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Current Stem Cell Reports

, Volume 3, Issue 3, pp 149–155 | Cite as

A New View of Stem Cell Dynamics

  • P. QuesenberryEmail author
  • S. Wen
  • M. Dooner
  • G. Camussi
  • L. Goldberg
In Vitro and In Vivo Models in Stem Cell Biology (E Scott, Section Editor)
  • 67 Downloads
Part of the following topical collections:
  1. Topical Collection on In Vitro and In Vivo Models in Stem Cell Biology

Abstract

Purpose of Review

Our understanding of the biology of hematopoietic stem cells is evolving beyond hierarchical models and markers of stem cell purification to a far more fluid model wherein degrees of multipotency of individual cells can change over time. This review is to outline these new concepts:

Recent Findings

The long-term repopulating hematopoietic stem cell is a proliferating cell, which is continually changing in phenotype. It cannot be purified by current surface epitope techniques. The cycling nature of the cell has been established by three separate approaches; separation of whole marrow into G0/G1 and S/G2/M fractions followed by evaluation of long-term in vivo repopulation in irradiated mice, tritiated thymidine suicide of marrow cells with repopulation assays, and in vivo BrdU studies to estimate flux through cycle. Other work has suggested that stem cell studies need to be considered within the context of transplant-based or normal baseline hematopoiesis; they are quite distinct and likely have differential influences governing stem cell self-renewal and differentiation. Hematopoietic stem cell functions are further modulated by interactions with a variety of extracellular vesicles and influenced by circadian rhythms and other variables.

Summary

The true nature of the system remains to be defined, and such definition will elucidate the basic nature of stem cell biology and indicate specifics of clinical relevance.

Keywords

Hematopoietic stem cells Cell cycle Extracellular vesicles Hematopoiesis 

Notes

Compliance with Ethical Standards

Conflict of Interest

P. Quesenberry, S. Wen, M. Dooner, and L. Goldberg declare that they have no conflict of interest.

G. Camussi has a patent EP2604271B1, US8,568,771B2 issued.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Seita J, Weissman IL. Hematopoietic stem cell: self-renewal versus differentiation. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):640–53. doi: 10.1002/wsbm.86.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Morrison SJ, Weissman IL. The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype. Immunity. 1994;1(8):661–73. doi: 10.1016/1074-7613(94)90037-X.CrossRefPubMedGoogle Scholar
  3. 3.
    Kiel MJ, Yilmaz OH, Iwashita T, Yilmaz OH, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121(7):1109–21. doi: 10.1016/j.cell.2005.05.026.CrossRefPubMedGoogle Scholar
  4. 4.
    Passegue E, Wagers AJ, Giuriato S, Anderson WC, Weissman IL. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202(11):1599–611. doi: 10.1084/jem.20050967.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Colvin GA, Berz D, Liu L, Dooner MS, Dooner G, Pascual S, et al. Heterogeneity of non-cycling and cycling synchronized murine hematopoietic stem/progenitor cells. J Cell Physiol. 2010;222(1):57–65. doi: 10.1002/jcp.21918.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Wolf NS, Koné A, Priestley GV, Bartelmez SH. In vivo and in vitro characterization of long-term repopulating primitive hematopoietic cells isolated by sequential Hoechst 33342-rhodamine 123 FACS selection. Exp Hematol. 1993;21:614–22.PubMedGoogle Scholar
  7. 7.
    Sieburg HB, Cho RH, Dykstra B, Uchida N, Eaves CJ, Muller-Sieburg CE. The hematopoietic stem compartment consists of a limited number of discrete stem cell subsets. Blood. 2006;107(6):2311–6.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Mazurier F, Gan OI, McKenzie JL, Doedens M, Dick JE. Lentivector-mediated clonal tracking reveals intrinsic heterogeneity in the human hematopoietic stem cell compartment and culture-induced stem cell impairment. Blood. 2004;103(2):545–52.CrossRefPubMedGoogle Scholar
  9. 9.
    Hüttmann A, Liu SL, Boyd AW, Li CL. Functional heterogeneity within rhodamine 123(lo) Hoechst33342(lo/sp) primitive hemopoietic stem cells revealed by pyronin Y. Exp Hematol. 2001;29(9):1109–16.CrossRefPubMedGoogle Scholar
  10. 10.
    Suda T, Suda J, Ogawa M. Single cell origin of mouse hemopoietic colonies expressing multiple lineages in variable combinations. Proc Natl Acad Sci U S A. 1983;80(21):6689–93.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    •• Goldberg LR, Dooner MS, Johnson K, Papa E, Pereira M, Del Tatto M, et al. The murine long-term multi-lineage renewal marrow stem cell is a cycling cell. Leukemia. 2014;28:813–22. doi: 10.1038/leu.2013.252. This work established that multi lineage repopulating pluripotent marrow stem cells are cycling and thus always changing. Ourification of stem cells is intrinsically misleading. CrossRefPubMedGoogle Scholar
  12. 12.
    Peters SO, Kittler EL, Ramshaw HS, Quesenberry PJ. Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts. Blood. 1996;87(1):30–7.PubMedGoogle Scholar
  13. 13.
    Habibian HK, Peters SO, Hsieh CC, Wuu J, Vergilis K, Grimaldi CI, et al. The fluctuating phenotype of the lympho-hematopoietic stem cell with cell cycle transit. J Exp Med. 1998;188(2):393–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Cerny J, Dooner M, McAuliffe C, Habibian H, Stencil K, Berrios V, et al. Homing of purified murine lympho-hematopoietic stem cells: a cytokine-induced defect. J Hematother Stem Cell Res. 2002;11(6):913–22.CrossRefPubMedGoogle Scholar
  15. 15.
    Colvin GA, Dooner MS, Dooner GJ, Sanchez-Guijo FM, Demers DA, Abedi M, et al. Stem cell continuum: directed differentiation hotspots. Exp Hematol. 2007;35:96–107.CrossRefPubMedGoogle Scholar
  16. 16.
    Lambert JF, Liu M, Colvin GA, Dooner M, McAuliffe CI, Becker PS, et al. Marrow stem cells shift gene expression and engraftment phenotype with cell cycle transit. J Exp Med. 2003;197(11):1563–72.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Becker PS, Nilsson SK, Li Z, Berrios VM, Dooner MS, Cooper CL, et al. Adhesion receptor expression by hematopoietic cell lines and murine progenitors: modulation by cytokines and cell cycle status. Exp Hematol. 1999;27(3):533–41.CrossRefPubMedGoogle Scholar
  18. 18.
    Colvin GA, Lambert JF, Moore BE, Carlson JE, Dooner MS, Abedi M, et al. Intrinsic hematopoietic stem cell/progenitor plasticity: inversions. J Cell Physiol. 2004;199:20–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Abedi M, Colvin G, Liu Q, Weier HU, Johnson KW, Quesenberry PJ. Conversion potential of marrow cells into lung cells fluctuates with cytokine-induced cell cycle. Stem Cells Dev. 2008;17(2):207–19. doi: 10.1089/scd.2007.0195.CrossRefPubMedGoogle Scholar
  20. 20.
    Aliotta JM, Lee D, Puente N, Faradyan S, Sears EH, Amaral A, et al. Progenitor/stem cell fate determination: interactive dynamics of cell cycle and microvesicles. Stem Cells Dev. 2012;21(10):1627–38. doi: 10.1089/scd.2011.0550.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Quesenberry PJ, Colvin GA, Abedi M, Dooner G, Dooner M, Aliotta J, et al. The stem cell continuum. Ann N Y Acad Sci. 2005;1044:228–35.CrossRefPubMedGoogle Scholar
  22. 22.
    Quesenberry PJ, Colvin G, Dooner G, Dooner M, Aliotta JM, Johnson K. The stem cell continuum: cell cycle, injury, and phenotype lability. Ann N Y Acad Sci. 2007;1106:20–9. Review.CrossRefPubMedGoogle Scholar
  23. 23.
    Quesenberry PJ, Goldberg L, Aliotta J, Dooner M. Marrow hematopoietic stem cells revisited: they exist in a continuum and are not defined by standard purification approaches; then there are the microvesicles. Front Oncol. 2014;4:56. doi: 10.3389/fonc.2014.00056. Review.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    D'Hondt L, McAuliffe C, Damon J, Reilly J, Carlson J, Dooner M, et al. Circadian variations of bone marrow engraftability. J Cell Physiol. 2004;200(1):63–70.CrossRefPubMedGoogle Scholar
  25. 25.
    Aardal N, Laerum O. Circadian variations in mouse bone marrow. Exp Hematol. 1983;9:792–801.Google Scholar
  26. 26.
    Méndez-Ferrer S, Lucas D, Battista M, Frenette PS. Haematopoietic stem cell release is regulated by circadian oscillations. Nature. 2008;452(7186):442–7.CrossRefPubMedGoogle Scholar
  27. 27.
    Smaaland R, Laerum O, Southern R, Stevold O, Bjerkners R, Lote K. Colny-forming units granulocyte/macrophage and DNA synthesis of human bone marrow are circadian stage dependent and show co-variation. Blood. 1992;79:2281–7.PubMedGoogle Scholar
  28. 28.
    Quesenberry PJ, Goldberg LR, Aliotta JM, Dooner MS, Pereira MG, Wen S, et al. Cellular phenotype and extracellular vesicles: basic and clinical considerations. Stem Cells Dev. 2014;23(13):1429–36. doi: 10.1089/scd.2013.0594.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nilsson SK, Johnston HM, Coverdale JA. Spatial localization of transplanted hemopoietic stem cells: inferences for the localization of stem cell niches. Blood. 2001;97:2293–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Xie Y, Yin T, Wiegraebe W, He XC, Miller D, Stark D, et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature. 2009;457(7225):97–101.CrossRefPubMedGoogle Scholar
  31. 31.
    Nombela-Arrieta C, Pivarnik G, Winkel B, Canty KJ, Harley B, Mahoney JE, et al. Quantitative imaging of haematopoietic stem and progenitor cell localization and hypoxic status in the bone marrow microenvironment. Nat Cell Biol. 2013;15(5):533–43.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Mantel CR, O'Leary HA, Chitteti BR, Huang X, Cooper S, Hangoc G, et al. Broxmeyer HE enhancing hematopoietic stem cell transplantation efficacy by mitigating oxygen shock. Cell. 2015;161(7):1553–65. doi: 10.1016/j.cell.2015.04.054.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pang WW, Schrier SL, Weissman IL. Age-associated changes in human hematopoietic stem cells. Semin Hematol. 2017;54(1):39–42. doi: 10.1053/j.seminhematol.2016.10.004. Review.CrossRefPubMedGoogle Scholar
  34. 34.
    Maloney MA, Weber CL, Patt HM. Myelocyte-metamyelocyte transition in the bone marrow of the dog. Nature. 1963;197:150–2.CrossRefPubMedGoogle Scholar
  35. 35.
    Drize NJ, Keller JR, Chertkov JL. Local clonal analysis of the hematopoietic system shows that multiple small short-living clones maintain life-long hematopoiesis in reconstituted mice. Blood. 1996;88(8):2927–38.PubMedGoogle Scholar
  36. 36.
    Sun J, Ramos A, Chapman B, Johnnidis JB, Le L, Ho YJ, et al. Clonal dynamics of native haematopoiesis. Nature. 2014;514(7522):322–7. doi: 10.1038/nature13824.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Quesenberry PJ, Aliotta J, Deregibus MC, Camussi G. Role of extracellular RNA-carrying vesicles in cell differentiation and reprogramming. Stem Cell Res Ther. 2015;6:153. Published online 2015 Sep 3. doi: 10.1186/s13287-015-0150-x.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Watson DC, Bayik D, Srivatsan A, Bergamaschi C, Valentin A, Niu G, et al. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials. 2016;105:195–205. doi: 10.1016/j.biomaterials.2016.07.003.CrossRefPubMedGoogle Scholar
  39. 39.
    Rilla K, Siiskonen H, Tammi M, Tammi R. Hyaluronan-coated extracellular vesicles—a novel link between hyaluronan and cancer. Adv Cancer Res. 2014;123:121–48. doi: 10.1016/B978-0-12-800092-2.00005-8.CrossRefPubMedGoogle Scholar
  40. 40.
    Grange C, Tapparo M, Bruno S, Chatterjee D, Quesenberry PJ, Tetta C, et al. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int J Mol Med. 2014;33(5):1055–63. doi: 10.3892/ijmm.2014.1663.PubMedPubMedCentralGoogle Scholar
  41. 41.
    • Wen S, Dooner M, Cheng Y, Papa E, Del Tatto M, Pereira M, et al. Mesenchymal stromal cell-derived extracellular vesicles rescue radiation damage to murine marrow hematopoietic cells. Leukemia. 2016;30(11):2221–31. doi: 10.1038/leu.2016.107. This work establishes vesicle potency in reversing irradiation damage to hematopoietic stem cells..CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Mulvey HE, Chang A, Adler J, Del Tatto M, Perez K, Quesenberry PJ, et al. Extracellular vesicle-mediated phenotype switching in malignant and non-malignant colon cells. BMC Cancer. 2015;15:571. doi: 10.1186/s12885-015-1568-3.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Aliotta JM, Pereira M, Wen S, Dooner MS, Del Tatto M, Papa E, et al. Exosomes induce and reverse monocrotaline-induced pulmonary hypertension in mice. Cardiovasc Res. 2016;110(3):319–30. doi: 10.1093/cvr/cvw054.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Aliotta JM, Pereira M, Amaral A, Sorokina A, Igbinoba Z, Hasslinger A, et al. Induction of pulmonary hypertensive changes by extracellular vesicles from monocrotaline-treated mice. Cardiovasc Res. 2013;100(3):354–62. doi: 10.1093/cvr/cvt184.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    •• Aliotta JM, Pereira M, Dooner M, Goldberg LR, Quesenberry PJ. Endothelial progenitor cells are the bone marrow cell population in mice with monocrotaline-induced pulmonary hypertension which induces pulmonary hypertension in healthy mice. Paper no3455 abstract ASH meeting Orlando Dec 2015. The manuscript provides a base for the concept of “good” versus “bad” vesicles with regard to tissue function, and disease models.Google Scholar
  46. 46.
    Aliotta JM, Pereira M, Sears EH, Dooner MS, Wen S, Goldberg LR, et al. Lung-derived exosome uptake into and epigenetic modulation of marrow progenitor/stem and differentiated cells. J Extracell Vesicles. 2015;4:26166. doi: 10.3402/jev.v4.26166. eCollection 2015.CrossRefPubMedGoogle Scholar
  47. 47.
    Dainiak N, Cohen CM. Surface membrane vesicles from mononuclear cells stimulate erythroid stem cells to proliferate in culture. Blood. 1982;60(3):583–94.PubMedGoogle Scholar
  48. 48.
    Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P, et al. Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 2006;20(5):847–56.CrossRefPubMedGoogle Scholar
  49. 49.
    Huan J, Hornick NI, Goloviznina NA, Kamimae-Lanning AN, David LL, Wilmarth PA, et al. Coordinate regulation of residual bone marrow function by paracrine trafficking of AML exosomes. Leukemia. 2015;29(12):2285–95. doi: 10.1038/leu.2015.163.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Aliotta JM, Sanchez-Guijo FM, Dooner GJ, Johnson KW, Dooner MS, Greer KA, et al. Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells. 2007;25(9):2245–56.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Aliotta JM, Pereira M, Johnson KW, de Paz N, Dooner MS, Puente N, et al. Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol. 2010;38(3):233–45. doi: 10.1016/j.exphem.2010.01.002.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Quesenberry PJ, Goldberg L, Aliotta J, Dooner M. Marrow hematopoietic stem cells revisited: they exist in a continuum and are not defined by standard purification approaches; then there are the microvesicles. Front Oncol. 2014;4:56. Published online 2014 Apr 4. Prepublished online 2013 Sep 26. doi: 10.3389/fonc.2014.00056.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • P. Quesenberry
    • 1
    Email author
  • S. Wen
    • 1
  • M. Dooner
    • 1
    • 2
  • G. Camussi
    • 2
  • L. Goldberg
    • 1
  1. 1.Brown University/Rhode Island HospitalProvidenceUSA
  2. 2.University of TurinTurinItaly

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