., Schuchert, R., Wagner, F., Thaler, R., Weinberger, T., Pick, R., Mass, E., Ishikawa-Ankerhold, H. C., Margraf, A., Hutter, S., et al. (2018). Yolk sac macrophage progenitors traffic to the embryo during defined stages of development. Nature Communications, 9(1), 75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Espin-Palazon, R., Stachura, D. L., Campbell, C. A., Garcia-Moreno, D., Del Cid, N., Kim, A. D., Candel, S., Meseguer, J., Mulero, V., & Traver, D. (2014). Proinflammatory signaling regulates hematopoietic stem cell emergence. Cell, 159(5), 1070–1085.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, L. K., Ghorbanian, Y., Wang, W., Wang, Y., Kim, Y. J., Weissman, I. L., Inlay, M. A., & Mikkola, H. K. A. (2016). LYVE1 Marks the divergence of yolk sac definitive hemogenic endothelium from the primitive erythroid lineage. Cell Reports, 17(9), 2286–2298.

    Article  CAS  PubMed  Google Scholar 

  84. Kim, I., He, S., Yilmaz, O. H., Kiel, M. J., & Morrison, S. J. (2006). Enhanced purification of fetal liver hematopoietic stem cells using SLAM family receptors. Blood, 108(2), 737–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kent, D. G., Copley, M. R., Benz, C., Wohrer, S., Dykstra, B. J., Ma, E., Cheyne, J., Zhao, Y., Bowie, M. B., Zhao, Y., et al. (2009). Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood, 113(25), 6342–6350.

    Article  CAS  PubMed  Google Scholar 

  86. Ye, M., Zhang, H., Amabile, G., Yang, H., Staber, P. B., Zhang, P., Levantini, E., Alberich-Jorda, M., Zhang, J., Kawasaki, A., et al. (2013). C/EBPa controls acquisition and maintenance of adult haematopoietic stem cell quiescence. Nature Cell Biology, 15(4), 385–394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Li, Z., Zhou, F., Chen, D., He, W., Ni, Y., Luo, L., & Liu, B. (2013). Generation of hematopoietic stem cells from purified embryonic endothelial cells by a simple and efficient strategy. Journal of Genetics and Genomics = Yi chuan xue bao, 40(11), 557–563.

    Article  PubMed  CAS  Google Scholar 

  88. Jones, M., Chase, J., Brinkmeier, M., Xu, J., Weinberg, D. N., Schira, J., Friedman, A., Malek, S., Grembecka, J., Cierpicki, T., et al. (2015). Ash1l controls quiescence and self-renewal potential in hematopoietic stem cells. The Journal of Clinical Investigation, 125(5), 2007–2020.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Magee, J. A., Ikenoue, T., Nakada, D., Lee, J. Y., Guan, K. L., & Morrison, S. J. (2012). Temporal changes in PTEN and mTORC2 regulation of hematopoietic stem cell self-renewal and leukemia suppression. Cell Stem Cell, 11(3), 415–428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Li, Y., Esain, V., Teng, L., Xu, J., Kwan, W., Frost, I. M., Yzaguirre, A. D., Cai, X., Cortes, M., Maijenburg, M. W., et al. (2014). Inflammatory signaling regulates embryonic hematopoietic stem and progenitor cell production. Genes and Development, 28(23), 2597–2612.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Sawamiphak, S., Kontarakis, Z., & Stainier, D. Y. (2014). Interferon gamma signaling positively regulates hematopoietic stem cell emergence. Developmental Cell, 31(5), 640–653.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kim, P. G., Canver, M. C., Rhee, C., Ross, S. J., Harriss, J. V., Tu, H. C., Orkin, S. H., Tucker, H. O., & Daley, G. Q. (2016). Interferon-alpha signaling promotes embryonic HSC maturation. Blood, 128(2), 204–216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Robin, C., Ottersbach, K., Durand, C., Peeters, M., Vanes, L., Tybulewicz, V., & Dzierzak, E. (2006). An unexpected role for IL-3 in the embryonic development of hematopoietic stem cells. Developmental Cell, 11(2), 171–180.

    Article  CAS  PubMed  Google Scholar 

  94. Essers, M. A., Offner, S., Blanco-Bose, W. E., Waibler, Z., Kalinke, U., Duchosal, M. A., & Trumpp, A. (2009). IFNalpha activates dormant haematopoietic stem cells in vivo. Nature, 458(7240), 904–908.

    Article  CAS  PubMed  Google Scholar 

  95. Haas, S., Hansson, J., Klimmeck, D., Loeffler, D., Velten, L., Uckelmann, H., Wurzer, S., Prendergast, A. M., Schnell, A., Hexel, K., et al. (2015). Inflammation-induced emergency megakaryopoiesis driven by hematopoietic stem cell-like megakaryocyte progenitors. Cell Stem Cell, 17(4), 422–434.

    Article  CAS  PubMed  Google Scholar 

  96. Pietras, E. M., Lakshminarasimhan, R., Techner, J. M., Fong, S., Flach, J., Binnewies, M., & Passegue, E. (2014). Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. Journal of Experimental Medicine, 211(2), 245–262.

    Article  CAS  Google Scholar 

  97. Nomura, N., Ito, C., Ooshio, T., Tadokoro, Y., Kohno, S., Ueno, M., Kobayashi, M., Kasahara, A., Takase, Y., Kurayoshi, K., et al. (2021). Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner. Scientific Reports, 11(1), 1666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jung, H. E., Shim, Y. R., Oh, J. E., Oh, D. S., & Lee, H. K. (2019). The autophagy Protein Atg5 Plays a Crucial Role in the Maintenance and Reconstitution Ability of Hematopoietic Stem Cells. Immune network, 19(2), e12.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Hirsch, E., Iglesias, A., Potocnik, A. J., Hartmann, U., & Fassler, R. (1996). Impaired migration but not differentiation of haematopoietic stem cells in the absence of beta1 integrins. Nature, 380(6570), 171–175.

    Article  CAS  PubMed  Google Scholar 

  100. Potocnik, A. J., Brakebusch, C., & Fassler, R. (2000). Fetal and adult hematopoietic stem cells require beta1 integrin function for colonizing fetal liver, spleen, and bone marrow. Immunity, 12(6), 653–663.

    Article  CAS  PubMed  Google Scholar 

  101. Mazo, I. B., Massberg, S., & von Andrian, U. H. (2011). Hematopoietic stem and progenitor cell trafficking. Trends in Immunology, 32(10), 493–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Prashad, S. L., Calvanese, V., Yao, C. Y., Kaiser, J., Wang, Y., Sasidharan, R., Crooks, G., Magnusson, M., & Mikkola, H. K. (2015). GPI-80 defines self-renewal ability in hematopoietic stem cells during human development. Cell Stem Cell, 16(1), 80–87.

    Article  CAS  PubMed  Google Scholar 

  103. Ueda, T., Yokota, T., Okuzaki, D., Uno, Y., Mashimo, T., Kubota, Y., Sudo, T., Ishibashi, T., Shingai, Y., Doi, Y., et al. (2019). Endothelial cell-selective adhesion molecule contributes to the development of definitive hematopoiesis in the fetal liver. Stem Cell Reports, 13(6), 992–1005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Emambokus, N. R., & Frampton, J. (2003). The glycoprotein IIb molecule is expressed on early murine hematopoietic progenitors and regulates their numbers in sites of hematopoiesis. Immunity, 19(1), 33–45.

    Article  CAS  PubMed  Google Scholar 

  105. Chou, S., & Lodish, H. F. (2010). Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells. Proceedings of the National Academy of Sciences U S A, 107(17), 7799–7804.

    Article  CAS  Google Scholar 

  106. Ara, T., Tokoyoda, K., Sugiyama, T., Egawa, T., Kawabata, K., & Nagasawa, T. (2003). Long-term hematopoietic stem cells require stromal cell-derived factor-1 for colonizing bone marrow during ontogeny. Immunity, 19(2), 257–267.

    Article  CAS  PubMed  Google Scholar 

  107. Ciau-Uitz, A., Monteiro, R., Kirmizitas, A., & Patient, R. (2014). Developmental hematopoiesis: Ontogeny, genetic programming and conservation. Experimental Hematology, 42(8), 669–683.

    Article  CAS  PubMed  Google Scholar 

  108. Ema, H., & Nakauchi, H. (2000). Expansion of hematopoietic stem cells in the developing liver of a mouse embryo. Blood, 95(7), 2284–2288.

    Article  CAS  PubMed  Google Scholar 

  109. Chou, S., Flygare, J., & Lodish, H. F. (2013). Fetal hepatic progenitors support long-term expansion of hematopoietic stem cells. Experimental Hematology, 41(5), 479-490 e474.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Tan, K. S., Kulkeaw, K., Nakanishi, Y., & Sugiyama, D. (2017). Expression of cytokine and extracellular matrix mRNAs in fetal hepatic stellate cells. Genes to Cells, 22(9), 836–844.

    Article  CAS  PubMed  Google Scholar 

  111. Zhang, C. C., & Lodish, H. F. (2004). Insulin-like growth factor 2 expressed in a novel fetal liver cell population is a growth factor for hematopoietic stem cells. Blood, 103(7), 2513–2521.

    Article  CAS  PubMed  Google Scholar 

  112. Zheng, J., Huynh, H., Umikawa, M., Silvany, R., & Zhang, C. C. (2011). Angiopoietin-like protein 3 supports the activity of hematopoietic stem cells in the bone marrow niche. Blood, 117(2), 470–479.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Sugiyama, D., Kulkeaw, K., Mizuochi, C., Horio, Y., & Okayama, S. (2011). Hepatoblasts comprise a niche for fetal liver erythropoiesis through cytokine production. Biochemical and Biophysical Research Communications, 410(2), 301–306.

    Article  CAS  PubMed  Google Scholar 

  114. Kordes, C., Sawitza, I., Gotze, S., & Haussinger, D. (2013). Hepatic stellate cells support hematopoiesis and are liver-resident mesenchymal stem cells. Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology, 31(2–3), 290–304.

    Article  CAS  Google Scholar 

  115. Liu, C., Han, T., Stachura, D. L., Wang, H., Vaisman, B. L., Kim, J., Klemke, R. L., Remaley, A. T., Rana, T. M., Traver, D., et al. (2018). Lipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply. Nature Communications, 9(1), 1310.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Iwasaki, H., Arai, F., Kubota, Y., Dahl, M., & Suda, T. (2010). Endothelial protein C receptor-expressing hematopoietic stem cells reside in the perisinusoidal niche in fetal liver. Blood, 116(4), 544–553.

    Article  CAS  PubMed  Google Scholar 

  117. Khan, J. A., Mendelson, A., Kunisaki, Y., Birbrair, A., Kou, Y., Arnal-Estape, A., Pinho, S., Ciero, P., Nakahara, F., Ma’ayan, A., et al. (2016). Fetal liver hematopoietic stem cell niches associate with portal vessels. Science, 351(6269), 176–180.

    Article  CAS  PubMed  Google Scholar 

  118. Tamplin, O. J., Durand, E. M., Carr, L. A., Childs, S. J., Hagedorn, E. J., Li, P., Yzaguirre, A. D., Speck, N. A., & Zon, L. I. (2015). Hematopoietic stem cell arrival triggers dynamic remodeling of the perivascular niche. Cell, 160(1–2), 241–252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gerlach, J. C., Thompson, R. L., Gridelli, B., & Schmelzer, E. (2019). Effects of delta-like noncanonical notch ligand 1 expression of human fetal liver hepatoblasts on hematopoietic progenitors. Stem Cells International, 2019, 7916275.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  120. Sigurdsson, V., Takei, H., Soboleva, S., Radulovic, V., Galeev, R., Siva, K., Leeb-Lundberg, L. M., Iida, T., Nittono, H., & Miharada, K. (2016). Bile acids protect expanding hematopoietic stem cells from unfolded protein stress in fetal liver. Cell Stem Cell, 18(4), 522–532.

    Article  CAS  PubMed  Google Scholar 

  121. Lee Y., Leslie J., Yang Y., Ding L. (2021) Hepatic stellate and endothelial cells maintain hematopoietic stem cells in the developing liver, Journal of Experimental Medicine, 218(3).

  122. Christensen, J. L., Wright, D. E., Wagers, A. J., & Weissman, I. L. (2004). Circulation and chemotaxis of fetal hematopoietic stem cells. PLoS Biology, 2(3), E75.

    Article  PubMed  PubMed Central  Google Scholar 

  123. Ciriza, J., Thompson, H., Petrosian, R., Manilay, J. O., & Garcia-Ojeda, M. E. (2013). The migration of hematopoietic progenitors from the fetal liver to the fetal bone marrow: Lessons learned and possible clinical applications. Experimental Hematology, 41(5), 411–423.

    Article  PubMed  Google Scholar 

  124. Theodore, L. N., Hagedorn, E. J., Cortes, M., Natsuhara, K., Liu, S. Y., Perlin, J. R., Yang, S., Daily, M. L., Zon, L. I., & North, T. E. (2017). Distinct roles for matrix metalloproteinases 2 and 9 in embryonic hematopoietic stem cell emergence, migration, and niche colonization. Stem Cell Reports, 8(5), 1226–1241.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Papayannopoulou, T., Priestley, G. V., Nakamoto, B., Zafiropoulos, V., & Scott, L. M. (2001). Molecular pathways in bone marrow homing: Dominant role of alpha(4)beta(1) over beta(2)-integrins and selectins. Blood, 98(8), 2403–2411.

    Article  CAS  PubMed  Google Scholar 

  126. Shao, L., Chang, J., Feng, W., Wang, X., Williamson, E. A., Li, Y., Schajnovitz, A., Scadden, D., Mortensen, L. J., Lin, C. P., et al. (2018). The Wave2 scaffold Hem-1 is required for transition of fetal liver hematopoiesis to bone marrow. Nature Communications, 9(1), 2377.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Chen, Z., Borek, D., Padrick, S. B., Gomez, T. S., Metlagel, Z., Ismail, A. M., Umetani, J., Billadeau, D. D., Otwinowski, Z., & Rosen, M. K. (2010). Structure and control of the actin regulatory WAVE complex. Nature, 468(7323), 533–538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Mizoguchi, T., Pinho, S., Ahmed, J., Kunisaki, Y., Hanoun, M., Mendelson, A., Ono, N., Kronenberg, H. M., & Frenette, P. S. (2014). Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Developmental Cell, 29(3), 340–349.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Coskun, S., Chao, H., Vasavada, H., Heydari, K., Gonzales, N., Zhou, X., de Crombrugghe, B., & Hirschi, K. K. (2014). Development of the fetal bone marrow niche and regulation of HSC quiescence and homing ability by emerging osteolineage cells. Cell Reports, 9(2), 581–590.

    Article  CAS  PubMed  Google Scholar 

  130. Cao, H., Cao, B., Heazlewood, C. K., Domingues, M., Sun, X., Debele, E., McGregor, N. E., Sims, N. A., Heazlewood, S. Y., & Nilsson, S. K. (2019). Osteopontin is an important regulative component of the fetal bone marrow hematopoietic stem cell niche. Cells, 8(9), 985.

    Article  CAS  PubMed Central  Google Scholar 

  131. Boulais, P. E., & Frenette, P. S. (2015). Making sense of hematopoietic stem cell niches. Blood, 125(17), 2621–2629.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Montecino-Rodriguez, E., & Dorshkind, K. (2012). B-1 B cell development in the fetus and adult. Immunity, 36(1), 13–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Souto-Carneiro, M. M., Sims, G. P., Girschik, H., Lee, J., & Lipsky, P. E. (2005). Developmental changes in the human heavy chain CDR3. The Journal of Immunology, 175(11), 7425–7436.

    Article  CAS  PubMed  Google Scholar 

  134. Roy, A., Bystry, V., Bohn, G., Goudevenou, K., Reigl, T., Papaioannou, M., Krejci, A., O’Byrne, S., Chaidos, A., Grioni, A., et al. (2017). High resolution IgH repertoire analysis reveals fetal liver as the likely origin of life-long, innate B lymphopoiesis in humans. Clinical Immunology, 183, 8–16.

    Article  CAS  PubMed  Google Scholar 

  135. Gronwall, C., Vas, J., & Silverman, G. J. (2012). Protective roles of natural IgM antibodies. Frontiers in Immunology, 3, 66.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Shaw, P. X., Horkko, S., Chang, M. K., Curtiss, L. K., Palinski, W., Silverman, G. J., & Witztum, J. L. (2000). Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. The Journal of Clinical Investigation, 105(12), 1731–1740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Moins-Teisserenc, H., Busson, M., Herda, A., & Apete, S. (2013). Peffault de Latour R, Robin M, Xhaard A, Toubert A, Socie G: CD19+CD5+ B cells and B1-like cells following allogeneic hematopoietic stem cell transplantation. Biology of Blood and Marrow Transplantation, 19(6), 988–991.

    Article  CAS  PubMed  Google Scholar 

  138. Xu, X., Deobagkar-Lele, M., Bull, K. R., Crockford, T. L., Mead, A. J., Cribbs, A. P., Sims, D., Anzilotti, C., & Cornall, R. J. (2020). An ontogenetic switch drives the positive and negative selection of B cells. Proceedings of the National Academy of Sciences U S A, 117(7), 3718–3727.

    Article  CAS  Google Scholar 

  139. Yoshimoto, M., Montecino-Rodriguez, E., Ferkowicz, M. J., Porayette, P., Shelley, W. C., Conway, S. J., Dorshkind, K., & Yoder, M. C. (2011). Embryonic day 9 yolk sac and intra-embryonic hemogenic endothelium independently generate a B-1 and marginal zone progenitor lacking B-2 potential. Proceedings of the National Academy of Sciences, 108(4), 1468–1473.

    Article  CAS  Google Scholar 

  140. Yoshimoto, M. (2015). The first wave of B lymphopoiesis develops independently of stem cells in the murine embryo. Annals of the New York Academy of Sciences, 1362, 16–22.

    Article  PubMed  Google Scholar 

  141. Montecino-Rodriguez, E., Leathers, H., & Dorshkind, K. (2006). Identification of a B-1 B cell-specified progenitor. Nature Immunology, 7(3), 293–301.

    Article  CAS  PubMed  Google Scholar 

  142. Kobayashi, M., Shelley, W. C., Seo, W., Vemula, S., Lin, Y., Liu, Y., Kapur, R., Taniuchi, I., & Yoshimoto, M. (2014). Functional B-1 progenitor cells are present in the hematopoietic stem cell-deficient embryo and depend on Cbfbeta for their development. Proceedings of the National Academy of Sciences U S A, 111(33), 12151–12156.

    Article  CAS  Google Scholar 

  143. Vosshenrich, C. A., Cumano, A., Muller, W., Di Santo, J. P., & Vieira, P. (2004). Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proceedings of the National Academy of Sciences U S A, 101(30), 11070–11075.

    Article  CAS  Google Scholar 

  144. Carpino, N., Thierfelder, W. E., Chang, M. S., Saris, C., Turner, S. J., Ziegler, S. F., & Ihle, J. N. (2004). Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Molecular and Cellular Biology, 24(6), 2584–2592.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Alhaj Hussen, K., Vu Manh, T. P., Guimiot, F., Nelson, E., Chabaane, E., Delord, M., Barbier, M., Berthault, C., Dulphy, N., Alberdi, A. J., et al. (2017). Molecular and functional characterization of lymphoid progenitor subsets reveals a bipartite architecture of human lymphopoiesis. Immunity, 47(4), 680-696 e688.

    Article  CAS  PubMed  Google Scholar 

  146. Sanz, E., Munoz, A. N., Monserrat, J., Van-Den-Rym, A., Escoll, P., Ranz, I., & Alvarez-Mon, M. (2010). de-la-Hera A: Ordering human CD34+CD10-CD19+ pre/pro-B-cell and CD19- common lymphoid progenitor stages in two pro-B-cell development pathways. Proceedings of the National Academy of Sciences U S A, 107(13), 5925–5930.

    Article  CAS  Google Scholar 

  147. Sanz, E., Alvarez-Mon, M., Martinez, A. C., & de la Hera, A. (2003). Human cord blood CD34+Pax-5+B-cell progenitors: Single-cell analyses of their gene expression profiles. Blood, 101(9), 3424–3430.

    Article  CAS  PubMed  Google Scholar 

  148. O’Byrne, S., Elliott, N., Rice, S., Buck, G., Fordham, N., Garnett, C., Godfrey, L., Crump, N. T., Wright, G., Inglott, S., et al. (2019). Discovery of a CD10-negative B-progenitor in human fetal life identifies unique ontogeny-related developmental programs. Blood, 134(13), 1059–1071.

    Article  CAS  PubMed  Google Scholar 

  149. Boiers, C., Richardson, S. E., Laycock, E., Zriwil, A., Turati, V. A., Brown, J., Wray, J. P., Wang, D., James, C., Herrero, J., et al. (2018). A human IPS model implicates embryonic B-Myeloid fate restriction as developmental susceptibility to B acute lymphoblastic leukemia-associated ETV6-RUNX1. Developmental Cell, 44(3), 362–377367.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Roy, A., Cowan, G., Mead, A. J., Filippi, S., Bohn, G., Chaidos, A., Tunstall, O., Chan, J. K., Choolani, M., Bennett, P., et al. (2012). Perturbation of fetal liver hematopoietic stem and progenitor cell development by trisomy 21. Proceedings of the National Academy of Sciences U S A, 109(43), 17579–17584.

    Article  CAS  Google Scholar 

  151. Michaelsson, J., Mold, J. E., McCune, J. M., & Nixon, D. F. (2006). Regulation of T cell responses in the developing human fetus. The Journal of Immunology, 176(10), 5741–5748.

    Article  CAS  PubMed  Google Scholar 

  152. Takahata, Y., Nomura, A., Takada, H., Ohga, S., Furuno, K., Hikino, S., Nakayama, H., Sakaguchi, S., & Hara, T. (2004). CD25+CD4+T cells in human cord blood: An immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 (Foxp3) gene. Experimental Hematology, 32(7), 622–629.

    Article  CAS  PubMed  Google Scholar 

  153. Mold, J. E., Venkatasubrahmanyam, S., Burt, T. D., Michaelsson, J., Rivera, J. M., Galkina, S. A., Weinberg, K., Stoddart, C. A., & McCune, J. M. (2010). Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans. Science, 330(6011), 1695–1699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Rudd, B. D. (2020). Neonatal T cells: A reinterpretation. Annual Review of Immunology, 38, 229–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Chea, S., Schmutz, S., Berthault, C., Perchet, T., Petit, M., Burlen-Defranoux, O., Goldrath, A. W., Rodewald, H. R., Cumano, A., & Golub, R. (2016). Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to notch signaling. Cell reports, 14(6), 1500–1516.

    Article  CAS  PubMed  Google Scholar 

  156. Rackaityte, E., & Halkias, J. (2020). Mechanisms of fetal T cell tolerance and immune regulation. Frontiers in Immunology, 11, 588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Xu, M. J., Matsuoka, S., Yang, F. C., Ebihara, Y., Manabe, A., Tanaka, R., Eguchi, M., Asano, S., Nakahata, T., & Tsuji, K. (2001). Evidence for the presence of murine primitive megakaryocytopoiesis in the early yolk sac. Blood, 97(7), 2016–2022.

    Article  CAS  Google Scholar 

  158. Ma, D. C., Sun, Y. H., Chang, K. Z., & Zuo, W. (1996). Developmental change of megakaryocyte maturation and DNA ploidy in human fetus. European Journal of Haematology, 57(2), 121–127.

    Article  CAS  PubMed  Google Scholar 

  159. Sparger, K. A., Ramsey, H., Lorenz, V., Liu, Z. J., Feldman, H. A., Li, N., Laforest, T., & Sola-Visner, M. C. (2018). Developmental differences between newborn and adult mice in response to romiplostim. Platelets, 29(4), 365–372.

    Article  CAS  PubMed  Google Scholar 

  160. Israels, S. J., Odaibo, F. S., Robertson, C., McMillan, E. M., & McNicol, A. (1997). Deficient thromboxane synthesis and response in platelets from premature infants. Pediatric Research, 41(2), 218–223.

    Article  CAS  PubMed  Google Scholar 

  161. Davizon-Castillo, P., Allawzi, A., Sorrells, M., Fisher, S., Baltrunaite, K., Neeves, K., Nozik-Grayck, E., DiPaola, J., & Delaney, C. (2020). Platelet activation in experimental murine neonatal pulmonary hypertension. Physiological Reports, 8(5), 14386.

    Article  CAS  Google Scholar 

  162. Margraf, A., Nussbaum, C., Rohwedder, I., Klapproth, S., Kurz, A. R. M., Florian, A., Wiebking, V., Pircher, J., Pruenster, M., Immler, R., et al. (2017). Maturation of platelet function during murine fetal development in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology, 37(6), 1076–1086.

    Article  CAS  PubMed  Google Scholar 

  163. Stolla, M. C., Catherman, S. C., Kingsley, P. D., Rowe, R. G., Koniski, A. D., Fegan, K., Vit, L., McGrath, K. E., Daley, G. Q., & Palis, J. (2019). Lin28b regulates age-dependent differences in murine platelet function. Blood Advances, 3(1), 72–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Rowe, R. G., Wang, L. D., Coma, S., Han, A., Mathieu, R., Pearson, D. S., Ross, S., Sousa, P., Nguyen, P. T., Rodriguez, A., et al. (2016). Developmental regulation of myeloerythroid progenitor function by the Lin28b-let-7-Hmga2 axis. Journal of Experimental Medicine, 213(8), 1497–1512.

    Article  CAS  Google Scholar 

  165. Dzierzak, E., & Philipsen, S. (2013). Erythropoiesis: Development and differentiation. Cold Spring Harbor Perspectives in Medicine, 3(4), 011601.

    Article  CAS  Google Scholar 

  166. Linderkamp, O., Wu, P. Y., & Meiselman, H. J. (1983). Geometry of neonatal and adult red blood cells. Pediatric Research, 17(4), 250–253.

    Article  CAS  PubMed  Google Scholar 

  167. Kim, I., Saunders, T. L., & Morrison, S. J. (2007). Sox17 dependence distinguishes the transcriptional regulation of fetal from adult hematopoietic stem cells. Cell, 130(3), 470–483.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Oliveira-Mateos, C., Sanchez-Castillo, A., Soler, M., Obiols-Guardia, A., Pineyro, D., Boque-Sastre, R., Calleja-Cervantes, M. E., Castro de Moura, M., Martinez-Cardus, A., Rubio, T., et al. (2019). The transcribed pseudogene RPSAP52 enhances the oncofetal HMGA2-IGF2BP2-RAS axis through LIN28B-dependent and independent let-7 inhibition. Nature Communications, 10(1), 3979.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Li, Y. S., Zhou, Y., Tang, L., Shinton, S. A., Hayakawa, K., & Hardy, R. R. (2015). A developmental switch between fetal and adult B lymphopoiesis. Annals of the New York Academy of Sciences, 1362, 8–15.

    Article  CAS  PubMed  Google Scholar 

  170. McKinney-Freeman, S., Cahan, P., Li, H., Lacadie, S. A., Huang, H. T., Curran, M., Loewer, S., Naveiras, O., Kathrein, K. L., Konantz, M., et al. (2012). The transcriptional landscape of hematopoietic stem cell ontogeny. Cell Stem Cell, 11(5), 701–714.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Xu, J., Shao, Z., Glass, K., Bauer, D. E., Pinello, L., Van Handel, B., Hou, S., Stamatoyannopoulos, J. A., Mikkola, H. K., Yuan, G. C., et al. (2012). Combinatorial assembly of developmental stage-specific enhancers controls gene expression programs during human erythropoiesis. Developmental Cell, 23(4), 796–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Huang, J., Liu, X., Li, D., Shao, Z., Cao, H., Zhang, Y., Trompouki, E., Bowman, T. V., Zon, L. I., Yuan, G. C., et al. (2016). Dynamic Control of Enhancer Repertoires Drives Lineage and Stage-Specific Transcription during Hematopoiesis. Developmental Cell, 36(1), 9–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Chen, C., Yu, W., Tober, J., Gao, P., He, B., Lee, K., Trieu, T., Blobel, G. A., Speck, N. A., & Tan, K. (2019). Spatial genome re-organization between fetal and adult hematopoietic stem cells. Cell Reports, 29(12), 4200-4211 e4207.

    Article  CAS  PubMed  Google Scholar 

  174. Gomes, A. M., Kurochkin, I., Chang, B., Daniel, M., Law, K., Satija, N., Lachmann, A., Wang, Z., Ferreira, L., Ma’ayan, A., et al. (2018). Cooperative transcription factor induction mediates hemogenic reprogramming. Cell reports, 25(10), 2821-2835 e2827.

    Article  CAS  PubMed  Google Scholar 

  175. Lopez, C. K., Noguera, E., Stavropoulou, V., Robert, E., Aid, Z., Ballerini, P., Bilhou-Nabera, C., Lapillonne, H., Boudia, F., Thirant, C., et al. (2019). Ontogenic changes in hematopoietic hierarchy determine pediatric specificity and disease phenotype in fusion oncogene-driven myeloid leukemia. Cancer Discovery, 9(12), 1736–1753.

    Article  CAS  PubMed  Google Scholar 

  176. Hotfilder, M., Rottgers, S., Rosemann, A., Schrauder, A., Schrappe, M., Pieters, R., Jurgens, H., Harbott, J., & Vormoor, J. (2005). Leukemic stem cells in childhood high-risk ALL/t(9;22) and t(4;11) are present in primitive lymphoid-restricted CD34+CD19- cells. Cancer Research, 65(4), 1442–1449.

    Article  CAS  PubMed  Google Scholar 

  177. Ford, A. M., Bennett, C. A., Price, C. M., Bruin, M. C., Van Wering, E. R., & Greaves, M. (1998). Fetal origins of the TEL-AML1 fusion gene in identical twins with leukemia. Proceedings of the National Academy of Sciences, 95(8), 4584–4588.

    Article  CAS  Google Scholar 

  178. Wiemels, J. L., Cazzaniga, G., Daniotti, M., Eden, O. B., Addison, G. M., Masera, G., Saha, V., Biondi, A., & Greaves, M. F. (1999). Prenatal origin of acute lymphoblastic leukaemia in children. Lancet, 354(9189), 1499–1503.

    Article  CAS  PubMed  Google Scholar 

  179. Zuna J, Madzo J, Krejci O, Zemanova Z, Kalinova M, Muzikova K, Zapotocky M, Starkova J, Hrusak O, Horak J et al (2011) ETV6/RUNX1 (TEL/AML1) is a frequent prenatal first hit in childhood leukemia. Blood, 117(1):368–369; author reply 370–361.

  180. Lausten-Thomsen, U., Madsen, H. O., Vestergaard, T. R., Hjalgrim, H., Nersting, J., & Schmiegelow, K. (2011). Prevalence of t(12;21)[ETV6-RUNX1]-positive cells in healthy neonates. Blood, 117(1), 186–189.

    Article  CAS  PubMed  Google Scholar 

  181. Fueller, E., Schaefer, D., Fischer, U., Krell, P. F., Stanulla, M., Borkhardt, A., & Slany, R. K. (2014). Genomic inverse PCR for exploration of ligated breakpoints (GIPFEL), a new method to detect translocations in leukemia. PLoS ONE, 9(8), e104419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  182. Kosik, P., Skorvaga, M., Durdik, M., Jakl, L., Nikitina, E., Markova, E., Kozics, K., Horvathova, E., & Belyaev, I. (2017). Low numbers of pre-leukemic fusion genes are frequently present in umbilical cord blood without affecting DNA damage response. Oncotarget, 8(22), 35824–35834.

    Article  PubMed  PubMed Central  Google Scholar 

  183. Skorvaga, M., Nikitina, E., Kubes, M., Kosik, P., Gajdosechova, B., Leitnerova, M., Copakova, L., & Belyaev, I. (2014). Incidence of common preleukemic gene fusions in umbilical cord blood in Slovak population. PLoS ONE, 9(3), e91116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  184. Schafer, D., Olsen, M., Lahnemann, D., Stanulla, M., Slany, R., Schmiegelow, K., Borkhardt, A., & Fischer, U. (2018). Five percent of healthy newborns have an ETV6-RUNX1 fusion as revealed by DNA-based GIPFEL screening. Blood, 131(7), 821–826.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Hein, D., Dreisig, K., Metzler, M., Izraeli, S., Schmiegelow, K., Borkhardt, A., & Fischer, U. (2019). The preleukemic TCF3-PBX1 gene fusion can be generated in utero and is present in approximately 0.6% of healthy newborns. Blood, 134(16), 1355–1358.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Puumala, S. E., Ross, J. A., Aplenc, R., & Spector, L. G. (2013). Epidemiology of childhood acute myeloid leukemia. Pediatric Blood and Cancer, 60(5), 728–733.

    Article  PubMed  Google Scholar 

  187. Andersson, A. K., Ma, J., Wang, J., Chen, X., Gedman, A. L., Dang, J., Nakitandwe, J., Holmfeldt, L., Parker, M., Easton, J., et al. (2015). The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias. Nature Genetics, 47(4), 330–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Pine, S. R., Guo, Q., Yin, C., Jayabose, S., Druschel, C. M., & Sandoval, C. (2007). Incidence and clinical implications of GATA1 mutations in newborns with Down syndrome. Blood, 110(6), 2128–2131.

    Article  CAS  PubMed  Google Scholar 

  189. Horton, S. J., Jaques, J., Woolthuis, C., van Dijk, J., Mesuraca, M., Huls, G., Morrone, G., Vellenga, E., & Schuringa, J. J. (2013). MLL-AF9-mediated immortalization of human hematopoietic cells along different lineages changes during ontogeny. Leukemia, 27(5), 1116–1126.

    Article  CAS  PubMed  Google Scholar 

  190. Liang, D. C., Liu, H. C., Yang, C. P., Jaing, T. H., Hung, I. J., Yeh, T. C., Chen, S. H., Hou, J. Y., Huang, Y. J., Shih, Y. S., et al. (2013). Cooperating gene mutations in childhood acute myeloid leukemia with special reference on mutations of ASXL1, TET2, IDH1, IDH2, and DNMT3A. Blood, 121(15), 2988–2995.

    Article  CAS  PubMed  Google Scholar 

  191. Cancer Genome Atlas Research N (2013) Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. New England Journal of Medicine, 368(22): 2059–2074.

  192. Bateman, C. M., Colman, S. M., Chaplin, T., Young, B. D., Eden, T. O., Bhakta, M., Gratias, E. J., van Wering, E. R., Cazzaniga, G., Harrison, C. J., et al. (2010). Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood, 115(17), 3553–3558.

    Article  CAS  PubMed  Google Scholar 

  193. Pagano, L., Pulsoni, A., Vignetti, M., Mele, L., Fianchi, L., Petti, M. C., Mirto, S., Falcucci, P., Fazi, P., Broccia, G., et al. (2002). Acute megakaryoblastic leukemia: Experience of GIMEMA trials. Leukemia, 16(9), 1622–1626.

    Article  CAS  PubMed  Google Scholar 

  194. Antonarakis, S. E., Lyle, R., Dermitzakis, E. T., Reymond, A., & Deutsch, S. (2004). Chromosome 21 and down syndrome: From genomics to pathophysiology. Nature Reviews Genetics, 5(10), 725–738.

    Article  CAS  PubMed  Google Scholar 

  195. Henry, E., Walker, D., Wiedmeier, S. E., & Christensen, R. D. (2007). Hematological abnormalities during the first week of life among neonates with Down syndrome: Data from a multihospital healthcare system. American Journal of Medical Genetics. Part A, 143A(1), 42–50.

    Article  CAS  PubMed  Google Scholar 

  196. de Rooij, J. D., Branstetter, C., Ma, J., Li, Y., Walsh, M. P., Cheng, J., Obulkasim, A., Dang, J., Easton, J., Verboon, L. J., et al. (2017). Pediatric non-down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes. Nature Genetics, 49(3), 451–456.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Gruber, T. A., & Downing, J. R. (2015). The biology of pediatric acute megakaryoblastic leukemia. Blood, 126(8), 943–949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Gruber, T. A., Larson Gedman, A., Zhang, J., Koss, C. S., Marada, S., Ta, H. Q., Chen, S. C., Su, X., Ogden, S. K., Dang, J., et al. (2012). An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell, 22(5), 683–697.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Morrow, M., Horton, S., Kioussis, D., Brady, H. J., & Williams, O. (2004). TEL-AML1 promotes development of specific hematopoietic lineages consistent with preleukemic activity. Blood, 103(10), 3890–3896.

    Article  CAS  PubMed  Google Scholar 

  200. Torrano, V., Procter, J., Cardus, P., Greaves, M., & Ford, A. M. (2011). ETV6-RUNX1 promotes survival of early B lineage progenitor cells via a dysregulated erythropoietin receptor. Blood, 118(18), 4910–4918.

    Article  CAS  PubMed  Google Scholar 

  201. Martin-Lorenzo, A., Hauer, J., Vicente-Duenas, C., Auer, F., Gonzalez-Herrero, I., Garcia-Ramirez, I., Ginzel, S., Thiele, R., Constantinescu, S. N., Bartenhagen, C., et al. (2015). Infection exposure is a causal factor in B-cell precursor acute lymphoblastic leukemia as a result of Pax5-Inherited susceptibility. Cancer Discovery, 5(12), 1328–1343.

    Article  CAS  PubMed  Google Scholar 

  202. Rodriguez-Hernandez, G., Hauer, J., Martin-Lorenzo, A., Schafer, D., Bartenhagen, C., Garcia-Ramirez, I., Auer, F., Gonzalez-Herrero, I., Ruiz-Roca, L., Gombert, M., et al. (2017). Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases. Cancer Research, 77(16), 4365–4377.

    Article  CAS  PubMed  Google Scholar 

  203. Burgler, S., & Nadal, D. (2017). Pediatric precursor B acute lymphoblastic leukemia: Are T helper cells the missing link in the infectious etiology theory? Molecular and Cellular Pediatrics, 4(1), 6.

    Article  PubMed  PubMed Central  Google Scholar 

  204. Sullivan, E. M., Jeha, S., Kang, G., Cheng, C., Rooney, B., Holladay, M., Bari, R., Schell, S., Tuggle, M., Pui, C. H., et al. (2014). NK cell genotype and phenotype at diagnosis of acute lymphoblastic leukemia correlate with postinduction residual disease. Clinical Cancer Research, 20(23), 5986–5994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Cazzaniga, G., van Delft, F. W., Lo Nigro, L., Ford, A. M., Score, J., Iacobucci, I., Mirabile, E., Taj, M., Colman, S. M., Biondi, A., et al. (2011). Developmental origins and impact of BCR-ABL1 fusion and IKZF1 deletions in monozygotic twins with Ph+ acute lymphoblastic leukemia. Blood, 118(20), 5559–5564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Wiemels, J. L., Ford, A. M., Van Wering, E. R., Postma, A., & Greaves, M. (1999). Protracted and variable latency of acute lymphoblastic leukemia after TEL-AML1 gene fusion in utero. Blood, 94(3), 1057–1062.

    Article  CAS  PubMed  Google Scholar 

  207. Maia, A. T., van der Velden, V. H., Harrison, C. J., Szczepanski, T., Williams, M. D., Griffiths, M. J., van Dongen, J. J., & Greaves, M. F. (2003). Prenatal origin of hyperdiploid acute lymphoblastic leukemia in identical twins. Leukemia, 17(11), 2202–2206.

    Article  CAS  PubMed  Google Scholar 

  208. Gamis, A. S., & Smith, F. O. (2012). Transient myeloproliferative disorder in children with Down syndrome: Clarity to this enigmatic disorder. British Journal of Haematology, 159(3), 277–287.

    Article  PubMed  Google Scholar 

  209. Matsuda, K., Shimada, A., Yoshida, N., Ogawa, A., Watanabe, A., Yajima, S., Iizuka, S., Koike, K., Yanai, F., Kawasaki, K., et al. (2007). Spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia with specific RAS mutations. Blood, 109(12), 5477–5480.

    Article  CAS  PubMed  Google Scholar 

  210. Pieters, R., De Lorenzo, P., Ancliffe, P., Aversa, L. A., Brethon, B., Biondi, A., Campbell, M., Escherich, G., Ferster, A., Gardner, R. A., et al. (2019). Outcome of infants younger than 1 year with acute lymphoblastic leukemia treated with the interfant-06 protocol: Results from an international phase III randomized study. Journal of Clinical Oncology, 37(25), 2246–2256.

    Article  CAS  PubMed  Google Scholar 

  211. Tomizawa, D., Miyamura, T., Imamura, T., Watanabe, T., Moriya Saito, A., Ogawa, A., Takahashi, Y., Hirayama, M., Taki, T., Deguchi, T., et al. (2020). A risk-stratified therapy for infants with acute lymphoblastic leukemia: A report from the JPLSG MLL-10 trial. Blood, 136(16), 1813–1823.

    Article  CAS  PubMed  Google Scholar 

  212. Pui, C. H., Carroll, W. L., Meshinchi, S., & Arceci, R. J. (2011). Biology, risk stratification, and therapy of pediatric acute leukemias: An update. Journal of Clinical Oncology, 29(5), 551–565.

    Article  PubMed  Google Scholar 

  213. Salzer, W. L., Devidas, M., Carroll, W. L., Winick, N., Pullen, J., Hunger, S. P., & Camitta, B. A. (2010). Long-term results of the pediatric oncology group studies for childhood acute lymphoblastic leukemia 1984–2001: A report from the children’s oncology group. Leukemia, 24(2), 355–370.

    Article  CAS  PubMed  Google Scholar 

  214. Jackson, T. R., Ling, R. E., & Roy, A. (2021). The Origin of B-cells: Human Fetal B Cell development and implications for the pathogenesis of childhood acute lymphoblastic leukemia. Frontiers in immunology, 12, 637975.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Greaves, M. (2018). A causal mechanism for childhood acute lymphoblastic leukaemia. Nature Reviews Cancer, 18(8), 471–484.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Montecino-Rodriguez, E., Li, K., Fice, M., & Dorshkind, K. (2014). Murine B-1 B cell progenitors initiate B-acute lymphoblastic leukemia with features of high-risk disease. The Journal of Immunology, 192(11), 5171–5178.

    Article  CAS  PubMed  Google Scholar 

  217. Choi, Y. J., Heck, A. M., Hayes, B. J., Lih, D., Rayner, S. G., Hadland, B., & Zheng, Y. (2021). WNT5A from the fetal liver vascular niche supports human fetal liver hematopoiesis. Stem Cell Research and Therapy, 12(1), 321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by NIH grants R01 HL133560-01 and R01 CA223194-01 through Loyola University Chicago, as well as Loyola program development funds to Jiwang Zhang.

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, 60153, USA

    Ryan Mack, Lei Zhang, Peter Breslin, SJ & Jiwang Zhang

  2. Departments of Molecular/Cellular Physiology and Biology, Loyola University Medical Center and Loyola University Chicago, Chicago, IL, 60660, USA

    Peter Breslin, SJ

Authors
  1. Ryan Mack
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter Breslin, SJ
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jiwang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ryan Mack and Lei Zhang drafted the first version of this review. All authors contributed to the writing of this manuscript. Peter Breslin did the final editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jiwang Zhang.

Ethics declarations

Conflicts of Interest

The authors declare that they have no competing financial or professional interests.

Ethics Approval

This is not applicable for this review.

Consent to Participate

This is not applicable for this review.

Consent for Publication

This is not applicable for this review.

Availability of Data and Material

This is not applicable for this review.

Code Availability

This is not applicable for this review.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mack, R., Zhang, L., Breslin, SJ, P. et al. The Fetal-to-Adult Hematopoietic Stem Cell Transition and its Role in Childhood Hematopoietic Malignancies. Stem Cell Rev and Rep 17, 2059–2080 (2021). https://doi.org/10.1007/s12015-021-10230-x

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-021-10230-x

Keywords

Search

Navigation