Robust, quantitative tools for modelling ex-vivo expansion of haematopoietic stem cells and progenitors.

Despite substantial research activity on bioreactor design and experiments, there are very few reports of modelling tools that can be used to generate predictive models describing how bioreactor parameters affect performance. New developments in mathematics, such as sparse Bayesian feature selection methods and nonlinear model-free modelling regression methods, offer considerable promise for modelling diverse types of data. The utility of these mathematical tools in stem cell biology are demonstrated by analysis of a large set of bioreactor data derived from the literature. In spite of the diversity of the data sources, and the inherent difficulty in representing bioreactor variables, these modelling methods were able to develop robust, quantitative, predictive models. These models relate bioreactor operational parameters to the degree of expansion of haematopoietic stem cells or their progenitors, and also identify the bioreactor variables that are most likely to affect performance across many experiments. These methods show substantial promise in assisting the design and optimisation of stem cell bioreactors.

[1]  K. Leong,et al.  Expansion of engrafting human hematopoietic stem/progenitor cells in three-dimensional scaffolds with surface-immobilized fibronectin. , 2006, Journal of biomedical materials research. Part A.

[2]  H. Mayani,et al.  In vitro proliferation and expansion of hematopoietic progenitors present in mobilized peripheral blood from normal subjects and cancer patients. , 2004, Stem cells and development.

[3]  Manfred Biselli,et al.  Development of a fixed bed bioreactor for the expansion of human hematopoietic progenitor cells , 1999, Cytotechnology.

[4]  David J. C. MacKay,et al.  Bayesian Interpolation , 1992, Neural Computation.

[5]  Alain Garnier,et al.  Efficient in vitro megakaryocyte maturation using cytokine cocktails optimized by statistical experimental design. , 2005, Experimental hematology.

[6]  I. Lamrissi‐Garcia,et al.  A clinical‐scale expansion of mobilized CD34+ hematopoietic stem and progenitor cells by use of a new serum‐free medium , 2006, Transfusion.

[7]  Chi-kong Li,et al.  Platelet-derived growth factor enhances expansion of umbilical cord blood CD34+ cells in contact with hematopoietic stroma. , 2005, Stem cells and development.

[8]  R. Hoffman,et al.  The in vitro and in vivo effects of stem cell factor on human hematopoiesis , 1993, Stem cells.

[9]  D. Möbest,et al.  Serum-free ex vivo expansion of CD34(+) hematopoietic progenitor cells. , 1998, Biotechnology and bioengineering.

[10]  A. Boehmler,et al.  Expansion of cord blood CD34+ hematopoietic progenitor cells in coculture with autologous umbilical vein endothelial cells (HUVEC) is superior to cytokine-supplemented liquid culture , 2005, Bone Marrow Transplantation.

[11]  D. Haylock,et al.  Principal signalling complexes in haematopoiesis: structural aspects and mimetic discovery. , 2011, Cytokine & growth factor reviews.

[12]  Christie M. Orschell,et al.  Impact of modeled microgravity on migration, differentiation, and cell cycle control of primitive human hematopoietic progenitor cells. , 2004, Experimental hematology.

[13]  T. Nakahata,et al.  Ex vivo expansion of hematopoietic stem cells by cytokines. , 2002, Biochimica et biophysica acta.

[14]  G. Rosner,et al.  Comparative effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) on priming peripheral blood progenitor cells for use with autologous bone marrow after high-dose chemotherapy. , 1993, Blood.

[15]  Julio Caballero,et al.  Bayesian-regularized genetic neural networks applied to the modeling of non-peptide antagonists for the human luteinizing hormone-releasing hormone receptor. , 2006, Journal of molecular graphics & modelling.

[16]  Frank R. Burden,et al.  An Optimal Self‐Pruning Neural Network and Nonlinear Descriptor Selection in QSAR , 2009 .

[17]  K. Ando,et al.  Rapid ex vivo expansion of human umbilical cord hematopoietic progenitors using a novel culture system. , 1999, Experimental hematology.

[18]  H. Koo,et al.  Mesenchymal stem cells feeder layer from human umbilical cord blood for ex vivo expanded growth and proliferation of hematopoietic progenitor cells , 2006, Annals of Hematology.

[19]  David A Winkler,et al.  Modelling blood-brain barrier partitioning using Bayesian neural nets. , 2004, Journal of molecular graphics & modelling.

[20]  W M Miller,et al.  Characterization of Hematopoietic Cell Expansion, Oxygen Uptake, and Glycolysis in a Controlled, Stirred‐Tank Bioreactor System , 1998, Biotechnology progress.

[21]  M. Conconi,et al.  Adrenomedullin and endothelin-1 stimulate in vitro expansion of cord blood hematopoietic stem cells. , 2004, International Journal of Molecular Medicine.

[22]  J G Bender,et al.  Development of novel perfusion chamber to retain nonadherent cells and its use for comparison of human “mobilized” peripheral blood mononuclear cell cultures with and without irradiated bone marrow stroma , 2000, Biotechnology and bioengineering.

[23]  G. Almeida-Porada,et al.  A Stro-1(+) human universal stromal feeder layer to expand/maintain human bone marrow hematopoietic stem/progenitor cells in a serum-free culture system. , 2006, Experimental hematology.

[24]  R. Nordon,et al.  Characterization of cytokine interactions by flow cytometry and factorial analysis. , 2001, Cytometry.

[25]  Frank R Burden,et al.  Broad-based quantitative structure-activity relationship modeling of potency and selectivity of farnesyltransferase inhibitors using a Bayesian regularized neural network. , 2004, Journal of medicinal chemistry.

[26]  Frank R. Burden,et al.  Robust QSAR Models from Novel Descriptors and Bayesian Regularised Neural Networks , 2000 .

[27]  G. Dravid,et al.  Ex Vivo Expansion of Stem Cells from Umbilical Cord Blood: Expression of Cell Adhesion Molecules , 2002, Stem cells.

[28]  Frank R. Burden,et al.  Optimal Sparse Descriptor Selection for QSAR Using Bayesian Methods , 2009 .

[29]  Yang Liu,et al.  Ex vivo expansion of hematopoietic stem cells derived from umbilical cord blood in rotating wall vessel. , 2006, Journal of biotechnology.

[30]  Jian Wang,et al.  Effects of human yolk sac endothelial cells on supporting expansion of hematopoietic stem/progenitor cells from cord blood , 2006, Cell biology international.

[31]  K. Ando,et al.  Ex vivo generation of CD34(+) cells from CD34(-) hematopoietic cells. , 1999, Blood.

[32]  P. Plett,et al.  Proliferation of human hematopoietic bone marrow cells in simulated microgravity , 2007, In Vitro Cellular & Developmental Biology - Animal.

[33]  David A Winkler,et al.  Modelling Inhalational Anaesthetics Using Bayesian Feature Selection and QSAR Modelling Methods , 2010, ChemMedChem.

[34]  Julio Caballero,et al.  QSAR modeling of matrix metalloproteinase inhibition by N-hydroxy-alpha-phenylsulfonylacetamide derivatives. , 2007, Bioorganic & medicinal chemistry.

[35]  J. Cabral,et al.  Ex vivo expansion of hematopoietic stem cells in bioreactors , 2001, Biotechnology Letters.

[36]  Julio Caballero,et al.  Linear and nonlinear modeling of antifungal activity of some heterocyclic ring derivatives using multiple linear regression and Bayesian-regularized neural networks , 2006, Journal of molecular modeling.

[37]  C A Sardonini,et al.  Expansion and Differentiation of Human Hematopoietic Cells from Static Cultures through Small‐Scale Bioreactors , 1993, Biotechnology progress.

[38]  R. Hoffman,et al.  Role of c-kit ligand in the expansion of human hematopoietic progenitor cells. , 1992, Blood.

[39]  M. Yamaguchi,et al.  Serum-free coculture system for ex vivo expansion of human cord blood primitive progenitors and SCID mouse-reconstituting cells using human bone marrow primary stromal cells. , 2001, Experimental hematology.

[40]  M. Pykett,et al.  Cytokine-augmented culture of haematopoietic progenitor cells in a novel three-dimensional cell growth matrix. , 2001, Cytokine.

[41]  E. Terry Papoutsakis,et al.  Ex vivo expansion of primitive hematopoietic cells for cellular therapies: An overview , 2004, Cytotechnology.

[42]  W M Miller,et al.  Stirred culture of peripheral and cord blood hematopoietic cells offers advantages over traditional static systems for clinically relevant applications. , 1998, Biotechnology and bioengineering.

[43]  David A Winkler,et al.  Predictive Bayesian neural network models of MHC class II peptide binding. , 2005, Journal of molecular graphics & modelling.

[44]  Bernhard O. Palsson,et al.  Large-scale Expansion of Human Stem and Progenitor Cells From Bone Marrow Mononuclear Cells in Continuous Perfusion Cultures , 1993 .

[45]  Z. Cui,et al.  Neural Network Analysis of Ex-vivo Expansion of Hematopoietic Stem Cells , 2007, Annals of Biomedical Engineering.

[46]  Guoping Huang,et al.  Marrow mesenchymal stem cells transduced with TPO/FL genes as support for ex vivo expansion of hematopoietic stem/progenitor cells , 2005, Cellular and Molecular Life Sciences CMLS.

[47]  J M Piret,et al.  Cytokine manipulation of primitive human hematopoietic cell self-renewal. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[48]  F. Burden,et al.  Robust QSAR models using Bayesian regularized neural networks. , 1999, Journal of medicinal chemistry.

[49]  Frank R. Burden,et al.  Predictive Human Intestinal Absorption QSAR Models Using Bayesian Regularized Neural Networks , 2005 .

[50]  I-Ming Chu,et al.  A systematic strategy to optimize ex vivo expansion medium for human hematopoietic stem cells derived from umbilical cord blood mononuclear cells. , 2004, Experimental hematology.

[51]  H. Mayani,et al.  In vitro proliferation, expansion, and differentiation of a CD34+ cell-enriched hematopoietic cell population from human umbilical cord blood in response to recombinant cytokines. , 2002, Archives of medical research.

[52]  J. Larghero,et al.  Ex vivo expansion of umbilical cord blood CD34+ cells in a closed system: a multicentric study , 2006, Vox sanguinis.

[53]  F. Burden,et al.  A quantitative structure--activity relationships model for the acute toxicity of substituted benzenes to Tetrahymena pyriformis using Bayesian-regularized neural networks. , 2000, Chemical research in toxicology.

[54]  P. Feugier,et al.  Human umbilical vein endothelial cells increase ex vivo expansion of human CD34(+) PBPC through IL-6 secretion. , 2006, Cytotherapy.

[55]  G. Almeida-Porada,et al.  A human stromal-based serum-free culture system supports the ex vivo expansion/maintenance of bone marrow and cord blood hematopoietic stem/progenitor cells. , 2005, Experimental Hematology.

[56]  Frank R. Burden,et al.  Use of Automatic Relevance Determination in QSAR Studies Using Bayesian Neural Networks , 2000, J. Chem. Inf. Comput. Sci..

[57]  R. Hoffman,et al.  Cocultivation of umbilical cord blood cells with endothelial cells leads to extensive amplification of competent CD34+CD38- cells. , 2000, Experimental hematology.

[58]  Mário A. T. Figueiredo Adaptive Sparseness for Supervised Learning , 2003, IEEE Trans. Pattern Anal. Mach. Intell..

[59]  P. Quesenberry,et al.  Ex vivo expansion of murine marrow cells with interleukin-3 (IL-3), IL-6, IL-11, and stem cell factor leads to impaired engraftment in irradiated hosts. , 1996, Blood.

[60]  M. Yamaguchi,et al.  Ex vivo expansion of human umbilical cord hematopoietic progenitor cells using a coculture system with human telomerase catalytic subunit (hTERT)-transfected human stromal cells. , 2003, Blood.