Catecholaminergic neurotransmitters regulate migration and repopulation of immature human CD34+ cells through Wnt signaling

Article metrics

Abstract

Catecholamines are important regulators of homeostasis, yet their functions in hematopoiesis are poorly understood. Here we report that immature human CD34+ cells dynamically expressed dopamine and β2-adrenergic receptors, with higher expression in the primitive CD34+CD38lo population. The myeloid cytokines G-CSF and GM-CSF upregulated neuronal receptor expression on immature CD34+ cells. Treatment with neurotransmitters increased the motility, proliferation and colony formation of human progenitor cells, correlating with increased polarity, expression of the metalloproteinase MT1-MMP and activity of the metalloproteinase MMP-2. Treatment with catecholamines enhanced human CD34+ cell engraftment of NOD-SCID mice through Wnt signaling activation and increased cell mobilization and bone marrow Sca-1+c-Kit+Lin cell numbers. Our results identify new functions for neurotransmitters and myeloid cytokines in the direct regulation of human and mouse progenitor cell migration and development.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Increased dopamine receptor expression in G-CSF-treated human CD34+ cells.
Figure 2: Dopamine receptor agonists increase the polarization and motility of CD34+ cells.
Figure 3: Dopamine receptor agonists increase the clonogenic progenitor content and engraftment potential of CD34+ cells.
Figure 4: Adrenergic neurotransmitters regulate CD34+ cell motility and proliferation.
Figure 5: Epinephrine induces progenitor cell proliferation, motility and in vivo mobilization.
Figure 6: Neurotransmitters activate the canonical Wnt signaling pathway.

References

  1. 1

    Adams, G.B. & Scadden, D.T. The hematopoietic stem cell in its place. Nat. Immunol. 7, 333–337 (2006).

  2. 2

    Suda, T., Arai, F. & Hirao, A. Hematopoietic stem cells and their niche. Trends Immunol. 26, 426–433 (2005).

  3. 3

    Yin, T. & Li, L. The stem cell niches in bone. J. Clin. Invest. 116, 1195–1201 (2006).

  4. 4

    Lapidot, T. et al. Cytokine stimulation of multilineage hematopoiesis from immature human cells engrafted in SCID mice. Science 255, 1137–1141 (1992).

  5. 5

    Larochelle, A. et al. Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy. Nat. Med. 2, 1329–1337 (1996).

  6. 6

    Peled, A. et al. Dependence of human stem cell engraftment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999).

  7. 7

    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).

  8. 8

    Kollet, O., Dar, A. & Lapidot, T. The multiple roles of osteoclasts in host defense: bone remodeling and hematopoietic stem cell mobilization. Annu. Rev. Immunol. (2006).

  9. 9

    Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657–664 (2006).

  10. 10

    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).

  11. 11

    Papayannopoulou, T. Current mechanistic scenarios in hematopoietic stem/progenitor cell mobilization. Blood 103, 1580–1585 (2004).

  12. 12

    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).

  13. 13

    Janowska-Wieczorek, A., Matsuzaki, A. & Marquez, L. The hematopoietic microenvironment: matrix metalloproteinases in the hematopoietic microenvironment. Hematology 4, 515–527 (2000).

  14. 14

    Link, D.C. Mechanisms of granulocyte colony-stimulating factor-induced hematopoietic progenitor-cell mobilization. Semin. Hematol. 37, 25–32 (2000).

  15. 15

    Morrison, S.J., Wright, D.E. & Weissman, I.L. Cyclophosphamide/granulocyte colony-stimulating factor induces hematopoietic stem cells to proliferate prior to mobilization. Proc. Natl. Acad. Sci. USA 94, 1908–1913 (1997).

  16. 16

    Yamazaki, K. & Allen, T.D. Ultrastructural and morphometric alterations in bone marrow stromal tissue after 7 Gy irradiation. Blood Cells 17, 527–549 (1991).

  17. 17

    Hasko, G. & Szabo, C. Regulation of cytokine and chemokine production by transmitters and co-transmitters of the autonomic nervous system. Biochem. Pharmacol. 56, 1079–1087 (1998).

  18. 18

    Brodde, O.E., Bruck, H. & Leineweber, K. Cardiac adrenoceptors: physiological and pathophysiological relevance. J. Pharmacol. Sci. 100, 323–337 (2006).

  19. 19

    Vallone, D., Picetti, R. & Borrelli, E. Structure and function of dopamine receptors. Neurosci. Biobehav. Rev. 24, 125–132 (2000).

  20. 20

    Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

  21. 21

    Cadigan, K.M. & Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286–3305 (1997).

  22. 22

    Nelson, W.J. & Nusse, R. Convergence of Wnt, β-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

  23. 23

    Austin, T.W., Solar, G.P., Ziegler, F.C., Liem, L. & Matthews, W. A role for the Wnt gene family in hematopoiesis: expansion of multilineage progenitor cells. Blood 89, 3624–3635 (1997).

  24. 24

    Van Den Berg, D.J., Sharma, A.K., Bruno, E. & Hoffman, R. Role of members of the Wnt gene family in human hematopoiesis. Blood 92, 3189–3202 (1998).

  25. 25

    Reya, T. et al. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423, 409–414 (2003).

  26. 26

    Willert, K. et al. Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature 423, 448–452 (2003).

  27. 27

    Duncan, A.W. et al. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat. Immunol. 6, 314–322 (2005).

  28. 28

    Murdoch, B. et al. Wnt-5A augments repopulating capacity and primitive hematopoietic development of human blood stem cells in vivo. Proc. Natl. Acad. Sci. USA 100, 3422–3427 (2003).

  29. 29

    Avigdor, A. et al. Membrane type 1-matrix metalloproteinase is directly involved in G-CSF induced human hematopoietic stem and progenitor cell mobilization. ASH Annu. Meet. Abstr. 104, 2675 (2004).

  30. 30

    Shirvaikar, N., Montano, J., Turner, A.R., Ratajczak, M.Z. & Janowska-Wieczorek, A. Upregulation of MT1-MMP expression by hyaluronic acid enhances homing-related responses of hematopoietic CD34+ cells to an SDF-1 gradient. ASH Annu. Meet. Abstr. 104, 2889 (2004).

  31. 31

    Wright, D.E. et al. Cyclophosphamide/granulocyte colony-stimulating factor causes selective mobilization of bone marrow hematopoietic stem cells into the blood after M phase of the cell cycle. Blood 97, 2278–2285 (2001).

  32. 32

    Tzahor, E. & Lassar, A.B. Wnt signals from the neural tube block ectopic cardiogenesis. Genes Dev. 15, 255–260 (2001).

  33. 33

    Neth, P. et al. Wnt signaling regulates the invasion capacity of human mesenchymal stem cells. Stem Cells 24, 1892–1903 (2006).

  34. 34

    Takahashi, M., Tsunoda, T., Seiki, M., Nakamura, Y. & Furukawa, Y. Identification of membrane-type matrix metalloproteinase-1 as a target of the β-catenin/Tcf4 complex in human colorectal cancers. Oncogene 21, 5861–5867 (2002).

  35. 35

    Hoagland, H.C. Hematologic complications of cancer chemotherapy. Semin. Oncol. 9, 95–102 (1982).

  36. 36

    Cancelas, J.A. & Williams, D.A. Stem cell mobilization by β2-agonists. Nat. Med. 12, 278–279 (2006).

  37. 37

    Larsson, J. & Scadden, D. Nervous activity in a stem cell niche. Cell 124, 253–255 (2006).

  38. 38

    Kondo, H. et al. Unloading induces osteoblastic cell suppression and osteoclastic cell activation to lead to bone loss via sympathetic nervous system. J. Biol. Chem. 280, 30192–30200 (2005).

  39. 39

    Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat. Immunol. 2, 172–180 (2001).

  40. 40

    Trowbridge, J.J., Xenocostas, A., Moon, R.T. & Bhatia, M. Glycogen synthase kinase-3 is an in vivo regulator of hematopoietic stem cell repopulation. Nat. Med. 12, 89–98 (2006).

  41. 41

    Kirstetter, P., Anderson, K., Porse, B.T., Jacobsen, S.E. & Nerlov, C. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block. Nat. Immunol. 7, 1048–1056 (2006).

  42. 42

    Scheller, M. et al. Hematopoietic stem cell and multilineage defects generated by constitutive β-catenin activation. Nat. Immunol. 7, 1037–1047 (2006).

  43. 43

    Trowbridge, J.J., Moon, R.T. & Bhatia, M. Hematopoietic stem cell biology: too much of a Wnt thing. Nat. Immunol. 7, 1021–1023 (2006).

  44. 44

    Spiegel, A. et al. Unique SDF-1-induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 103, 2900–2907 (2004).

  45. 45

    Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687–694 (2002).

  46. 46

    Goichberg, P., Shtutman, M., Ben-Ze'ev, A. & Geiger, B. Recruitment of β-catenin to cadherin-mediated intercellular adhesions is involved in myogenic induction. J. Cell Sci. 114, 1309–1319 (2001).

Download references

Acknowledgements

We thank L. Abel for assistance; E. Tzahor (Weizmann Institute of Science) for CRD-Frzb-enriched conditioned medium; and A. Globerson and S. Berrih-Aknin for discussions and critical review of the manuscript. Supported by Ares-Serono, the Gabriella Rich Center for Transplantation Biology, the Israel Science Foundation (796/04) and the Helen and Martin Kimmel Institute for Stem Cell Research at the Weizmann Institute of Science.

Author information

A.S. designed and did experiments, analyzed data and wrote the manuscript; S.S., A.K., A.L., N.N., Y.A. and P.G. did experiments and analyzed data; I.R., I.H., H.B.-H. and A.N. provided human blood and bone marrow cells; M.R. provided advice on experimental design and manuscript preparation; and T.L. designed the research and wrote the manuscript.

Correspondence to Tsvee Lapidot.

Ethics declarations

Competing interests

Funding for this study was provided by Serono, and a patent is being filed on the basis of some of the results.

Rights and permissions

Reprints and Permissions

About this article

Further reading