Analyzing the immunobiology of cultured mesenchymal stromal cells

ANALYZING THE IMMUNOBIOLOGY OF CULTURED MESENCHYMAL STROMAL CELLS LIU HUA NATIONAL UNIVERSITY OF SINGAPORE 2009 ANALYZING THE IMMUNOBIOLOGY OF CULTURED MESENCHYMAL STROMAL CELLS LIU HUA (Bachelor of Medicine/ Bachelor of Surgery, Master of Science) A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY FACULTY OF DENTISTRY NATIONAL UNIVERSITY OF SINGAPORE 2009 ACKNOWLEDGEMENTS I wish to present my deepest gratitude and devout thankfulness to my supervisors – Associate Professor Tong CAO, Faculty of Dentistry (FOD), National University of Singapore (NUS) and Professor David Michael KEMENY, Immunology Programme, Life Sciences Institute (LSI), NUS – for their continuous encouragement, invaluable guidance, generous financial support, infinite patience and meticulous solicitude through the period of this study I wish to express my heartfelt gratitude to Dr Paul Anthony MACARY, Immunology Programme, LSI, NUS for his incessant encouragement, altruistic help, and exhaustive comments on the presentation of data and thesis preparation I would like to cordially thank Dr Veronique ANGELI, Immunology Programme, LSI, NUS, and Dr Stephan GASSER, Immunology Programme, LSI, NUS, for their earnest help in the consultation of this study And I would like to thank Dr Boon Chin HENG, School of Materials Science and Engineering, Nanyang Technological University for his critical comments on my writing I would like to sincerely thank Associate Professor Varawan SAE-LIM, Vice Dean of Research, FOD, NUS; Associate Professor Jin Fei YEO, Head, Department of Oral & Maxillofacial Surgery, FOD, NUS; Miss Bee Wee NG, Ms Yue Peng LEE (Linda), Ms Siuh Eng SING (Cynthia), Ms Lay Hoon ONG (Jane) of Dean’s office, FOD, NUS i for their administrative support Without their strong support, the work would have not been possible I would like to present my cordial appreciation to Mr Swee Heng CHAN, Miss Tok Lin HAN, Mr Wee Wah TOK, Mdm Jamanah AHMAD (Lina) of FOD, NUS, as well as Ms Lip Chuen HO, Ms Fei Chuin LEW, Mr Yen Leong CHUA, and Mr Wei Qiang CHEN of Immunology Programme, LSI, NUS for their help in lab and animal maintenance I would present my impassioned thankfulness to the members of Stem Cell Lab, FOD, NUS and Immunology Programme, LSI, NUS – Mr Kai LU, Mr Wei Seong TOH, Dr Kok Loon WONG, Mr Ren Jie CHUA, Mr Gen LIN, Mr Kok Sum WONG, Mr Wei Siong HO, Miss Chien Tei TOO and Miss Yan Ting LIM, as well as Mr Abdul Malik S MUHAMMAD of the satellite Animal Holding Unit – for their warm-hearted technical assistance and material support I also would like to grant my gratitude to all other members in both Stem Cell Lab, FOD, NUS and Immunology Programme lab, LSI, NUS for their concern and help all heart and soul Last but not the least, I am grateful to my husband Dr Gang Hua ZHU, my parents, my parents in law and other family members for their endless love, tacit understanding and implicit support ii This work was partially supported by grants from the Ministry of Education of Singapore (R221000011712, R221000007112, R223000014112 and R223000018112) iii TABLE OF CONTENTS ACKNOWLEDGEMENTS i TABLE OF CONTENTS iv LIST OF FIGURES xi LIST OF TABLES xiii ABBREVIATION xiv SUMMARY xvii LIST OF PUBLICATIONS, AWARD AND CONFERENCES xxii 1.0 LITERATURE REVIEW 1.1 INTRODUCTION 1.2 WHAT ARE STEM CELLS 1.2.1 Definition of stem cells 1.2.2 History of stem cells 1.2.3 Common characteristics of stem cells 1.2.4 Classification of stem cells 1.3 WHAT ARE MESENCHYMAL STROMAL CELLS 1.3.1 Definition of mesenchymal stromal cells 1.3.2 Heterogeneity of mesenchymal stromal cells 10 1.3.3 Homing of mesenchymal stromal cells 14 1.3.3.1 Mechanism of MSC homing 15 1.3.3.2 Factors influencing MSC homing 17 iv 1.3.4 Paracrine effects of mesenchymal stromal cells 1.4 19 PROGRESS IN IMMUNOLOGICAL STUDY OF MESENCHYMAL STROMAL CELLS 20 1.4.1 Immunogenicity of mesenchymal stem cells 22 1.4.2 Immune modulation by mesenchymal stromal cells 23 1.4.2.1 Effect on innate immunity 23 1.4.2.1.1 Effect on natural killer cells 24 1.4.2.1.2 Effect on monocytes and dendritic cells 26 1.4.2.1.3 Effect on neutrophils 28 1.4.2.2 Effect on adaptive immunity 28 1.4.2.2.1 Effect on T cells 29 1.4.2.2.2 Effect on B cells 34 1.4.3 Effect on mesenchymal stromal cells by immune system 1.4.4 Summary 1.5 36 38 APPLICATION POTENTIALS OF MESENCHYMAL STROMAL CELLS 39 1.5.1 Application of mesenchymal stromal cells 1.5.2 Limitation of mesenchymal stromal cells 1.6 39 42 ANIMAL MODEL 46 2.0 HYPOTHESIS AND OBJECTIVE 49 3.0 MATERIALS AND METHODS 50 3.1 INTRODUCTION 50 3.1.1 Experimental design 50 v 3.1.2 Experimental animals 3.1.3 Common materials and consumables 3.2 50 51 51 3.2.1 Isolation and culture of mouse bone marrow cells 52 3.2.2 Enrichment and propagation of mouse MSC (mMSC) 53 3.2.3 Detection of surface molecules of mMSC 54 3.2.4 Colony forming unit assay of mMSC 55 3.2.5 Tri-lineage differentiation of mMSC 55 3.2.6 Karyotyping of mMSC chromosomes 58 3.2.7 In vivo osteogenic potential comparison of mMSC 3.3 CULTURE AND CHARACTERIZATION OF MSC 59 IMMUNOLOGICAL TESTING OF MSC IN VITRO 60 3.3.1 Detection of MHC molecules on mMSC at serial passage numbers 61 3.3.2 Coculture of allogeneic mMSC at serial passage numbers and naïve spleen mononuclear cells 61 3.3.3 Incubation of allogeneic mMSC at serial passage numbers and one-way mixed lymphocyte culture 63 3.3.4 Incubation of allogeneic mMSC at serial passage numbers, Concanavalin A and spleen mononuclear cells 64 3.3.5 Testing the effect of mMSC secretion on allogeneic MNC proliferation 64 3.3.6 Testing of soluble molecules in mMSC supernatant 65 3.3.7 TGF-β bioassay 66 3.3.8 Analysis of TGF-β and IL-10 secreting cells in coculture of mMSC and MLC 67 vi 3.4 IMMUNOLOGICAL TESTING OF MSC IN VIVO 68 3.4.1 Delayed-type hypersensitivity reaction of allogeneic mMSC at different passage numbers 68 3.4.2 Testing of the inhibitory effect of allogeneic mMSC at different passage numbers on recalled immune responses 70 3.4.3 Testing of the inhibitory effect of allogeneic mMSC secretion at a late passage number on recalled immune responses 70 3.4.4 Testing of the role of TGF-β and IL-10 in the inhibitory effect of allogeneic mMSC 72 3.4.5 Analysis of immune cell components in blood and spleens 3.4.6 Analysis of immune molecules in serum 3.5 74 74 STATISTICAL ANALYSIS 74 4.0 RESULTS 76 4.1 THE IDENTITY OF MSC 76 4.1.1 Bone marrow stromal cells were free of hematopoietic cell contamination 76 4.1.2 Bone marrow stromal cells displayed MSC phenotype 77 4.1.3 Bone marrow stromal cells displayed tri-lineage differentiation ability 78 4.1.4 Bone marrow stromal cells displayed rapid proliferation 83 4.1.5 Bone marrow stromal cells kept normal karyotype during long-term culture 85 4.1.6 Selected bone marrow stromal cell subpopulation displayed normal biological function at local graft site 86 4.1.7 Summary 88 vii 4.2 THE IMMUNE PROPERTIES OF MSC ALTERED WITH EXTENDED CULTURE 88 4.2.1 Low expression of MHC did not increase along extended culture 88 4.2.2 Allo-immune responses increased along extended culture 89 4.2.3 Immuno-inhibition decreased along extended culture 90 4.2.4 Cytokines played a major role in the immuno-inhibition of MSC 91 4.2.4.1 TGF-β and IL-10 were produced by different cell components in the co-culture of MSC and immune MNC 93 4.2.4.2 TGF-β and IL-10 attended the immuno-inhibition of MSC 95 4.2.4.3 The amount of TGF-β secretion did not decrease along extended culture of MSC 97 4.2.5 Summary 4.3 98 THE IMMUNE PROPERTIES OF MSC ALTERED IN IN VIVO APPLICATION 4.3.1 Significant MHC-I expression was detected on MSC grafts 99 99 4.3.2 MSC at both early and late passage numbers displayed similar immunogenicity 100 4.3.3 MSC at an early passage number displayed immuno-inhibition by exposing to engraftment milieu 100 4.3.4 MSC at a late passage number displayed immuno-inhibition by encapsulation 102 4.3.5 Immuno-inhibition of encapsulated MSC at a late passage number could not be reversed by 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