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Circulating hematopoietic progenitors with T lineage potential

Abstract

The thymus is seeded via the blood, but the identity of hematopoietic progenitors with access to the circulation in adult mice is unknown. We report here that the only progenitors in blood with efficient T lineage potential were lineage negative with high expression of stem cell antigen 1 and c-Kit (LSK cells). The blood LSK population, like its counterpart in the bone marrow, contained hematopoietic stem cells and nonrenewing, multipotent progenitors, including early lymphoid progenitors and CD62L+ cells previously described as efficient T lineage progenitors. Common lymphoid progenitors could not be identified in the circulation, suggesting they are not physiological T lineage precursors. We conclude that blood LSK cells are the principal circulating progenitors with T lineage potential.

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Figure 1: Analysis of bone marrow, blood and thymus for LSK cells and CLPs.
Figure 2: T lineage potential of blood populations.
Figure 3: Surface phenotype of bone marrow and blood LSK cells.
Figure 4: Lineage potential and kinetics of LSK populations.
Figure 5: Bone marrow analysis for long-term HSC reconstitution by LSK populations.
Figure 6: Early kinetics of LSK populations.

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References

  1. Morrison, S.J., Uchida, N. & Weissman, I.L. The biology of hematopoietic stem cells. Annu. Rev. Cell. Dev. Biol. 11, 35–71 (1995).

    Article  CAS  Google Scholar 

  2. Miller, J.F. & Osoba, D. Current concepts of the immunological function of the thymus. Physiol. Rev. 47, 437–520 (1967).

    Article  CAS  Google Scholar 

  3. Goldschneider, I., Komschlies, K.L. & Greiner, D.L. Studies of thymocytopoiesis in rats and mice. I. Kinetics of appearance of thymocytes using a direct intrathymic adoptive transfer assay for thymocyte precursors. J. Exp. Med. 163, 1–17 (1986).

    Article  CAS  Google Scholar 

  4. Scollay, R., Smith, J. & Stauffer, V. Dynamics of early T cells: prothymocyte migration and proliferation in the adult mouse thymus. Immunol. Rev. 91, 129–157 (1986).

    Article  CAS  Google Scholar 

  5. Donskoy, E. & Goldschneider, I. Thymocytopoiesis is maintained by blood-borne precursors throughout postnatal life. A study in parabiotic mice. J. Immunol. 148, 1604–1612 (1992).

    CAS  PubMed  Google Scholar 

  6. Foss, D.L., Donskoy, E. & Goldschneider, I. The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J. Exp. Med. 193, 365–374 (2001).

    Article  CAS  Google Scholar 

  7. Petrie, H. Cell migration and the control of post-natal T-cell lymphopoiesis in the thymus. Nat. Rev. Immunol. 3, 859–866 (2003).

    Article  CAS  Google Scholar 

  8. Bhandoola, A., Sambandam, A., Allman, D., Meraz, A. & Schwarz, B. Early T lineage progenitors: new insights, but old questions remain. J. Immunol. 171, 5653–5658 (2003).

    Article  CAS  Google Scholar 

  9. Spangrude, G.J., Heimfeld, S. & Weissman, I.L. Purification and characterization of mouse hematopoietic stem cells. Science 241, 58–62 (1988).

    Article  CAS  Google Scholar 

  10. Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin Sca1+ c- kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001).

    Article  CAS  Google Scholar 

  11. Christensen, J.L. & Weissman, I.L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl. Acad. Sci. USA 98, 14541–14546 (2001).

    Article  CAS  Google Scholar 

  12. Kondo, M., Weissman, I.L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).

    Article  CAS  Google Scholar 

  13. Spangrude, G.J. & Scollay, R. Differentiation of hematopoietic stem cells in irradiated mouse thymic lobes. Kinetics and phenotype of progeny. J. Immunol. 145, 3661–3668 (1990).

    CAS  PubMed  Google Scholar 

  14. Allman, D. et al. Thymopoiesis independent of common lymphoid progenitors. Nat. Immunol. 4, 168–174 (2003).

    Article  CAS  Google Scholar 

  15. Igarashi, H., Gregory, S., Yokota, T., Sakaguchi, N. & Kincade, P. Transcription from the RAG1 locus marks the earliest lymphocyte progenitors in bone marrow. Immunity 17, 117–130 (2002).

    Article  CAS  Google Scholar 

  16. Perry, S.S. et al. L-selectin defines a bone marrow analog to the thymic early T-lineage progenitor. Blood 103, 2990–2996 (2004).

    Article  CAS  Google Scholar 

  17. Rodewald, H.R., Kretzschmar, K., Takeda, S., Hohl, C. & Dessing, M. Identification of pro-thymocytes in murine fetal blood: T lineage commitment can precede thymus colonization. EMBO J. 13, 4229–4240 (1994).

    Article  CAS  Google Scholar 

  18. Delassus, S. & Cumano, A. Circulation of hematopoietic progenitors in the mouse embryo. Immunity 4, 97–106 (1996).

    Article  CAS  Google Scholar 

  19. Dunon, D., Allioli, N., Vainio, O., Ody, C. & Imhof, B.A. Quantification of T-cell progenitors during ontogeny: thymus colonization depends on blood delivery of progenitors. Blood 93, 2234–2243 (1999).

    CAS  PubMed  Google Scholar 

  20. Ikawa, T. et al. Identification of the earliest prethymic T-cell progenitors in murine fetal blood. Blood 103, 530–537 (2004).

    Article  CAS  Google Scholar 

  21. Yamamoto, Y. et al. Characterization of peripheral blood stem cells in mice. Blood 88, 445–454 (1996).

    CAS  PubMed  Google Scholar 

  22. Harrison, D.E. & Astle, C.M. Short- and long-term multilineage repopulating hematopoietic stem cells in late fetal and newborn mice: models for human umbilical cord blood. Blood 90, 174–181 (1997).

    CAS  PubMed  Google Scholar 

  23. To, L.B., Haylock, D.N., Simmons, P.J. & Juttner, C.A. The biology and clinical uses of blood stem cells. Blood 89, 2233–2258 (1997).

    CAS  Google Scholar 

  24. Papayannopoulou, T. Hematopoietic stem/progenitor cell mobilization: a continuing quest for etiologic mechanisms. Ann. NY Acad. Sci. 872, 187–199 (1999).

    Article  CAS  Google Scholar 

  25. Lapidot, T. & Petit, I. Current understanding of stem cell mobilization: the roles of chemokines proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp. Hematol. 30, 973–981 (2002).

    Article  CAS  Google Scholar 

  26. Goodman, J.W. & Hodgson, G.S. Evidence for stem cells in the peripheral blood of mice. Blood 19, 702–714 (1962).

    CAS  PubMed  Google Scholar 

  27. Wright, D.E., Wagers, A.J., Gulati, A.P., Johnson, F.L. & Weissman, I.L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).

    Article  CAS  Google Scholar 

  28. Wallis, V.J., Leuchars, E., Chwalinski, S. & Davies, A.J. On the sparse seeding of bone marrow and thymus in radiation chimaeras. Transplantation 19, 2–11 (1975).

    Article  CAS  Google Scholar 

  29. Okada, S. et al. Enrichment and characterization of murine hematopoietic stem cells that express c-kit molecule. Blood 78, 1706–1712 (1991).

    CAS  PubMed  Google Scholar 

  30. Ikuta, K. & Weissman, I.L. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc. Natl. Acad. Sci. USA 89, 1502–1506 (1992).

    Article  CAS  Google Scholar 

  31. Izon, D. et al. A common pathway for dendritic cell and early B cell development. J. Immunol. 167, 1387–1392 (2001).

    Article  CAS  Google Scholar 

  32. Sitnicka, E. et al. Key role of flt3 ligand in regulation of the common lymphoid progenitor but not in maintenance of the hematopoietic stem cell pool. Immunity 17, 463–472 (2002).

    Article  CAS  Google Scholar 

  33. Donskoy, E., Foss, D. & Goldschneider, I. Gated importation of prothymocytes by adult mouse thymus is coordinated with their periodic mobilization from bone marrow. J. Immunol. 171, 3568–3575 (2003).

    Article  CAS  Google Scholar 

  34. Peters, L.L. et al. Large-scale, high-throughput screening for coagulation and hematologic phenotypes in mice. Physiol. Genomics 11, 185–193 (2002).

    Article  CAS  Google Scholar 

  35. Akashi, K., Traver, D., Miyamoto, T. & Weissman, I.L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000).

    Article  CAS  Google Scholar 

  36. Gounari, F. et al. Tracing lymphopoiesis with the aid of a pTα-controlled reporter gene. Nat. Immunol. 3, 489–496 (2002).

    Article  CAS  Google Scholar 

  37. Martin, C.H. et al. Efficient thymic immigration of B220+ lymphoid-restricted bone marrow cells with T precursor potential. Nat. Immunol. 4, 866–873 (2003).

    Article  CAS  Google Scholar 

  38. Yokota, T. et al. Unique properties of fetal lymphoid progenitors identified according to RAG1 gene expression. Immunity 19, 365–375 (2003).

    Article  CAS  Google Scholar 

  39. Kadish, J.L. & Basch, R.S. Hematopoietic thymocyte precursors. I. Assay and kinetics of the appearance of progeny. J. Exp. Med. 143, 1082–1099 (1976).

    Article  CAS  Google Scholar 

  40. Allman, D. et al. Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol. 167, 6834–6840 (2001).

    Article  CAS  Google Scholar 

  41. Na Nakorn, T., Traver, D., Weissman, I.L. & Akashi, K. Myeloerythroid-restricted progenitors are sufficient to confer radioprotection and provide the majority of day 8 CFU-S. J. Clin. Invest. 109, 1579–1585 (2002).

    Article  Google Scholar 

  42. Shortman, K. & Wu, L. Early T lymphocyte progenitors. Annu. Rev. Immunol. 14, 29–47 (1996).

    Article  CAS  Google Scholar 

  43. Porritt, H.E., Gordon, K. & Petrie, H.T. Kinetics of steady-state differentiation and mapping of intrathymic-signaling environments by stem cell transplantation in nonirradiated mice. J. Exp. Med. 198, 957–962 (2003).

    Article  CAS  Google Scholar 

  44. Montecino-Rodriguez, E. & Dorshkind, K. To T or not to T: reassessing the common lymphoid progenitor. Nat. Immunol. 4, 100–101 (2003).

    Article  CAS  Google Scholar 

  45. Egerton, M., Scollay, R. & Shortman, K. Kinetics of mature T-cell development in the thymus. Proc. Natl. Acad. Sci. USA 87, 2579–2582 (1990).

    Article  CAS  Google Scholar 

  46. Chu, V. et al. Method for non-invasively recording electrocardiograms in conscious mice. BMC Physiol. 1, 6 (2001).

    Article  CAS  Google Scholar 

  47. Yang, B., Larson, D.F. & Watson, R. Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships. Am. J. Physiol. Heart. Circ. Physiol. 277, H1906–H1913 (1999).

    Article  CAS  Google Scholar 

  48. Fleming, W.H., Alpern, E.J., Uchida, N., Ikuta, K. & Weissman, I.L. Steel factor influences the distribution and activity of murine hematopoietic stem cells in vivo. Proc. Natl. Acad. Sci. USA 90, 3760–3764 (1993).

    Article  CAS  Google Scholar 

  49. Heissig, B. et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 109, 625–637 (2002).

    Article  CAS  Google Scholar 

  50. Pear, W.S. & Radtke, F. Notch signaling in lymphopoiesis. Semin. Immunol. 15, 69–79 (2003).

    Article  CAS  Google Scholar 

  51. Yu, W. et al. Continued RAG expression in late stages of B cell development and no apparent re-induction after immunization. Nature 400, 682–687 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank G. Spangrude, D. Allman, W. Pear, I. Maillard, R. Gerstein and D. Fonseca for critical comments; and R. Schretzenmair and H. Pletcher of the Abramson Cancer Center Flow Cytometry and Cell Sorting Shared Resource (Philadelphia, Pennsylvania) for technical support. Supported by National Institutes of Health (AI059621; T32-AI-055428) and Concern Foundation.

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Correspondence to Avinash Bhandoola.

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Schwarz, B., Bhandoola, A. Circulating hematopoietic progenitors with T lineage potential. Nat Immunol 5, 953–960 (2004). https://doi.org/10.1038/ni1101

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