Characterization and Quantification of Clonal Heterogeneity Among Hematopoietic Stem Cells: a Model-based Approach

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2008 Sep 24

PMID 18809760

Citations 24

Authors

Ingo Roeder

Katrin Horn

Hans-Bernd Sieburg

Rebecca Cho

Christa Muller-Sieburg

Markus Loeffler

Affiliations

Soon will be listed here.

Abstract

Hematopoietic stem cells (HSCs) show pronounced heterogeneity in self-renewal and differentiation behavior, which is reflected in their repopulation kinetics. Here, a single-cell-based mathematical model of HSC organization is used to examine the basis of HSC heterogeneity. Our modeling results, which are based on the analysis of limiting dilution competitive repopulation experiments in mice, demonstrate that small quantitative but clonally fixed differences of cellular properties are necessary and sufficient to account for the observed functional heterogeneity. The model predicts, and experimental data validate, that competitive pressures will amplify small clonal differences into large changes in the number of differentiated progeny. We further predict that the repertoire of HSC clones will evolve over time. Last, our results suggest that larger differences in cellular properties have to be assumed to account for genetically determined differences in HSC behavior as observed in different inbred mice strains. The model provides comprehensive systemic and quantitative insights into the clonal heterogeneity among HSCs with potential applications in predicting the behavior of malignant and/or genetically modified cells.

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References

Loeffler M, Roeder I . Tissue stem cells: definition, plasticity, heterogeneity, self-organization and models--a conceptual approach. Cells Tissues Organs. 2002; 171(1):8-26. DOI: 10.1159/000057688. View

Van Zant G, Thompson B, Fleischman R, Perkins S . Stem cell quiescence/activation is reversible by serial transplantation and is independent of stromal cell genotype in mouse aggregation chimeras. Exp Hematol. 1992; 20(4):470-5. View

Roeder I, Glauche I . Pathogenesis, treatment effects, and resistance dynamics in chronic myeloid leukemia--insights from mathematical model analyses. J Mol Med (Berl). 2007; 86(1):17-27. DOI: 10.1007/s00109-007-0241-y. View

Ott M, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U . Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006; 12(4):401-9. DOI: 10.1038/nm1393. View

Muller-Sieburg C, Cho R, Thoman M, Adkins B, Sieburg H . Deterministic regulation of hematopoietic stem cell self-renewal and differentiation. Blood. 2002; 100(4):1302-9. View

Abkowitz J, Catlin S, Guttorp P . Strategies for hematopoietic stem cell gene therapy: insights from computer simulation studies. Blood. 1997; 89(9):3192-8. View

Komarova N, Wodarz D . Effect of cellular quiescence on the success of targeted CML therapy. PLoS One. 2007; 2(10):e990. PMC: 1991595. DOI: 10.1371/journal.pone.0000990. View

Baum C . Insertional mutagenesis in gene therapy and stem cell biology. Curr Opin Hematol. 2007; 14(4):337-42. DOI: 10.1097/MOH.0b013e3281900f01. View

Ritchie E, Nichols G . Mechanisms of resistance to imatinib in CML patients: a paradigm for the advantages and pitfalls of molecularly targeted therapy. Curr Cancer Drug Targets. 2006; 6(8):645-57. DOI: 10.2174/156800906779010209. View

10.

Cho R, Sieburg H, Muller-Sieburg C . A new mechanism for the aging of hematopoietic stem cells: aging changes the clonal composition of the stem cell compartment but not individual stem cells. Blood. 2008; 111(12):5553-61. PMC: 2424153. DOI: 10.1182/blood-2007-11-123547. View

11.

Osawa M, Nakamura K, Nishi N, Takahasi N, Tokuomoto Y, Inoue H . In vivo self-renewal of c-Kit+ Sca-1+ Lin(low/-) hemopoietic stem cells. J Immunol. 1996; 156(9):3207-14. View

12.

Kamminga L, Akkerman I, Weersing E, Ausema A, Dontje B, Van Zant G . Autonomous behavior of hematopoietic stem cells. Exp Hematol. 2001; 28(12):1451-9. DOI: 10.1016/s0301-472x(00)00543-9. View

13.

Muller-Sieburg C, Cho R, Karlsson L, Huang J, Sieburg H . Myeloid-biased hematopoietic stem cells have extensive self-renewal capacity but generate diminished lymphoid progeny with impaired IL-7 responsiveness. Blood. 2004; 103(11):4111-8. DOI: 10.1182/blood-2003-10-3448. View

14.

Hochhaus A, Kreil S, Corbin A, La Rosee P, Muller M, Lahaye T . Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002; 16(11):2190-6. DOI: 10.1038/sj.leu.2402741. View

15.

Roeder I, Kamminga L, Braesel K, Dontje B, de Haan G, Loeffler M . Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization. Blood. 2004; 105(2):609-16. DOI: 10.1182/blood-2004-01-0282. View

16.

Sato T, Laver J, Ogawa M . Reversible expression of CD34 by murine hematopoietic stem cells. Blood. 1999; 94(8):2548-54. View

17.

Theise N, Wilmut I . Cell plasticity: flexible arrangement. Nature. 2003; 425(6953):21. DOI: 10.1038/425021a. View

18.

Morrison S, Weissman I . 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. View

19.

Kishihara K, Penninger J, Wallace V, Kundig T, Kawai K, Wakeham A . Normal B lymphocyte development but impaired T cell maturation in CD45-exon6 protein tyrosine phosphatase-deficient mice. Cell. 1993; 74(1):143-56. DOI: 10.1016/0092-8674(93)90302-7. View

20.

Down J, Boudewijn A, van Os R, Thames H, Ploemacher R . Variations in radiation sensitivity and repair among different hematopoietic stem cell subsets following fractionated irradiation. Blood. 1995; 86(1):122-7. View