Reusing and composing models of cell fate regulation of human bone precursor cells

In order to treat osteoporosis and other bone mass disorders it is necessary to understand the regulatory processes that control the cell fate decisions responsible for going from bone precursor cells to bone tissue. Many processes interact to regulate cell division, differentiation and apoptosis. There are models for these basic processes, but not for their interactions. In this work we use the theory of switched systems, reuse and composition of validated models to describe the cell fate decisions leading to bone and fat formation. We describe the differentiation of osteo-adipo progenitor cells by composing its model with differentiation stimuli. We use the activation of the Wnt pathway as stimulus to osteoblast lineage, including regulation of cell division and apoptosis. This model is our first step to simulate physiological responses in silico to treatments for bone mass disorders.

[1]  John P. Bilezikian,et al.  Principles of Bone Biology , 1996 .

[2]  Sui Huang,et al.  Bifurcation dynamics in lineage-commitment in bipotent progenitor cells. , 2007, Developmental biology.

[3]  I. Langmuir.  THE CONSTITUTION AND FUNDAMENTAL PROPERTIES OF SOLIDS AND LIQUIDS , 1917 .

[4]  Rodrigo Assar.  Modeling and simulation of Hybrid Systems and Cell factory applications , 2011 .

[5]  Sandeep Krishna,et al.  Stress-specific response of the p53-Mdm2 feedback loop , 2010, BMC Systems Biology.

[6]  Robert Shorten,et al.  Stability Criteria for Switched and Hybrid Systems , 2007, SIAM Rev..

[7]  Hidde de Jong,et al.  Modeling and Simulation of Genetic Regulatory Systems: A Literature Review , 2002, J. Comput. Biol..

[8]  S. Bernard,et al.  Adipocyte Turnover: Relevance to Human Adipose Tissue Morphology , 2009, Diabetes.

[9]  A. Cleton-Jansen,et al.  Inactive Wnt/β‐catenin pathway in conventional high‐grade osteosarcoma , 2010, The Journal of pathology.

[10]  G. Meinhardt,et al.  Cell-cell contact mediated signalling - no fear of contact. , 2006, Experimental oncology.

[11]  A. Hill,et al.  The possible effects of the aggregation of the molecules of haemoglobin on its dissociation curves , 1910 .

[12]  S Waldherr,et al.  Cell differentiation modeled via a coupled two-switch regulatory network. , 2010, Chaos.

[13]  Mehrdad Sabetzadeh,et al.  A Relationship-Driven Framework for Model Merging , 2007, International Workshop on Modeling in Software Engineering (MISE'07: ICSE Workshop 2007).

[14]  A. Maass,et al.  Calcium/calmodulin‐dependent protein kinase type IV is a target gene of the Wnt/β‐catenin signaling pathway , 2009, Journal of cellular physiology.

[15]  Paul Crubillé,et al.  Construction and Analysis of Transition Systems with MEC , 1995, AMAST Series in Computing.

[16]  I. Weissman,et al.  Cell fate determination from stem cells , 2002, Gene Therapy.

[17]  Darren J. Wilkinson.  Stochastic Modelling for Systems Biology , 2006 .

[18]  J. Kumar,et al.  LRP4 association to bone properties and fracture and interaction with genes in the Wnt- and BMP signaling pathways. , 2011, Bone.

[19]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[20]  Michael Hucka,et al.  The Systems Biology Markup Language (SBML): Language Specification for Level 3 Version 1 Core (Release 1 Candidate) , 2010 .

[21]  David James Sherman,et al.  BioRica: A multi model description and simulation system , 2007 .

[22]  I. Greenwald,et al.  LIN-12/Notch signaling: lessons from worms and flies. , 1998, Genes & development.

[23]  Branicky.  [IEEE 1994 33rd IEEE Conference on Decision and Control - Lake Buena Vista, FL, USA (14-16 Dec. 1994)] Proceedings of 1994 33rd IEEE Conference on Decision and Control - Stability of switched and hybrid systems , 1994 .

[24]  L. Mosekilde,et al.  Age- and sex-related changes in iliac cortical bone mass and remodeling. , 1993, Bone.

[25]  Gerhard-Wilhelm Weber,et al.  Modeling gene regulatory networks with piecewise linear differential equations , 2007, Eur. J. Oper. Res..

[26]  Rodrigo Assar,et al.  Genome-wide identification of new Wnt/β-catenin target genes in the human genome using CART method , 2010, BMC Genomics.

[27]  M. Maurin,et al.  REVIEW ARTICLE doi: 10.1111/j.1472-8206.2008.00633.x The Hill equation: a review of its capabilities in pharmacological modelling , 2008 .

[28]  Luke H. Hoeppner,et al.  Wnt signaling as a therapeutic target for bone diseases , 2009, Expert opinion on therapeutic targets.

[29]  Hidde de Jong,et al.  The Carbon Assimilation Network in Escherichia coli Is Densely Connected and Largely Sign-Determined by Directions of Metabolic Fluxes , 2010, PLoS Comput. Biol..

[30]  J. Park,et al.  Homocysteine enhances apoptosis in human bone marrow stromal cells. , 2006, Bone.

[31]  S. V. Aksenov,et al.  A systems biology dynamical model of mammalian G1 cell cycle progression , 2007, Molecular systems biology.

[32]  D. Kim,et al.  A hidden oncogenic positive feedback loop caused by crosstalk between Wnt and ERK Pathways , 2007, Oncogene.

[33]  B. Alberts,et al.  Molecular Biology of the Cell 4th edition , 2007 .

[34]  S. Manolagas,et al.  Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. , 2000, Endocrine reviews.

[35]  JOHN J. TYSON.  Modeling the cell division cycle : cdc 2 and cyclin interactions ( maturation promoting factor / metaphase arrest , .

[36]  O. MacDougald,et al.  Regulation of bone mass by Wnt signaling. , 2006, The Journal of clinical investigation.

[37]  N. Lane,et al.  Targeting the Wnt signaling pathway to augment bone formation , 2008, Current osteoporosis reports.

[38]  Mathias John,et al.  Hierarchical Modeling for Computational Biology , 2008, SFM.

[39]  Christian Clausen,et al.  Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. , 2003, Bone.

[40]  Attila Csikász-Nagy,et al.  Computational systems biology of the cell cycle , 2009, Briefings Bioinform..

[41]  L. Tavernini.  Differential automata and their discrete simulators , 1987 .

[42]  K. Ozono,et al.  Wnt signaling in bone metabolism , 2009, Journal of Bone and Mineral Metabolism.

[43]  S. K. Zaidi,et al.  Runx2/Cbfa1 Functions: Diverse Regulation of Gene Transcription by Chromatin Remodeling and Co-Regulatory Protein Interactions , 2003, Connective tissue research.

[44]  Min Zhu,et al.  Comparison of Multi-Lineage Cells from Human Adipose Tissue and Bone Marrow , 2003, Cells Tissues Organs.

[45]  J. Latham,et al.  Sclerostin promotes the apoptosis of human osteoblastic cells: a novel regulation of bone formation. , 2004, Bone.

[46]  ALBERT GOLDBETER Facultd.  A minimal cascade model for the mitotic oscillator involving cyclin and cdc 2 kinase ( cell cycle / maturation-promoting factor / phosphorylation cascade / thresholds / biochemical oscillations ) , .

[47]  Antoine Rauzy,et al.  The AltaRica Formalism for Describing Concurrent Systems , 1999, Fundam. Informaticae.

[48]  Y. Wan,et al.  PGC1beta mediates PPARgamma activation of osteoclastogenesis and rosiglitazone-induced bone loss. , 2010, Cell metabolism.

[49]  M. Branicky.  Stability of switched and hybrid systems , 1994, Proceedings of 1994 33rd IEEE Conference on Decision and Control.

[50]  Kartik Shankar,et al.  Obesity Reduces Bone Density Associated with Activation of PPARγ and Suppression of Wnt/β-Catenin in Rapidly Growing Male Rats , 2010, PloS one.

[51]  David L. Helfet,et al.  Role of Wnt Signaling in Bone Remodeling and Repair , 2008, HSS Journal.

[52]  Irving Langmuir,et al.  The constitution and fundamental properties of solids and liquids. Part II.—Liquids , 1917 .