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Monitoring and Mathematical Modeling of in Vitro Human Megakaryocyte Expansion and Maturation Dynamics

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Monitoring and Mathematical Modeling of in Vitro Human Megakaryocyte Expansion and Maturation Dynamics YOUNES LEYSI-DERILOU MONITORING AND MATHEMATICAL MODELING OF IN VITRO HUMAN MEGAKARYOCYTE EXPANSION AND MATURATION DYNAMICS Thèse présentée à la Faculté des études supérieures de l’Université Laval dans le cadre du programme de doctorat en génie chimique pour l’obtention du grade de Philosophiae doctor (Ph.D.) DEPARTMENT DE GÉNIE CHIMIQUE FACULTÉ DE SCIENCES ET GÉNIE UNIVERSITÉ LAVAL QUÉBEC 2011 © Younes Leysi-Derilou, 2011 ii Résumé La mégakaryopoïèse est un processus complexe, qui prend naissance à partir des cellules souches hématopoïétiques (HSC). Ces dernières se différencient par étapes successives en mégakaryocytes (MKs) qui, suite à leur maturation, libèrent les plaquettes. Afin de modéliser le sort des HSCs lors de la mégakaryopoïèse en culture, un nouveau modèle mathématique a été développé, basé sur un programme de différenciation tridimensionnelle (3-D) où chaque sous-population est représentée par un compartiment. Dans le but d’évaluer la prolifération, la différenciation des MKs immatures puis matures, la cinétique de mort cellulaire ainsi que le nombre de plaquettes produites, à partir des cellules de sang de cordon (CB) ombilical enrichies en CD34+, un ensemble d'équations différentielles a été déployé. Les cellules CD34+ ont été placées en culture dans un milieu optimisé pour la différenciation mégakaryocytaire. Les paramètres cinétiques ont été estimés pour deux températures d'incubation (37°C versus 39°C). Les résultats des régressions ont été validés par l'évaluation de l'estimabilité des paramètres, en utilisant des analyses de sensibilité locale et globale, puis la détermination d'un intervalle de confiance. Ceux-ci ont été comparés par le biais de tests statistiques et d’analyses en composante principale (ACP). Le modèle proposé pourrait permettre de mieux comprendre les phénomènes complexes observés. Les MKs sont uniques parmi les cellules hématopoïétiques, étant les seules à devenir polyploïdes au cours de leur développement par l’entremise de l’endomitose, un processus mitotique qui se termine prématurément durant la cytocinèse. Pour obtenir une image plus complète et exhaustive de la mégacaryopoïèse, une approche d’imagerie cellulaire à grand champ et à long terme a été développée permettant de suivre individuellement l'évolution des HSCs lors de leur différenciation ex vivo. Cela a permis de démontrer que les MKs polyploïdes sont encore capables de se diviser et de produire des cellules filles polyploïdes, et que ce processus est plus fréquent chez les MKs issues de CB que de moelle osseuse d'adulte. De plus, le processus de formation des proplaquettes semble également réversible. Les phénomènes énoncés plus haut étaient inversement proportionnels au niveau de ploïdie des MKs. En conclusion, cette étude a dévoilé de nouvelles propriétés jusqu’ici inconnues des MKs. iii Abstract Megakaryopoiesis is a complex process, which is initiated with the proliferation and the differentiation of hematopoietic stem cells (HSC) into megakaryocytes (MK), followed by the maturation of MK and ended by platelet release. To describe the fates of HSC during ex vivo megakaryopoiesis, a new mathematical model was developed based on a 3- dimensional kinetic developmental program. To address this, a set of differential equations was applied to analyze the proliferation, differentiation and death kinetic rates of purified cord blood (CB)-CD34+ cells, immature and mature MKs, as well as platelet number and productivity. CB-CD34+ cells were placed in culture optimized for MK differentiation. The kinetic parameters were estimated for two incubation temperatures (37°C vs. 39°C). The regression results have been validated by assessing the parameter identifiability using local and global sensitivity analyses and confidence intervals, and compared using statistical tests and principal component analysis (PCA). Furthermore, PCA was applied on the solution matrix to construct a simplified MK differentiation pathway model, and to reveal dependencies among the model parameters. The proposed model provides insight into phenomena that would be otherwise difficult to interpret. MKs are unique among mammalian marrow cells as they polyploidize during their natural development. It is universally accepted that MK becomes polyploid by repeatedly deviating from normal cell cycling, where it ceases to complete cytokinesis and divide. To challenge this long-standing hypothesis and to obtain a more comprehensive picture of megakaryopoiesis, a long-term and large-field live cell imaging approach of in vitro MK culture was developed. Using CB- and bone marrow (BM)-CD34+ as starting cells, the direct observation of cells undergoing differentiation and maturation over a 5-day culture period is reported for the first time. Herein, direct visual proof that polyploid MKs can complete cytokinesis during its normal development is presented. This phenomenon was found not restricted to CB- as the BM-derived polyploid MK also underwent division. However the latter showed significantly lower proliferation rate. This new finding explains in part the unresolved issue of low ploidy levels observed in CB-MK and contests the notion that polyploid MKs do not divide. iv Avant-Propos Dr. Alain Garnier supervised the graduate student for the entire research work; helped designing the experiments, and provided expertise in cell culture engineering; gave advice on live cell imaging approach, its development, and consultation on digital image processing; proposed and developed mathematical models and sensitivity analyses, and helped programming with MATLAB® and ImageJ softwares; helped, guided, criticized, and corrected the manuscripts and thesis. Dr. Garnier’s lab in chemical engineering department supported financially the graduate student and the required materials and tools, provided the environment for some cell manipulation and live cell imaging apparatus. Dr. Nicolas Pineault cosupervised the graduate student, provided expertise in stem cell and megakaryocyte biology; helped experimental designs, and provided expertise in cell culturing, flow cytometry, and cell assays; helped, guided, criticized, and corrected the manuscripts and thesis. All CB-cells were provided and manipulated in Dr. Pineault’s lab at Héma-Québec R&D department. Dr. Carl Duchesne cosupervised the graduate student, provided expertise in mathematical modeling, sensitivity analysis of the models, statistical analysis, and programming using MATLAB® software. Dr. Duchesne’s lab in chemical engineering department provided the live cell imaging apparatus. Ms. Lucie Boyer, co-author of the paper on polyploid cell division, helped design the experiments and provided technical assistance on cell culturing, CB-cell purification, flow cytometry, and cell assays in Dr. Pineault’s lab at Héma-Québec R&D department. Ms. Amélie Robert, co-author of the paper on polyploid cell division, performed the confocal microscopy experiment, interpreted the related results and edited the manuscript. Younes Leysi-Derilou, designed and performed the experiments of cell culturing, flow cytometry, microscopy, cell tracking, data storage, data management, statistical analysis and mathematical modeling; wrote the programs for cell segmentation, image analysis, mathematical modeling, and flow cytometry using ImageJ, MATLAB®, ImagePro Plus, QED InVivo, FCS Express softwares and analyzed the results; and is the principal author of the manuscripts and the author of this thesis. v Acknowledgements I wish to express my hearty gratitude to Dr. Alain Garnier, for his guidance and inspiration during the time of my graduate study and research. I would like to thank Dr. Nicolas Pineault for serving as my co-advisor and for his valuable guidance and suggestions on biological aspects of this research, and Dr. Carl Duchesne, my other co-director for his help on mathematical modeling. Dr. Nicolas Pineault’s lab in Héma-Québec R&D department has been a very warm environment. I have wonderful memory with my colleagues who worked, studied and discussed together during my graduate studies, Lucie Boyer, Jean-François Boucher, Amélie Robert, Valérie Cortin, Marie-Christine Hains, and Marichou Boulette. I deeply thank my family, my wife, her family and my friends for their endless support and encouragement. Without their emotional and spiritual support, completion of this PhD degree might have been impossible. Last but not least, this thesis is dedicated to my wife, Sanaz Haratifar, and my brother, Rustam Salimi, and his family members, who have given me their love and concern during my school life. I do appreciate NSERC and FQRNT, grants # 194430-06 and PR-113931, respectively, for their financial support of this research work. I would also like to sincerely thank Dr. Renée Bazin (R&D department of Héma-Québec) for providing the murine bone marrow samples. vi Table of Contents Résumé ................................................................................................................................... ii Abstract ................................................................................................................................. iii Avant-Propos ........................................................................................................................ iv Acknowledgements .................................................................................................................v Table of Contents .................................................................................................................
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