Abstract
The competitive repopulation assay in recipients has emerged as the gold standard test that enables characterization of hematopoietic stem cells (HSCs) by their capacity for reconstitution of the lymphohematopoietic system. When combined with a limiting dilution design, this assay, termed limiting-dilution competitive repopulation assay (LDCRA) allows measurement of HSC numbers in vivo. Thus far, the statistical single-hit Poisson model (SHPM) has played a prominent role in analyzing LDCRAs to estimate HSC frequencies. This chapter presents a review of a new statistical method for analyzing LDCRAs, called multi-cell Poisson modeling, with aim to more accurately estimate the frequency of HSCs. Multi-cell Poisson models (MCPM) stand for a general family of Poisson models that extend the SHPM hypothesis, including the traditional SHPM as a special case of the model series. Through examples of re-analyses of LDCRAs from previously published papers, it is shown the ability of MCPM to model LDCRAs in comparison to the traditional SHPM. The results emphasize that MCPM can provide more reliable HSC frequency estimates than obtained from the exclusive use of the SHPM. It is concluded that the use of proper Poisson models alternative to the traditional SHPM appears as critical to ensure accurate HSC frequency estimates, and MCPM should be routinely used to model LDCRAs. More generally, MCPM provide substantial refinement in the art of modeling limiting dilution assays.
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References
Akala OO, Park IK, Qian D, Pihalja M, Becker MW, Clarke MF (2008) Long-term haematopoietic reconstitution by Trp53 -/- p16 lnk4a-/- p19 Arf-/- multipotent progenitors. Nature 453:228–232
Anderson DR (2008) Model based inference in the life sciences: a primer on evidence. Springer, New York, NY
Bonnefoix T, Callanan M (2010) Accurate hematopoietic stem cell frequency estimates by fitting multicell Poisson models substituting to the single-hit Poisson model in limiting dilution transplantation assays. Blood 116:2472–2475
Bonnefoix T, Bonnefoix P, Perron P, Mi JQ, Ng WF, Lechler R, Bensa JC, Cahn JY, Leroux D (2005) Quantitating effector and regulatory T lymphocytes in immune responses by limiting dilution analysis modeling. J Immunol 174:3421–3431
Burnham KP, Anderson DR (2002) Model selection and multimodel inference: a practical information – Theoretic approach, 2nd edn. Springer, New York, NY
Buske C, Feuring-Buske M, Abramovich C, Spiekermann K, Eaves CJ, Coulombel L, Sauvageau G, Hogge DE, Humphries RK (2002) Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood 100:862–868
Cho RH, Sieburg HB, Muller-Sieburg CE (2008) 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 111:5553–5561
Chute JP, Muramoto GG, Whitesides J, Colvin M, Safi R, Chao NJ, McDonnell DP (2006) Inhibition of aldehyde dehydrogenase and retinoid signaling induces the expansion of human hematopoietic stem cells. Proc Natl Acad Sci USA 103:11707–11712
Geiger H, Van Zant G (2002) The aging of lympho-hematopoietic stem cells. Nat Immunol 3:329–333
Hess DA, Meyerrose TE, Wirthlin L, Craft TP, Herrbrich PE, Creer MH, Nolta JA (2004) Functional characterization of highly purified human hematopoietic repopulating cells isolated according to aldehyde dehydrogenase activity. Blood 104:1648–1655
Himburg HA, Muramoto GG, Daher P, Meadows SK, Lauren Russell J, Doan P, Chi JT, Salter AB, Lento WE, Reya T, Chao NJ, Chute JP (2010) Pleiotrophin regulates the expansion and regeneration of hematopoietic stem cells. Nat Med 16:475–482
Hu Y, Smyth GK (2009) ELDA: Extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 347:70–78
Kent DG, Copley MR, Benz C, Wöhrer S, Dykstra BJ, Ma E, Cheyne J, Zhao Y, Bowie MB, Zhao Y, Gasparetto M, Delaney A, Smith C, Marra M, Eaves CJ (2009) Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential. Blood 113:6342–6350
Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE, Stevens C, Barker JN, Gale RP, Lazarus HM, Marks DI, van Rood JJ, Scaradavou A, Horowitz MM (2004) Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 351:2265–2275
Liang Y, Van Zant G, Szilvassy SJ (2005) Effects of aging on the homing and engraftment of murine hematopoietic stem and progenitor cells. Blood 106:1479–1487
McDermott SP, Eppert K, Lechman ER, Doedens M, Dick JE (2010) Comparison of human cord blood engraftment between immunocompromised mouse strains. Blood 116:193–200
Morita Y, Ema H, Nakauchi H (2010) Heterogeneity and hierarchy within the most primitive hematopoietic stem cell compartment. J Exp Med 207:1173–1182
Muramoto GG, Russell JL, Safi R, Salter AB, Himburg HA, Daher P, Meadows SK, Doan P, Storms RW, Chao NJ, McDonnell DP, Chute JP (2010) Inhibition of aldehyde dehydrogenase expands hematopoietic stem cells with radioprotective capacity. Stem Cells 28:523–534
North TE, Goessling W, Walkley CR, Lengerke C, Kopani KR, Lord AM, Weber GJ, Bowman TV, Jang IH, Grosser T, Fitzgerald GA, Daley GQ, Orkin SH, Zon LI (2007) Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature 447:1007–1011
Osawa M, Hanada K, Hamada H, Nakauchi H (1996) Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273:242–245
Purton LE, Scadden DT (2007) Limiting factors in murine hematopoietic stem cell assays. Cell Stem Cell 1:263–270
Rawat VPS, Arsenib N, Ahmedb F, Mulawb MA, Thoenea S, Heilmeierb B, Sadlond T, D’Andread RJ, Hiddemannb W, Bohlanderb SK, Buske C, Feuring-Buske M (2010) The vent-like homeobox gene VENTX promotes human myeloid differentiation and is highly expressed in acute myeloid leukemia. Proc Natl Acad Sci USA 107:16946–16951
Roeder I, Horn K, Sieburg HB, Cho R, Muller-Sieberg C, Loeffler M (2008) Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: A model-based approach. Blood 112:4874–4883
Storms RW, Green PD, Safford KM, Niedzwiecki D, Cogle CR, Colvin OM, Chao NJ, Rice HE, Smith CA (2005) Distinct hematopoietic progenitor compartments are delineated by the expression of aldehyde dehydrogenase and CD34. Blood 106:95–102
Szilvassy SJ, Humphries RK, Lansdorp PM, Eaves AC, Eaves CJ (1990) Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc Natl Acad Sci USA 87:8736–8740
Taswell C (1981) Limiting dilution assays for the determination of immunocompetent cell frequencies. I. Data analysis. J Immunol 126:1614–1649
Weissman IL, Shizuru JA (2008) The origins of the identification and isolation of hematopoietic stem cells, and their capability to induce donor-specific transplantation tolerance and treat autoimmune diseases. Blood 112:3543–3553
Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E, Lió P, Macdonald HR, Trumpp A (2008) Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell 135:1118–1129
Yahata T, Ando K, Sato T, Miyatake H, Nakamura Y, Muguruma Y, Kato S, Hotta T (2003) A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD/SCID mice bone marrow. Blood 101:2905–2913
Zon LI (2008) Intrinsic and extrinsic control of haematopoietic stem-cell self-renewal. Nature 453:306–313
Acknowledgment
The authors would like to thank Philippe Carbonnel for expert design of Fig. 2.1.
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Bonnefoix, T., Callanan, M. (2012). Hematopoietic Stem Cell Frequency Estimate: Statistical Approach to Model Limiting Dilution Competitive Repopulation Assays. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 2. Stem Cells and Cancer Stem Cells, vol 2. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-2016-9_2
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