Figure 4-10 Migration quantification of the MSCs toward uninjured and injured cartilage tissue Migration distance of the MSCs toward the complete media (CM) alone, uninjured and injured tissues were showed in this graph (Error bars represent standard errors of the means, one star: p-value < 0.05, two star: p-value < 0.01, and star: p-value < 0.001)   107   4.4.6 Quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) Custom-designed RT-PCR array was used to evaluate the differences in gene expressions of uninjured and injured cartilage tissue The factors were chosen according to the literature review and the availability of the primers for the RTPCR (Table 4.1) RT-PCR results showed that the injured cartilage upregulated expressions of collagen type I A1 (COL1A1), chemokine C-X-C motif 10 (CXCL10), transforming growth factor alpha (TGFA), insulin-like growth factor (IGF2), chemokine C-X-C motif 12 (CXCL12), angiopoietin (ANGPT1), fibroblast growth factor (FGF2), transforming growth factor beta3 (TGFβ3), bone morphogenetic protein (BMP4), and vitronectin (VTN) ligands Figure 4.8 showed the relative increase of gene expressions of these factors 108     Figure 4-11 Gene expression change of candidate ligands in injured cartilage Gene expression level (sample number = 2) increases of the candidate ligands, which could be involved in the MSCs migration 109   4.5 Discussion To evaluate if the migration of MSCs toward the injured cartilage, which was shown in previous chapter, is an active reaction to the injury site or a random translocation of MSCs to that site, the behavior of MSCs were studied in a microfluidic device I developed a new microfluidic device to simulate the in vivo interaction of MSCs with injured cartilage tissue in a three dimensional (3D) environment This simulation allows monitoring of the interactions between MSCs and the tissue in cellular and molecular level However, our system still lacks many of the characteristics of an actual in vivo situation For example in living animals, the host cells such as immune cells (e.g macrophages, monocytes, T cells, etc.) have interactions with both injured tissues and transplanted stem cells, which may affect their behaviors Moreover, in in vivo the blood circulation and joint motion may have some role in stem cell migration, which I not have in this in vitro model Although, these factors may make a difference between behavior of stem cells and injured tissue in vivo and in vitro (microfluidic device), microfluidic device has many advantages to the current methods and mimics the environment of real tissue better than conventional methods such as Boyden chamber, scratch migration assay, and under agarose migration system Boyden chamber, scratch test and under-agarose migration assay are the most common migration assay systems The Boyden chamber assay uses a membrane to separate the upper chamber (cell chamber) from the bottom chamber, which is too thin to make a gradient In Boyden chamber assay only the final results of the migration can be collected and this system allows testing only one condition at a time In the scratch migration test, cells are 110   scratched and the migration of the cells is evaluated by monitoring how the cells fill the gap.This system does not make a gradient of the chemotactic factors, which is one of the effective components in the tissue regeneration Also with this system we cannot use any tissue as the origin of chemotactic factors Under agarose migration assay system is dependent on the concept that solidified agarose does not attach to glass surfaces To perform this assay, a thick layer of warm agarose should be poured into a glass plate After solidification, three holes punched out; one hole for cell seeding, one for the cytokine source and one as control After gradient formation of the cytokine the cell migration can be observed, however this migration can be in any direction, and monitoring of the cells can be very difficult Other potential limitation of this system is the risk of cross-contamination of the cytokines between the holes through the porous agarose By using microfluidic system, I could study the cell migration in a 3D environment, which was more similar to in vivo situation and provided the control of the gradient between channels By having the specific channels for the 3D scaffold parallel to the cell channel on both sides, I decreased the risk of cross-contamination of the cytokines and also I could control the migration of the cells in a certain direction (collagen channel), which made it easier to monitor and image the cells migration Moreover, the high quality imaging capabilities of microfluidic system provided real-time monitoring of cells simultaneously at two different conditions over time The results of this study showed that MSCs could be primed and migrated toward the injured cartilage The migration (distance) toward the injured tissue 111   is longer than that of uninjured cartilage, suggesting injured tissue may secret factors attracting the MSCs As I showed that the injured cartilage attracts the MSCs, and the engraftment of the MSCs in the injured cartilage could be an active migration and homing, I also evaluated the potential chemotactic candidates for this phenomenon There are many chemotactic factors named in the literature that are secreted by different injured tissues such as skin wound, acute and chronic inflammation in brain and etc Previous studies (Table 4-2) have shown that CXCL10 (247), TGFA (157), IGF2 (152), CXCL12 (248), FGF2 (148), TGFB3 (249), BMP4 (154) and ANGPT1 (158) are stimulatory factors for MSCs migration However, to our knowledge, there is not any study on the injured cartilage As the nature of the cartilage is different from the other tissues due to lack of blood vessels and lymphatic drainage, in this study I evaluated the factors, which were up-regulated by the chondrocytes after acute cartilage injury It is crucial to understand the chemotactic factors secreted by injured cartilage to be able to use a sub-population of MSCs, which show stronger response to such factors in the clinical setting to design more effective treatment plan for patients RT-PCR results of injured cartilage tissues demonstrated that, chemotactic factors such as CXCL10, TGFA, IGF2, CXCL12, ANGPT1, FGF2, TGFB3, BMP4, and the extracellular matrix (ECM) proteins genes such as COL1A1, and VTN were up-regulated after cartilage injury 112   Table 4-2 Other studies done on stem cell stimulatory chemotactic factors Ligand genes COL1A1 CXCL10 TGFA IGF2 CXCL12 ANGPT1 Chemokine source Assay method Condition and outcome Reference Commercially available Modified Boyden chamber Collagen I induced significant motogenic activity for both rabbit and human MSCs Thibault et al (161) Recombinant human chemokine Commercially available Agarose drop migration assay Boyden chamber / Wound assay Rice et al (247) Ozaki et al (157) Recombinant human chemokine Modified Boyden chamber CXCL10 chemokine trigger hMSC migration and promote hMSC proliferation The factors that induced the migration of rabbit and human MSCs also enhanced their proliferation IGF2 is a chemotactic factor for hMSCs and stimulates migration of human mesenchymal progenitor cells Supernatant of cultured human pancreatic islets Commercially available Fiedler et al (152) Modified Boyden chamber Human pancreatic islets as an in vitro model released CXCL12, which is able to attract BM MSCs in vitro Sordi et al (248) Transwell dishes Migration values of the TNFα-stimulated BM MSCs were higher than un-stimulated cells Ponte et al (158) Low concentrations of FGF2 leads to migration, whereas higher concentrations resulted in repulsion of the MSCs Schmidt et al (148) FGF2 Commercially available TGFB3 Commercially available Boyden chamber / Wound Assay / methyl cellulose disc Modified Boyden chamber BMP4 Commercially available VTN Commercially available TGFB3 stimulates chemotaxis/chemokinesis of multipotent C3H10T1/2 cells Makhijani et al (249) Modified Boyden chamber Migration of primary human progenitor cells was stimulated by rxBMP-4 in a dose-dependent manner Fiedler et al (154) Modified Boyden chamber Vitronectin induced significant motogenic activity for both rabbit and human MSCs Thibault et al (161) 113   Our results agreed with those of Thibault et al who demonstrated that ECM proteins such as Col1 and VTN could induce significant migratory and motogenic activity for MSCs (161) Then, these ECM proteins could be used in the clinical setting for cartilage repair as a scaffold to carry the stem cells and/or attract the endogenous or exogenous stem cells (endogenous from the bone marrow and exogenous by multiple intra-articular injection of the expanded autologous stem cells) As I showed, in the previous chapter, that injection of stem cells is a promising method for cartilage repair, in this chapter I confirmed that engraftment of the MSCs in injured cartilage is an active migration and homing process and injured cartilage encourage the migration of the MSCs toward the injury site I also showed that the cartilage injury up-regulate some specific chemotactic factors, which can help to find and select a sub-population of MSCs which show stronger response to such factors in cartilage repair On one hand, enhancement of the homing capacity of MSC can be achieved by modulating their response to chemotactic factors; for example by finding and selecting sub-population of MSCs which show stronger response to such factors (because of higher expression of surface receptors which responsible for those chemotactic signals) (250) On the other hand, modulation can be applied in the site of injury for example with stimulating the target site to attract more MSCs (with releasing more signals) 114   Chapter Autologous Bone Marrow Derived Mesenchymal Stem Cell versus Autologous Chondrocyte Implantation: An Observational Cohort Study 1 The final, definitive version of this paper has been published in “The American Journal of Sports Medicine”, 38(6): 1110-6, 2010 June by SAGE Publications Ltd SAGE Publications, Inc., All rights reserved © 115   5.1 Abstract Background: First generation ACI has limitations and introducing new effective cell sources can improve cartilage repair Purpose: To compare the clinical outcomes of patients treated with first generation autologous chondrocyte implantation (ACI) to patients treated with autologous bone marrow derived mesenchymal stem cell (BM MSCs) Study Design: Cohort Study, Level of Evidence, Methods: Seventy-two matched (lesion site and age) patients underwent cartilage repair using chondrocytes (n=36) or BM MSCs (n=36) Clinical outcomes were measured pre-operation and 3, 6, 9, 12, 18, and 24 months post-operation using the International Cartilage Repair Society (ICRS) Cartilage Injury Evaluation Package which included questions from the ShortForm (SF-36) Health Survey, International Knee Documentation Committee (IKDC) subjective knee evaluation form, Lysholm24 knee scale, and Tegner activity level scale Results: There was significant improvement in the patients’ quality of life (physical and mental components of the SF-36 questionnaire included in the ICRS package) after cartilage repair in both groups (ACI and BM MSCs) However, there was no difference between the BM MSCs and the ACI group in terms of clinical outcomes except for “Physical Role Functioning” with a greater improvement over time in the BM MSCs group (P = 0.044 for interaction effect) IKDC subjective knee evaluation (P = 0.861), Lysholm (P = 0.627), and Tegner (P = 0.200) scores did not have any significant difference between groups over time However, in general, men showed significantly better improvements than women Patients younger than 45 years scored 116   engineering Tissue Eng 2006 Oct;12(10):2765-75 PubMed PMID: 17518646 Epub 2007/05/24 eng 108 Ko IK, Song HT, Cho EJ, Lee ES, 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the bone marrow and exogenous by multiple intra -articular injection of the expanded autologous stem cells) As I showed, in the previous chapter, that injection