Skip to main content
NCBI home page
Cytotechnology logoLink to Cytotechnology
. 2003 Mar;41(2-3):75–92. doi: 10.1023/A:1024866504538

Towards predictive models of stem cell fate

Sowmya Viswanathan 1, Peter W Zandstra 1,✉
PMCID: PMC3466685  PMID: 19002945

Abstract

Quantitative approaches are essential for the advancement of strategies to manipulate stem cells or their derivatives for therapeutic applications. Predictive models of stem cell systems would provide the means to pose and validate non-intuitive hypotheses and could thus serve as an important tool for discerning underlying regulatory mechanisms governing stem cell fate decisions. In this paper we review the development of computational models that attempt to describe mammalian adult and embryonic stem (ES) cell responses. Early stochastic models that relied exclusively on statistical distributions to describe the in vitro or in vivo output of stem cells are being revised to incorporate the contributions of exogenous and endogenous parameters on specific stem cell fate processes. Recent models utilize cell specific data (for example, cell-surface receptor distributions, transcription factor half-lives, cell-cycle status, etc.) to provide mechanistic descriptions that are consistent with biologically observed phenomena. Ultimately, the goal of these computational models is to, a priori, predict stem cell output given an initial set of conditions. Our efforts to develop a predictive model of ES cell fate are discussed. The quantitative studies presented in this review represent an important step in developing bioengineering approaches to characterize and predict stem cell behavior. Ongoing efforts to incorporate genetic and signaling network data into computational models should accelerate our understanding of fundamental principles governing stem cell fate decisions.

Keywords: computational models, deterministic andstochastic processes, statistical distributions, stem cells

Full Text

The Full Text of this article is available as a PDF (198.8 KB).

References

  1. Agur Z, Daniel Y, Ginosar Y. The universal properties of stem cells as pinpointed by a simple discrete model. J Math Biol. 2002;44:79–86. doi: 10.1007/s002850100115. [DOI] [PubMed] [Google Scholar]
  2. Alexander WS, Maurer AB, Novak U, Harrison-Smith M. Tyrosine-599 of the c-Mpl receptor is required for Shc phosphorylation and the induction of cellular differentiation. Embo J. 1996;15:6531–6540. [PMC free article] [PubMed] [Google Scholar]
  3. Audet J, Miller CL, Eaves CJ, Piret JM. Common and distinct features of cytokine effects on hematopoietic stem and progenitor cells revealed by dose-response surface analysis. Biotechnol Bioeng. 2002;80:393–404. doi: 10.1002/bit.10399. [DOI] [PubMed] [Google Scholar]
  4. Audet J, Miller CL, Rose-John S, Piret JM, Eaves CJ. Distinct role of gp130 activation in promoting self-renewal divisions by mitogenically stimulated murine hematopoietic stem cells. Proc Natl Acad Sci USA. 2001;98:1757–1762. doi: 10.1073/pnas.98.4.1757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baffy G, Miyashita T, Williamson JR, Reed JC. Apoptosis induced by withdrawal of interleukin-3 (IL-3) from an IL-3-dependent hematopoietic cell line is associated with repartitioning of intracellular calcium and is blocked by enforced Bcl-2 oncoprotein production. J Biol Chem. 1993;268:6511–6519. [PubMed] [Google Scholar]
  6. Bhalla US, Iyengar R. Emergent properties of networks of biological signaling pathways. Science. 1999;283:381–387. doi: 10.1126/science.283.5400.381. [DOI] [PubMed] [Google Scholar]
  7. Bhalla US, Ram PT, Iyengar R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science. 2002;297:1018–1023. doi: 10.1126/science.1068873. [DOI] [PubMed] [Google Scholar]
  8. Bjerknes M. Simple stochastic theory of stem cell differentiation is not simultaneously consistent with crypt extinction probability and the expansion of mutated clones. J Theor Biol. 1994;168:349–365. doi: 10.1006/jtbi.1994.1115. [DOI] [PubMed] [Google Scholar]
  9. Bjerknes M. A test of the stochastic theory of stem cell differentiation. Biophys J. 1986;49:1223–1227. doi: 10.1016/S0006-3495(86)83751-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blackett NM. Haemopoietic spleen colony growth: A versatile, parsimonious, predictive model. Cell Tissue Kinet. 1987;20:393–402. doi: 10.1111/j.1365-2184.1987.tb01324.x. [DOI] [PubMed] [Google Scholar]
  11. Borzillo GV, Ashmun RA, Sherr CJ. Macrophage lineage switching of murine early pre-B lymphoid cells expressing transduced fms genes. Mol Cell Biol. 1990;10:2703. doi: 10.1128/mcb.10.6.2703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Boucher K, Yakovlev AY, Mayer-Proschel M, Noble M. A stochastic model of temporally regulated generation of oligodendrocytes in cell culture. Math Biosci. 1999;159:47–78. doi: 10.1016/s0025-5564(99)00010-3. [DOI] [PubMed] [Google Scholar]
  13. Boucher K, Zorin A, Yakovlev AY, Mayer-Proschel M, Noble M. An alternative stochastic model of generation of oligodendrocytes in cell culture. J Math Biol. 2001;43:22–36. doi: 10.1007/s002850100085. [DOI] [PubMed] [Google Scholar]
  14. Bradley A, Evans M, Kaufman MH, Robertson E. Formation of germ-line chimaeras from embryo-derived teratocarcinoma cell lines. Nature. 1984;309:255–256. doi: 10.1038/309255a0. [DOI] [PubMed] [Google Scholar]
  15. Ching-An P., Bernhard MRK, Palsson Ø. Unilineage model of hematopoiesis predicts self-renewal of stem and progenitor cells based on ex vivo growth data. Biotech Bioengin. 1996;52:24–33. doi: 10.1002/(SICI)1097-0290(19961005)52:1<24::AID-BIT3>3.0.CO;2-0. [DOI] [PubMed] [Google Scholar]
  16. Cross MA, Heyworth CM, Dexter TM. How do stem cells decide what to do? Ciba Found Symp. 1997;204:3–14. doi: 10.1002/9780470515280.ch2. [DOI] [PubMed] [Google Scholar]
  17. Curry JL, Trentin JJ. Hemopoietic spleen colony studies. I. Growth and differentiation. Dev Biol. 1967;15:395–413. doi: 10.1016/0012-1606(67)90034-6. [DOI] [PubMed] [Google Scholar]
  18. Domen J, Cheshier SH, Weissman IL. The role of apoptosis in the regulation of hematopoietic stem cells: Overexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med. 2000;191:253–264. doi: 10.1084/jem.191.2.253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Enver T, Heyworth CM, Dexter TM. Do stem cells play dice? Blood. 1998;92:348–351. [PubMed] [Google Scholar]
  20. Evans MJ, Kaufman MH. Establishment in culture of pluripotential cells from mouse embryos. Nature. 1981;292:154–6. doi: 10.1038/292154a0. [DOI] [PubMed] [Google Scholar]
  21. Fairbairn LJ, Stewart JP, Hampson IN, Arrand JR, Dexter TM. Expression of Epstein-Barr virus latent membrane protein influences self-renewal and differentiation in a multipotential murine haemopoietic 'tem cell' line. J Gen Virol. 1993;74:247–254. doi: 10.1099/0022-1317-74-2-247. [DOI] [PubMed] [Google Scholar]
  22. Fischer M, Goldschmitt J, Peschel C, Brakenhoff JP, Kallen KJ, Wollmer A, Grotzinger J, Rose-John S. A bioactive designer cytokine for human hematopoietic progenitor cell expansion. Nat Biotechnol. 1997;15:142–145. doi: 10.1038/nbt0297-142. [DOI] [PubMed] [Google Scholar]
  23. Furukawa T, Mukherjee S, Bao ZZ, Morrow EM, Cepko CL. Hes1 and notch1 promote the formation of mullerglia by postnatal retinal progenitor cells. Neuron. 2000;26:383–394. doi: 10.1016/s0896-6273(00)81171-x. [DOI] [PubMed] [Google Scholar]
  24. Furusawa C, Kaneko K. Emergence of multicellular organisms with dynamic differentiation and spatial pattern. Artif Life. 1998;4:79–93. doi: 10.1162/106454698568459. [DOI] [PubMed] [Google Scholar]
  25. Furusawa C, Kaneko K. Complex organization in multicellularity as a necessity in evolution. Artif Life. 2000;6:265–281. doi: 10.1162/106454600300103638. [DOI] [PubMed] [Google Scholar]
  26. Furusawa C, Kaneko K. Origin of complexity in multicellular organisms. Phys Rev Lett. 2000;84:6130–6133. doi: 10.1103/PhysRevLett.84.6130. [DOI] [PubMed] [Google Scholar]
  27. Furusawa C, Kaneko K. Theory of robustness of irreversible differentiation in a stem cell system: Chaos hypothesis. J Theor Biol. 2001;209:395–416. doi: 10.1006/jtbi.2001.2264. [DOI] [PubMed] [Google Scholar]
  28. Furusawa C, Kaneko K. Origin of multicellular organisms as an inevitable consequence of dynamical systems. Anat Rec. 2002;268:327–342. doi: 10.1002/ar.10164. [DOI] [PubMed] [Google Scholar]
  29. Gaiano N, Nye JS, Fishell G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron. 2000;26:395–404. doi: 10.1016/s0896-6273(00)81172-1. [DOI] [PubMed] [Google Scholar]
  30. Gordon MY, Blackett NM. Routes to repopulation – A unification of the stochastic model and separation of stem-cell subpopulations. Leukemia. 1994;8:1068–1072. [PubMed] [Google Scholar]
  31. Gross RE, Mehler MF, Mabie PC, Zang Z, Santschi L, Kessler JA. Bone morphogenetic proteins promote astroglial lineage commitment bymammalian subventricular zone progenitor cells. Neuron. 1996;17:595–606. doi: 10.1016/s0896-6273(00)80193-2. [DOI] [PubMed] [Google Scholar]
  32. Harris . The Theory of Branching Process. Berlin: Springer-Verlag; 1963. [Google Scholar]
  33. Hilton DJ, Nicola NA. Kinetic analyses of the binding of leukemia inhibitory factor to receptor on cells and membranes and in detergent solution. J Biol Chem. 1992;267:10238–10247. [PubMed] [Google Scholar]
  34. Hilton DJ, Nicola NA, Metcalf D. Distribution and comparison of receptors for leukemia inhibitory factor on murine hemopoietic and hepatic cells. J Cell Physiol. 1991;146:207–215. doi: 10.1002/jcp.1041460204. [DOI] [PubMed] [Google Scholar]
  35. Hojo M, Ohtsuka T, Hashimoto N, Gradwohl G, Guillemot F, Kageyama R. Glial cell fate specification modulated by the bHLH genes Hes5 in mouse retina. Development. 2000;127:2515–2522. doi: 10.1242/dev.127.12.2515. [DOI] [PubMed] [Google Scholar]
  36. Hu M, Krause D, Greaves M, Sharkis S, Dexter M, Heyworth C, Enver T. Multilineage gene expression precedes commitment in the hemopoietic system. Genes Dev. 1997;11:774–785. doi: 10.1101/gad.11.6.774. [DOI] [PubMed] [Google Scholar]
  37. Humphries RK, Eaves AC, Eaves CJ. Self-renewal of hemopoietic stem cells during mixed colony formation in vitro. Proc Natl Acad Sci USA. 1981;78:3629–3633. doi: 10.1073/pnas.78.6.3629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Ibarrola N, Mayer-Proschel M, Rodriguez-Pena A, Noble M. Evidence for the existence of at least two timing mechanisms that contribute to oligodendrocyte generation in vitro. Dev Biol. 1996;180:1–21. doi: 10.1006/dbio.1996.0280. [DOI] [PubMed] [Google Scholar]
  39. Johe H, Hazel TG, Muller T, Dugich-Djordjevic MM, McKay RD. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 1996;10:3129–3140. doi: 10.1101/gad.10.24.3129. [DOI] [PubMed] [Google Scholar]
  40. Korn AP, Henkelman RM, Ottensmeyer FP, Till JE. Investigations of a stochastic model of haemopoiesis. Exp Hematol. 1973;1:362–375. [PubMed] [Google Scholar]
  41. Kurnit DM, Matthysse S, Papayannopoulou T, Stamatoyannopoulos G. Stochastic branching model for hemopoietic progenitor cell differentiation. J Cell Physiol. 1985;123:55–63. doi: 10.1002/jcp.1041230110. [DOI] [PubMed] [Google Scholar]
  42. Leary AG, Ogawa M, Strauss LC, Civin CI. Single cell origin of multilineage colonies in culture. Evidence that differentiation of multipotent progenitors and restriction of proliferative potential of monopotent progenitors are stochastic processes. J Clin Invest. 1984;74:2193–2197. doi: 10.1172/JCI111645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Leary AG, Strauss LC, Civin CI, Ogawa M. Disparate differentiation in hemopoietic colonies derived from human paired progenitors. Blood. 1985;66:327–32. [PubMed] [Google Scholar]
  44. Li W, Cogswell CA, LoTurco JJ. Neuronal differentiation of precursors in the neocortical ventricular zone is triggered by BMP. J Neurosci. 1998;18:8853–8862. doi: 10.1523/JNEUROSCI.18-21-08853.1998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Liu F, Malaval L, Gupta AK, Aubin JE. Simultaneous detection of multiple bone-related mRNAs and protein expression during osteoblast differentiation: Polymerase chain reaction and immunocytochemical studies at the single cell level. Dev Biol. 1994;166:220–34. doi: 10.1006/dbio.1994.1309. [DOI] [PubMed] [Google Scholar]
  46. Lo L, Tiveron MC, Anderson DJ. MASH1 activates expression of the paired homeodomain transcription factor Phox2a, and couples pan-neuronal and subtype-specific components of autonomic neuronal identity. Development. 1998;125:609–620. doi: 10.1242/dev.125.4.609. [DOI] [PubMed] [Google Scholar]
  47. Loeffler M, Birke A, Winton D, Potten C. Somatic mutation, monoclonality and stochastic models of stem cell organization in the intestinal crypt. J Theor Biol. 1993;160:471–91. doi: 10.1006/jtbi.1993.1031. [DOI] [PubMed] [Google Scholar]
  48. Loeffler M, Bratke T, Paulus U, Li YQ, Potten CS. Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization. J Theor Biol. 1997;186:41–54. doi: 10.1006/jtbi.1996.0340. [DOI] [PubMed] [Google Scholar]
  49. Loeffler M, Grossmann B. A stochastic branching model with formation of subunits applied to the growth of intestinal crypts. J Theor Biol. 1991;150:175–191. doi: 10.1016/s0022-5193(05)80330-3. [DOI] [PubMed] [Google Scholar]
  50. Loeffler M, Stein R, Wichmann HE, Potten CS, Kaur P, Chwalinski S. Intestinal cell proliferation. I. A comprehensive model of steady-state proliferation in the crypt. Cell Tissue Kinet. 1986;19:627–645. doi: 10.1111/j.1365-2184.1986.tb00763.x. [DOI] [PubMed] [Google Scholar]
  51. Ma Q, Chen ZF, Barrantes IB, De la Pompa JL, Anderson DJ. Neurogenin 1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron. 1998;20:469–482. doi: 10.1016/s0896-6273(00)80988-5. [DOI] [PubMed] [Google Scholar]
  52. Madras N, Gibbs AL, Zhou Y, Zandstra PW, Aubin JE. Modeling stem cell development by retrospective analysis of gene expression profiles in single progenitor-derived colonies. Stem Cells. 2002;20:230–240. doi: 10.1634/stemcells.20-3-230. [DOI] [PubMed] [Google Scholar]
  53. Martin GR. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA. 1981;78:7634–7638. doi: 10.1073/pnas.78.12.7634. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Mayani H, Dragowska W, Lansdorp PM. Lineage commitment in human hemopoiesis involves asymmetric cell division of multipotent progenitors and does not appear to be influenced by cytokines. J Cell Physiol. 1993;157:579–586. doi: 10.1002/jcp.1041570318. [DOI] [PubMed] [Google Scholar]
  55. Metcalf D. Haemopoietic growth factors. Med J Aust. 1988;148:516–519. doi: 10.5694/j.1326-5377.1988.tb99462.x. [DOI] [PubMed] [Google Scholar]
  56. Metcalf D. Lineage commitment and maturation in hematopoietic cells: The case for extrinsic regulation. Blood. 1998;92:345–347. [PubMed] [Google Scholar]
  57. Metcalf D. Lineage commitment in the progeny of murine hematopoietic preprogenitor cells: Influence of thrombopoietin and interleukin 5. Proc Natl Acad Sci USA. 1998;95:6408–6412. doi: 10.1073/pnas.95.11.6408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Metcalf D. Lineage commitment of hemopoietic progenitor cells in developing blast cell colonies: Influence of colonystimulating factors. Proc Natl Acad Sci USA. 1991;88:11310. doi: 10.1073/pnas.88.24.11310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Metcalf D, Nicola NA. The regulatory factors controlling murine erythropoiesis in vitro. Prog Clin Biol Res. 1984;148:93–105. [PubMed] [Google Scholar]
  60. Miller CL, Eaves CJ. Expansion in vitro of adult murine hematopoietic stem cells with transplantable lympho-myeloid reconstituting ability. Proc Natl Acad Sci USA. 1997;94:13648–13653. doi: 10.1073/pnas.94.25.13648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Morrison SJ. Neuronal potential and lineage determination by neural stem cells. Curr Opin Cell Biol. 2001;13:666–672. doi: 10.1016/s0955-0674(00)00269-6. [DOI] [PubMed] [Google Scholar]
  62. Morrison SJ. The last shall not be first: The ordered generation of progeny from stem cells. Neuron. 2000;28:1–3. doi: 10.1016/s0896-6273(00)00075-1. [DOI] [PubMed] [Google Scholar]
  63. Morrison SJ, Perez SE, Qiao Z, Verdi JM, Hicks C, Weinmaster G, Anderson DJ. Transient Notch activation initiates an irreversible switch from neurogenesis to gliogenesis by neural crest stem cells. Cell. 2000;101:499–510. doi: 10.1016/s0092-8674(00)80860-0. [DOI] [PubMed] [Google Scholar]
  64. Morrison SJ, Shah NM, Anderson DJ. Regulatory mechanisms in stem cell biology. Cell. 1997;88:287–298. doi: 10.1016/s0092-8674(00)81867-x. [DOI] [PubMed] [Google Scholar]
  65. Nakahata T, Gross AJ, Ogawa M. A stochastic model of self-renewal and commitment to differentiation of the primitive hemopoietic stem cells in culture. J Cell Physiol. 1982;113:455–458. doi: 10.1002/jcp.1041130314. [DOI] [PubMed] [Google Scholar]
  66. Nakahata T, Tsuji K, Ishiguro A, Ando O, Norose N, Koike K, Akabane T. Single-cell origin of human mixed hemopoietic colonies expressing various combinations of cell lineages. Blood. 1985;65:1010–1016. [PubMed] [Google Scholar]
  67. Nieto MSC, Britz O, Guillemot F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron. 2001;29:401–413. doi: 10.1016/s0896-6273(01)00214-8. [DOI] [PubMed] [Google Scholar]
  68. Nordon RE, Ginsberg SS, Eaves CJ. High-resolution cell division tracking demonstrates the FLt3-ligand-dependence of human marrow CD34+CD38– cell production in vitro. Br J Haematol. 1997;98:528–539. doi: 10.1046/j.1365-2141.1997.2823097.x. [DOI] [PubMed] [Google Scholar]
  69. Nordon RE, Nakamura M, Ramirez C, Odell R. Analysis of growth kinetics by division tracking. Immunol Cell Biol. 1999;77:523–529. doi: 10.1046/j.1440-1711.1999.00869.x. [DOI] [PubMed] [Google Scholar]
  70. Novak JP, Stewart CC. Stochastic versus deterministic in haemopoiesis. Br J Haematol. 1991;78:149–154. doi: 10.1111/j.1365-2141.1991.tb04409.x. [DOI] [PubMed] [Google Scholar]
  71. Nunez G, London L, Hockenbery D, Alexander M, McKearn JP, Korsmeyer SJ. Deregulated Bcl-2 gene expression selectively prolongs survival of growth factor-deprived hemopoietic cell lines. J Immunol. 1990;144:3602–3610. [PubMed] [Google Scholar]
  72. Ogawa M. Differentiation and proliferation of hematopoietic stem cells. Blood. 1993;81:2844–2853. [PubMed] [Google Scholar]
  73. Ogawa M. Stem cell differentiation. Nippon Ketsueki Gakkai Zasshi. 1983;46:1374–1379. [PubMed] [Google Scholar]
  74. Ogawa M. Stochastic model revisited. Int J Hematol. 1999;69:2–5. [PubMed] [Google Scholar]
  75. Oostendorp RA, Audet J, Eaves CJ. High-resolution tracking of cell division suggests similar cell cycle kinetics of hematopoietic stem cells stimulated in vitro and in vivo. Blood. 2000;95:855–862. [PubMed] [Google Scholar]
  76. Orkin SH. Diversification of haematopoietic stem cells to specific lineages. Nat Rev Genet. 2000;1:57–64. doi: 10.1038/35049577. [DOI] [PubMed] [Google Scholar]
  77. Paulus JM, Levin J, Debili N, Albert A, Vainchenker W. Genesis of clone size heterogeneity in megakaryocytic and other hemopoietic colonies: the stochastic model revisited. Exp Hematol. 2001;29:1256–1269. doi: 10.1016/s0301-472x(01)00728-7. [DOI] [PubMed] [Google Scholar]
  78. Pharr PN, Nedelman J, Downs HP, Ogawa M, Gross AJ. A stochastic model for mast cell proliferation in culture. J Cell Physiol. 1985;125:379–386. doi: 10.1002/jcp.1041250304. [DOI] [PubMed] [Google Scholar]
  79. Preisler HD, Kauffman S. A proposal regarding the mechanism which underlies lineage choice during hematopoietic differentiation. Leuk Res. 1999;23:685–694. doi: 10.1016/s0145-2126(99)00077-6. [DOI] [PubMed] [Google Scholar]
  80. Qian X, Shen Q, Goderie SH, He W, Capela A, Davis AA, Temple S. Timing of CNS cell generation: A programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron. 2000;28:69–80. doi: 10.1016/s0896-6273(00)00086-6. [DOI] [PubMed] [Google Scholar]
  81. Ramsfjell V, Bryder D, Bjorgvinsdottir H, Kornfalt S, Nilsson L, Borge OJ, Jacobsen SE. Distinct requirements for optimal growth and In vitro expansion of human CD34(+)CD38(–) bone marrow long-term culture-initiating cells (LTC-IC), extended LTC-IC, and murine in vivo long-term reconstituting stem cells. Blood. 1999;94:4093–4102. [PubMed] [Google Scholar]
  82. Roeder I, Loeffler M. A novel dynamic model of hematopoietic stem cell organization based on the concept of withintissue plasticity. Exp Hematol. 2002;30:853–861. doi: 10.1016/s0301-472x(02)00832-9. [DOI] [PubMed] [Google Scholar]
  83. Shah NM, Marchionni MA, Isaacs I, Stroobant PW, Anderson DJ. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cel. 1994;77:349–360. doi: 10.1016/0092-8674(94)90150-3. [DOI] [PubMed] [Google Scholar]
  84. Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell. 1996;85:331–343. doi: 10.1016/s0092-8674(00)81112-5. [DOI] [PubMed] [Google Scholar]
  85. Siminovitch L, McCulloch EA, Till JE. The distribution of colony-forming cells among spleen colonies. J Cell Comp Physiol. 1963;62:327. doi: 10.1002/jcp.1030620313. [DOI] [PubMed] [Google Scholar]
  86. Smith A, Metcalf D, Nicola NA. Cytoplasmic domains of the common beta-chain of the GM-CSF/IL-3/IL-5 receptors that are required for inducing differentiation or clonal suppression in myeloid leukaemic cell lines. Embo J. 1997;16:451–464. doi: 10.1093/emboj/16.3.451. [DOI] [PMC free article] [PubMed] [Google Scholar]
  87. Smith AG, Heath JK, Donaldson DD, Wong GG, Moreau J, Stahl M, Rogers D. Inhibition of pluripotential embryonic stem cell differentiation by purified polypeptides. Nature. 1988;336:688–690. doi: 10.1038/336688a0. [DOI] [PubMed] [Google Scholar]
  88. Smith AG, Hooper ML. Buffalo rat liver cells produce a diffusible activity which inhibits the differentiation of murine embryonal carcinoma and embryonic stem cells. Dev Biol. 1987;121:1–9. doi: 10.1016/0012-1606(87)90132-1. [DOI] [PubMed] [Google Scholar]
  89. Solberg LA., Jr A biological and computational model of megakaryocyte development as a stochastic branching process. Int J Cell Cloning. 1990;8:283–290. doi: 10.1002/stem.5530080413. [DOI] [PubMed] [Google Scholar]
  90. Suda J, Suda T, Ogawa M. Analysis of differentiation of mouse hemopoietic stem cells in culture by sequential replating of paired progenitors. Blood. 1984;64:393–399. [PubMed] [Google Scholar]
  91. Suda T, Suda J, Ogawa M. Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. Proc Natl Acad Sci USA. 1984;81:2520–2524. doi: 10.1073/pnas.81.8.2520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Suda T, Suda J, Ogawa M. Single-cell origin of mouse hemopoietic colonies expressing multiple lineages in variable combinations. Proc Natl Acad Sci USA. 1983;80:6689–6693. doi: 10.1073/pnas.80.21.6689. [DOI] [PMC free article] [PubMed] [Google Scholar]
  93. Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G, Greenberg ME. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell. 2001;104:365–376. doi: 10.1016/s0092-8674(01)00224-0. [DOI] [PubMed] [Google Scholar]
  94. Swain PS, Elowitz MB, Siggia ED. Intrinsic and extrinsic contributions to stochasticity in gene expression. Proc Natl Acad Sci USA. 2002;99:2795–12800. doi: 10.1073/pnas.162041399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  95. Tang DG, Tokumoto YM, Apperly JA, Lloyd AC, Raff MC. Lack of replicative senescence in cultured rat oligodendrocyte precursor cells. Science. 2001;291:868–871. doi: 10.1126/science.1056780. [DOI] [PubMed] [Google Scholar]
  96. Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T. Notch1 and Notch3 instructively restrict bFGFresponsive multipotent neural progenitor cells to an astroglial fate. Neuron. 2001;29:45–55. doi: 10.1016/s0896-6273(01)00179-9. [DOI] [PubMed] [Google Scholar]
  97. Till JE, McCulloch EA, Siminovitch L. A stochastic model of stem cell proliferation, based on the growth of spleen colonyforming cells. Proc Natl Acad Sci USA. 1964;51:29. doi: 10.1073/pnas.51.1.29. [DOI] [PMC free article] [PubMed] [Google Scholar]
  98. Tomita K, Moriyoshi K, Nakanishi S, Guillemot F, Kageyama R. Mammalian achaete-scute and atonal homologs regulate neuronal versus glial fate determination in the central nervous system. EMBO J. 2000;19:5460–5472. doi: 10.1093/emboj/19.20.5460. [DOI] [PMC free article] [PubMed] [Google Scholar]
  99. Trentin JJ. Hemopoietic microenvironments. Tran splant Proc. 1978;10:77–82. [PubMed] [Google Scholar]
  100. Van Zant G, Goldwasser E. Competition between erythropoietin and colony-stimulating factor for target cells in mouse marrow. Blood. 1979;53:946–965. [PubMed] [Google Scholar]
  101. Viswanathan S, Benatar T, Rose-John S, Lauffenburger DA, Zandstra PW. Ligand/receptor signaling threshold (LIST) model accounts for gp130-mediated embryonic stem cell selfrenewal responses to LIF and HIL-6. Stem Cells. 2002;20:119–138. doi: 10.1634/stemcells.20-2-119. [DOI] [PubMed] [Google Scholar]
  102. Viswanathan S, Raghu R, Mileikovsky M, Nagy A, Lauffenburger DA & Zandstra PW (2002a) Computational Model Based on Ligand/ Receptor Signaling Threshold (LIST) Model Predicts Stem Cell Population Dynamic Responses to Leukemia Inhibitory Factor (submitted).
  103. Viswanathan S, Benatar T, Mileikovsky M, Lauffenburger DA, Nagy A & Zandstra PW (2002b) Growth Factor Interactions Modulate Competitive Dynamics Between Embryonic Stem Cells and Their Immediate Derivatives (submitted).
  104. Vogel H, Niewisch H, Matioli G. Stochastic development of stem cells. J Theor Biol. 1969;22:249–270. doi: 10.1016/0022-5193(69)90004-6. [DOI] [PubMed] [Google Scholar]
  105. Von Collani E, Tsodikov, Yakovlev A, Mayer-Proschel M, Noble M. A random walk model of oligodendrocyte generation in vitro and associated estimation problems. Math Biosci. 1999;159:189–204. doi: 10.1016/s0025-5564(99)00017-6. [DOI] [PubMed] [Google Scholar]
  106. Waddington CH, Robertson E. Selection for developmental canalisation. Genet Res. 1966;7:303–312. doi: 10.1017/S0016672300009769. [DOI] [PubMed] [Google Scholar]
  107. Williams RL, Hilton DJ, Pease S, Willson TA, Stewart CL, Gearing DP, Wagner EF, Metcalf D, Nicola NA, Gough NM. Myeloid leukaemia inhibitory factor maintains the developmental potential of embryonic stem cells. Nature. 1988;336:684–687. doi: 10.1038/336684a0. [DOI] [PubMed] [Google Scholar]
  108. Winton DJ, Ponder BA. Stem-cell organization in mouse small intestine. Proc R Soc Lond B Biol Sci. 1990;241:13–18. doi: 10.1098/rspb.1990.0059. [DOI] [PubMed] [Google Scholar]
  109. Withers HR, Elkind MM. Dose-survival characteristics of epithelial cells of mouse intestinal mucosa. Radiology. 1968;91:998–1000. doi: 10.1148/91.5.998. [DOI] [PubMed] [Google Scholar]
  110. Withers HR, Elkind MM. Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int J Radiat Biol Relat Stud Phys Chem Med. 1970;17:261–267. doi: 10.1080/09553007014550291. [DOI] [PubMed] [Google Scholar]
  111. Wu AM. Regulation of self-renewal of human T lymphocyte colony-forming units (TL-CFUs) J Cell Physiol. 1983;117:101–108. doi: 10.1002/jcp.1041170114. [DOI] [PubMed] [Google Scholar]
  112. Yakovlev AY, Boucher K, Mayer-Proschel M, Noble M. Quantitative insight into proliferation and differentiation of oligodendrocyte type 2 astrocyte progenitor cells in vitro. ProcNatl Acad Sci USA. 1998;95:14164–7. doi: 10.1073/pnas.95.24.14164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  113. Yakovlev AY, Mayer-Proschel M, Noble M. A stochastic model of brain cell differentiation in tissue culture. J Math Biol. 1998;37:49–60. doi: 10.1007/s002850050119. [DOI] [PubMed] [Google Scholar]
  114. Zandstra PW, Conneally E, Petzer AL, Piret JM, Eaves CJ. Cytokine manipulation of primitive human hematopoietic cell self-renewal. Proc Natl Acad Sci USA. 1997;94:4698–4703. doi: 10.1073/pnas.94.9.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
  115. Zandstra PW, Lauffenburger DA, Eaves CJ. A ligandreceptor signaling threshold model of stem cell differentiation control: A biologically conserved mechanism applicable to hematopoiesis. Blood. 2000;96:1215–22. [PubMed] [Google Scholar]
  116. Zandstra PW, Le HV, Daley GQ, Griffith LG, Lauffenburger DA. Leukemia inhibitory factor (LIF) concentration modulates embryonic stem cell self-renewal and differentiation independently of proliferation. Biotechnol Bioeng. 2000;69:607–617. [PubMed] [Google Scholar]
  117. Zandstra PW, Nagy A. Stem cell bioengineering. Annu Rev Biomed Eng. 2001;3:275–305. doi: 10.1146/annurev.bioeng.3.1.275. [DOI] [PubMed] [Google Scholar]
  118. Zhang XW, Audet J, Piret JM, Li YX. Cell cycle distribution of primitive haematopoietic cells stimulated in vitro and in vivo. Cell Prolif. 2001;34:321–330. doi: 10.1046/j.0960-7722.2001.00210.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  119. Zorin A, Mayer-Proschel M, Noble M, Yakovlev AY. Estimation problems associated with stochastic modeling of proliferation and differentiation of O-2A progenitor cells in vitro. Math Biosci. 2000;167:109–121. doi: 10.1016/s0025-5564(00)00040-7. [DOI] [PubMed] [Google Scholar]

Articles from Cytotechnology are provided here courtesy of Springer Science+Business Media B.V.

RESOURCES