Asymmetry of stem cell fate and the potential impact of the niche

Asymmetric cell division is a common concept to explain the capability of stem cells to simultaneously produce a continuous output of differentiated cells and to maintain their own population of undifferentiated cells. Whereas for some stem cell systems, an asymmetry in the division process has explicitly been demonstrated, no evidence for such a functional asymmetry has been shown for hematopoietic stem cells (HSC) so far. This raises the question regarding whether asymmetry of cell division is a prerequisite to explain obvious heterogeneity in the cellular fate of HSC.Through the application of a mathematical model based on self-organizing principles, we demonstrate that the assumption of asymmetric stem cell division is not necessary to provide a consistent account for experimentally observed asymmetries in the development of HSC. Our simulation results show that asymmetric cell fate can alternatively be explained by a reversible expression of functional stem cell potentials, controlled by changing cell-cell and cell-microenvironment interactions. The proposed view on stem cell organization is pointing to the potential role of stem cell niches as specific signaling environments, which induce developmental asymmetries and therefore, generate cell fate heterogeneity.The self-organizing concept is fully consistent with the functional definition of tissue stem cells. It naturally includes plasticity phenomena without contradicting a hierarchical appearance of the stem cell population. The concept implies that stem cell fate is only predictable in a probabilistic sense and that retrospective categorization of stem cell potential, based on individual cellular fates, provides an incomplete picture.

[1]  Christopher S Potten,et al.  1 – Stem cells and cellular pedigrees – a conceptual introduction , 1997 .

[2]  Haiyang Huang,et al.  Identification of the haematopoietic stem cell niche and control of the niche size , 2003, Nature.

[3]  N. Theise.  Blood to liver and back again: seeds of understanding. , 2003, Haematologica.

[4]  Ting Xie,et al.  Germline Stem Cells Anchored by Adherens Junctions in the Drosophila Ovary Niches , 2002, Science.

[5]  Juergen A. Knoblich.  Cell division: Asymmetric cell division during animal development , 2001, Nature Reviews Molecular Cell Biology.

[6]  J. Till,et al.  A STOCHASTIC MODEL OF STEM CELL PROLIFERATION, BASED ON THE GROWTH OF SPLEEN COLONY-FORMING CELLS. , 1964, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Ingo Roeder,et al.  Tissue Stem Cells: Definition, Plasticity, Heterogeneity, Self-Organization and Models – A Conceptual Approach , 2002, Cells Tissues Organs.

[8]  A. Ho,et al.  The symmetry of initial divisions of human hematopoietic progenitors is altered only by the cellular microenvironment. , 2003, Experimental hematology.

[9]  E. Deryugina,et al.  The stromal cells' guide to the stem cell universe , 1995, Stem cells.

[10]  Peter W. Zandstra,et al.  Towards predictive models of stem cell fate , 2003, Cytotechnology.

[11]  R. Hardy,et al.  The germinal proliferation center in the testis of Drosophila melanogaster. , 1979, Journal of Ultrastructure Research.

[12]  T. Graf.  Differentiation plasticity of hematopoietic cells. , 2002, Blood.

[13]  N. Testa.  Leukemia: Recent Advances in Biology and Treatment , 1987 .

[14]  P. Quesenberry,et al.  Physical and physiological plasticity of hematopoietic stem cells. , 2001, Blood cells, molecules & diseases.

[15]  T. Schroeder.  Tracking Hematopoiesis at the Single Cell Level , 2005, Annals of the New York Academy of Sciences.

[16]  M. Fuller,et al.  Orientation of Asymmetric Stem Cell Division by the APC Tumor Suppressor and Centrosome , 2003, Science.

[17]  C. Potten,et al.  The intestinal epithelial stem cell: the mucosal governor , 1997, International journal of experimental pathology.

[18]  I. Weissman,et al.  In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  H. Kay.  HOW MANY CELL-GENERATIONS? , 1965, Lancet.

[20]  B. Williams,et al.  Quiescence, cycling, and turnover in the primitive hematopoietic stem cell compartment. , 1997, Experimental hematology.

[21]  K. Moore,et al.  In vitro maintenance of highly purified, transplantable hematopoietic stem cells. , 1997, Blood.

[22]  Ingo Roeder,et al.  Competitive clonal hematopoiesis in mouse chimeras explained by a stochastic model of stem cell organization. , 2005, Blood.

[23]  M. Entman,et al.  Stem Cell Plasticity in Muscle and Bone Marrow , 2001, Annals of the New York Academy of Sciences.

[24]  P. Quesenberry,et al.  The fleet feet of haematopoietic stem cells: rapid motility, interaction and proteopodia , 2001, British journal of haematology.

[25]  K. Kemphues,et al.  par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed , 1995, Cell.

[26]  D. Marshak,et al.  Stem Cell Biology , 2001 .

[27]  M. Ogawa,et al.  Reversible expression of CD34 by murine hematopoietic stem cells. , 1999, Blood.

[28]  Brian I Lord,et al.  13 – Biology of the haemopoietic stem cell , 1997 .

[29]  Peter Guttorp,et al.  Evidence that hematopoiesis may be a stochastic process in vivo , 1996, Nature Medicine.

[30]  U. Paulus,et al.  Clonality and life cycles of intestinal crypts explained by a state dependent stochastic model of epithelial stem cell organization. , 1997, Journal of Theoretical Biology.

[31]  K. Moore,et al.  Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells. , 1996, Blood.

[32]  M. Loeffler,et al.  Cell migration and organization in the intestinal crypt using a lattice‐free model , 2001, Cell proliferation.

[33]  Haifan Lin.  Stem cells: To be and not to be , 2003, Nature.

[34]  Elaine Fuchs,et al.  Asymmetric cell divisions promote stratification and differentiation of mammalian skin , 2005, Nature.

[35]  M. Loeffler,et al.  A stochastic branching model with formation of subunits applied to the growth of intestinal crypts. , 1991, Journal of theoretical biology.

[36]  Linheng Li,et al.  Stem cell niche: structure and function. , 2005, Annual review of cell and developmental biology.

[37]  M. Loeffler,et al.  Stem cells: attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. , 1990, Development.

[38]  H. Nakauchi,et al.  Asymmetric Division and Lineage Commitment at the Level of Hematopoietic Stem Cells , 2004, The Journal of experimental medicine.

[39]  R. Schofield.  The relationship between the spleen colony-forming cell and the haemopoietic stem cell. , 1978, Blood cells.

[40]  H Cheng,et al.  Clonal analysis of mouse intestinal epithelial progenitors. , 1999, Gastroenterology.

[41]  Lesilee S. Rose,et al.  Early patterning of the C. elegans embryo. , 1998, Annual review of genetics.

[42]  H. L. Carson,et al.  The Genetics and Biology of Drosophila , 1976, Heredity.

[43]  J. Wuu,et al.  The Fluctuating Phenotype of the Lymphohematopoietic Stem Cell with Cell Cycle Transit , 1998, The Journal of experimental medicine.

[44]  M. Loeffler,et al.  Quantitative tissue stem cell modeling. , 2003, Blood.

[45]  Peng Li,et al.  Inscuteable and Staufen Mediate Asymmetric Localization and Segregation of prospero RNA during Drosophila Neuroblast Cell Divisions , 1997, Cell.

[46]  F. Doetsch,et al.  A niche for adult neural stem cells. , 2003, Current opinion in genetics & development.

[47]  T. Suda,et al.  Disparate differentiation in mouse hemopoietic colonies derived from paired progenitors. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Ingo Roeder,et al.  A novel dynamic model of hematopoietic stem cell organization based on the concept of within-tissue plasticity. , 2002, Experimental hematology.

[49]  Haifan Lin.  The stem-cell niche theory: lessons from flies , 2002, Nature Reviews Genetics.

[50]  S. Mcconnell,et al.  Cleavage orientation and the asymmetric inheritance of notchl immunoreactivity in mammalian neurogenesis , 1995, Cell.

[51]  H. Blau,et al.  Plasticity of cell fate: insights from heterokaryons. , 1999, Seminars in cell & developmental biology.

[52]  M. Loeffler,et al.  Modeling the effect of deregulated proliferation and apoptosis on the growth dynamics of epithelial cell populations in vitro. , 2005, Biophysical journal.

[53]  A. Brand,et al.  Asymmetric cell division: microtubule dynamics and spindle asymmetry. , 2002, Journal of cell science.

[54]  Lily Yeh Jan,et al.  Development: Asymmetric cell division in the Drosophila nrevous system , 2001, Nature Reviews Neuroscience.

[55]  N. Theise,et al.  Bone marrow to liver: the blood of Prometheus. , 2002, Seminars in cell & developmental biology.

[56]  Martin Raff,et al.  Asymmetric segregation of Numb: a mechanism for neural specification from Drosophila to mammals , 2002, Nature Neuroscience.