Daisuke Mori

The University of Tokyo, 白山, Tōkyō, Japan

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Publications (38)84.02 Total impact

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    ABSTRACT: Objective: Prevalence of ankle osteoarthritis (OA) is lower than that of knee OA, however, the molecular mechanisms underlying the difference remain unrevealed. In the present study, we developed mouse ankle OA models for use as tools to investigate pathophysiology of ankle OA and molecular characteristics of ankle cartilage. Design: We anatomically and histologically examined ankle and knee joints of C57BL/6 mice, and compared them with human samples. We examined joints of 8-week-old and 25-month-old mice. For experimental models, we developed three different ankle OA models: a medial model, a lateral model, and a bilateral model, by resection of respective structures. OA severity was evaluated eight weeks after the surgery by safranin O staining, and cartilage degradation in the medial model was sequentially examined. Results: Anatomical and histological features of human and mouse ankle joints were comparable. Additionally, the mouse ankle joint was more resistant to cartilage degeneration with aging than the mouse knee joint. In the medial model, the tibiotalar joint was markedly affected while the subtalar joint was less degenerated. In the lateral model, the subtalar joint was mainly affected while the tibiotalar joint was less altered. In the bilateral model, both joints were markedly degenerated. In the time course of the medial model, TUNEL staining and Adamts5 expression were enhanced at early and middle stages, while Mmp13 expression was gradually increased during the OA development. Conclusion: Since human and mouse ankles are comparable, the present models will contribute to ankle OA pathophysiology and general cartilage research in future.
    No preview · Article · Nov 2015 · Osteoarthritis and Cartilage
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    ABSTRACT: Induced pluripotent stem cells (iPSCs) are a promising cell source for cartilage regenerative medicine. Meanwhile, the risk of tumorigenesis should be considered in the clinical application of human iPSCs (hiPSCs). Here, we report in vitro chondrogenic differentiation of hiPSCs and maturation of the differentiated hiPSCs through transplantation into mouse knee joints. Three hiPSC clones showed efficient chondrogenic differentiation using an established protocol for human embryonic stem cells. The differentiated hiPSCs formed hyaline cartilage tissues at 8 weeks after transplantation into the articular cartilage of NOD/SCID mouse knee joints. Although tumors were not observed during the 8 weeks after transplantation, an immature teratoma had developed in one mouse at 16 weeks. In conclusion, hiPSCs are a potent cell source for regeneration of hyaline articular cartilage. However, the risk of tumorigenesis should be managed for clinical application in the future.
    Preview · Article · Jul 2015 · Biomedical Research
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    ABSTRACT: Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1(fl/fl) mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre(ERT);Hes1(fl/fl) mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.
    Full-text · Article · Mar 2015 · Proceedings of the National Academy of Sciences
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    ABSTRACT: CCAAT/enhancer-binding protein (C/EBP) β regulates chondrocyte differentiaion and proliferation during endochondral ossification. However, expression and function of other C/EBP family members in chondrocytes have not been fully understood. To understand the comprehensive regulation of chondrocyte differentiation by C/EBPs, we initially examined their expression levels. Among four members (C/EBPα, C/EBPβ, C/EBPδ and C/EBPε) with transactivation domain, expression of Cebpb and Cebpd was abundant compared to Cebpa, while Cebpe was hardly expressed in mouse isolated chondrocytes. Doxycycline (DOX)-inducible overexpression of each of the three C/EBPs (C/EBPα, C/EBPβ and C/EBPδ) in ATDC5 cells suppressed expressions of early differentiation markers including Col2a1, aggrecan and Sox9, enhanced those of late differentiation markers including Mmp13, Vegfa and Col10a1, and decelerated cell proliferation, indicating their overlapped functions in chondrocytes. In contrast, DOX-inducible overexpression of A-CEBP, which exerts a dominant-negative effect against all C/EBPs, increased expressions of early differentiation markers and decreased those of late differentiation markers. Finally, microarray and gene ontology analyses showed that A-CEBP altered many genes related with various events or tissues such as skeletal development, cartilage, cell cycle, inflammation and apoptosis. In conclusion, C/EBPα, C/EBPβ and C/EBPδ regulate proliferation and differentiation of chondrocytes and possibly is involved with apoptosis and inflammation. C/EBPs may play a variety of roles in the homeostasis of joint cartilage under physiological and pathological conditions.
    Preview · Article · Feb 2015 · Biomedical research (Tokyo, Japan)
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    ABSTRACT: Transcription factors SOX9, SOX5 and SOX6 are indispensable for generation and differentiation of chondrocytes. However, molecular mechanisms to induce the SOX genes are poorly understood. To address this issue, we previously determined the human embryonic enhancer of SOX6 by 5'RACE analysis, and identified the 46-bp core enhancer region (CES6). We initially performed yeast one-hybrid assay for screening other chondrogenic factors using CES6 as bait, and identified a zinc finger protein ZNF449. ZNF449 and Zfp449, a counterpart in mouse, transactivated enhancers or promoters of SOX6, SOX9 and COL2A1. Zfp449 was expressed in mesenchyme-derived tissues including cartilage, calvaria, muscle and tendon, as well as in other tissues including brain, lung and kidney. In limb cartilage of mouse embryo, Zfp449 protein was abundantly located in periarticular chondrocytes, and decreased in accordance with the differentiation. Zfp449 protein was also detected in articular cartilage of an adult mouse. During chondrogenic differentiation of human mesenchymal stem cells, ZNF449 was increased at an early stage, and its overexpression enhanced SOX9 and SOX6 only at the initial stage of the differentiation. We further generated Zfp449 knockout mice to examine the in vivo roles; however, no obvious abnormality was observed in skeletal development or articular cartilage homeostasis. ZNF449 may regulate chondrogenic differentiation from mesenchymal progenitor cells, although the underlying mechanisms are still unknown.
    Preview · Article · Dec 2014 · PLoS ONE
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    ABSTRACT: S100A1 and S100B are induced by the SOX trio transcription factors (SOX9, SOX5, and SOX6) in chondrocytes, and inhibit their hypertrophic differentiation in culture. However, functional roles of S100A1 and S100B during in vivo skeletal development are yet to be determined. Here we show that mice deficient of both the S100a1 and S100b genes displayed normal skeletal growth from embryonic stage to adulthood. Although no compensatory upregulation of other S100 family members was observed in S100a1/S100b double mutants, the related S100a2, S100a4, S100a10, and S100a11 were expressed at similarly high levels to S100a1 and S100b in mouse primary chondrocytes. Furthermore, overexpression of these other S100 members suppressed the hypertrophic differentiation of chondrocytes in vitro as efficiently as S100A1 and S100B. Taken together, the present study demonstrates that S100A1 and S100B are dispensable for endochondral ossification during skeletal development, most likely because their deficiency may be masked by other S100 proteins which have similar functions to those of S100A1 and S100B.
    No preview · Article · Aug 2014 · Biomedical research (Tokyo, Japan)
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    Full-text · Article · Jun 2014
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    ABSTRACT: Induced pluripotent stem cells (iPSC) are a promising cell source for cartilage regenerative medicine; however, the methods for chondrocyte induction from iPSC are currently developing and not yet sufficient for clinical application. Here, we report the establishment of a fluorescent indicator system for monitoring chondrogenic differentiation from iPSC to simplify screening for effective factors that induce chondrocytes from iPSC. We generated iPSC from embryonic fibroblasts of Col2a1-EGFP transgenic mice by retroviral transduction of Oct4, Sox2, Klf4, and c-Myc. Among the 30 clones of Col2a1-EGFP iPSC we established, two clones showed high expression levels of embryonic stem cell (ESC) marker genes, similar to control ESC. A teratoma formation assay showed that the two clones were pluripotent and differentiated into cell types from all three germ layers. The fluorescent signal was observed during chondrogenic differentiation of the two clones concomitant with the increase in chondrocyte marker expression. In conclusion, Col2a1-EGFP iPSC are useful for monitoring chondrogenic differentiation and will contribute to research in cartilage regenerative medicine.
    Full-text · Article · Sep 2013 · PLoS ONE
  • Elaheh Rahbar · Daisuke Mori · James E Moore
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    ABSTRACT: To assess the hemodynamics associated with clot captured within two different types of inferior vena cava (IVC) filters. Computational flow models were constructed for different clot sizes and shapes captured within the Greenfield (GF) (Medi-tech/Boston Scientific, Watertown, Massachusetts) and TrapEase (Cordis, Miami Lakes, Florida) IVC filters. Two models were employed; one was a straight tube (ST), and the other was a realistic model (RM) that included iliac and renal veins and lumbar curvature, with filter deployment between these inflows. Calculations were based on the Lattice Boltzmann method (LBM), allowing for accurate modeling of flows that are in transition from laminar to turbulent. Flow disturbances were noted downstream of captured clots, with turbulence intensities reaching 41%. Disturbances were strongest with large clot volumes and in ST models. The RM vessel geometry greatly reduced the level of flow disturbance (majority of <2%; maximum turbulence intensity of 11%). Implementing flow rate representative of the infrarenal vena cava (rather than suprarenal) was also shown to reduce the amount of flow disturbance in ST models. Although there is a mild amount of flow disturbance caused by captured clots, these flow patterns are not of the variety that have been shown to trigger platelet activation in other studies. Turbulence intensities were lower in the RMs, indicating the need to perform such flow studies under physiologic conditions.
    No preview · Article · Mar 2011 · Journal of vascular and interventional radiology: JVIR
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    ABSTRACT: An effective way for preventing injuries and diseases among the elderly is to monitor their daily lives. In this regard, we propose the use of a "Hyper Hospital Network", which is an information support system for elderly people and patients. In the current study, we developed a wearable system for monitoring electromyography (EMG) and acceleration using the Hyper Hospital Network plan. The current system is an upgraded version of our previous system for gait analysis (Yoshida et al. [13], Telemedicine and e-Health 13 703-714), and lets us monitor decreases in exercise and the presence of a hemiplegic gait more accurately. To clarify the capabilities and reliability of the system, we performed three experimental evaluations: one to verify the performance of the wearable system, a second to detect a hemiplegic gait, and a third to monitor EMG and accelerations simultaneously. Our system successfully detected a lack of exercise by monitoring the iEMG in healthy volunteers. Moreover, by using EMG and acceleration signals simultaneously, the reliability of the Hampering Index (HI) for detecting hemiplegia walking was improved significantly. The present study provides useful knowledge for the development of a wearable computer designed to monitor the physical conditions of older persons and patients.
    No preview · Article · Feb 2009 · Technology and health care: official journal of the European Society for Engineering and Medicine
  • E. Rahbar · D. Mori · J. Moore

    No preview · Article · Feb 2009 · Journal of Vascular and Interventional Radiology
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    ABSTRACT: The transcription factor Klf4 has demonstrated activity in the reprogramming of somatic cells to a pluripotent state, but the molecular mechanism of this process remains unknown. It is, therefore, of great interest to understand the functional role of Klf4 and related genes in ESC regulation. Here, we show that homozygous disruption of Klf5 results in the failure of ESC derivation from ICM cells and early embryonic lethality due to an implantation defect. Klf5 KO ESCs show increased expression of several differentiation marker genes and frequent, spontaneous differentiation. Conversely, overexpression of Klf5 in ESCs suppressed the expression of differentiation marker genes and maintained pluripotency in the absence of LIF. Our results also suggest that Klf5 regulates ESC proliferation by promoting phosphorylation of Akt1 via induction of Tcl1. These results, therefore, provide new insights into the functional and mechanistic role of Klf5 in regulation of pluripotency.
    Full-text · Article · Dec 2008 · Cell stem cell

  • No preview · Article · Jul 2008 · Journal of Biomechanics
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    ABSTRACT: Cerebral aneurysms are an important cerebrovascular condition because aneurysm rupture is the most common cause of subarachnoid hemorrhage, which has a high mortality rate and a poor prognosis. Since the mechanism of cerebral aneurysm pathogenesis has not yet been understood, the preventative treatment for unruptured aneurysms is surgery only; however, the morbidity of the surgery is as high as over 10% [1]. On the other hand, the annual risk of rupture of cerebral aneurysms is not so high, reported to be 1.9% [2]. Consequently, it is difficult to judge whether a patient with an unruptured cerebral aneurysm should undergo surgery, when it is detected. Thus, it is important to develop a better understanding of the mechanism of cerebral aneurysm pathogenesis.
    No preview · Conference Paper · Jun 2008
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    ABSTRACT: CUG-binding protein 1 (CUG-BP1) is a member of the CUG-BP1 and ETR-3-like factors (CELF) family of RNA-binding proteins, and is involved in myotonic dystrophy type 1 (DM1). Several mRNA targets of CUG-BP1 have been identified, including the insulin receptor, muscle chloride channel, and cardiac troponin T. On the other hand, CUG-BP1 has only a weak affinity for CUG repeats. We conducted quantitative-binding assays to assess CUG-BP1 affinities for several repeat RNAs by surface plasmon resonance (SPR). Although we detected interactions between CUG-BP1 and CUG repeats, other UG-rich sequences actually showed stronger interactions. Binding constants of CUG-BP1 for RNAs indicated that the affinity for UG repeats was far stronger than for CUG repeats. We also found that N-terminal deletion mutant of CUG-BP1 has UG repeat-binding activity in a yeast three-hybrid system, although C-terminal deletion mutant does not. Our data indicates that CUG-BP1 specifically recognized UG repeats, probably through cooperative binding of RNA recognition motifs at both ends of the protein. This is the first report of a binding constant for CUG-BP1 calculated in vitro.
    No preview · Article · Apr 2008 · Journal of Biochemistry
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    ABSTRACT: We propose a method to analyze platelet adhesion and aggregation computationally, taking into account the distinct properties of two plasma proteins, von Willebrand factor (vWF) and fibrinogen (Fbg). In this method, the hydrodynamic interactions between platelet particles under simple shear flow were simulated using Stokesian dynamics based on the additivity of velocities. The binding force between particles mediated by vWF and Fbg was modeled using the Voigt model. Two Voigt models with different properties were introduced to consider the distinct behaviors of vWF and Fbg. Our results qualitatively agreed with the general observation of a previous in-vitro experiment, thus demonstrating that the significant development of thrombus formation in height requires not only vWF, but also Fbg. This agreement of simulation and experimental results qualitatively validates our model and suggests that consideration of the distinct roles of vWF and Fbg is essential to investigate the physiological and pathophysiological mechanisms of thrombus formation using a computational approach.
    No preview · Article · Feb 2008 · Thrombosis and Haemostasis
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    ABSTRACT: We have performed numerical simulations to examine saccular cerebral aneurysm formation at the outer curve of a bent artery. A U-shaped arterial geometry with torsion, which was modeled on part of the human internal carotid artery, has been employed. A new numerical model was proposed to take into account proliferation as well as degradation of the arterial wall. Proliferation of the arterial wall was modeled by surface area expansion in high wall shear stress region. Based on wall shear stress distribution on the artery, we have investigated aneurysm formation for the following three conditions: (a) strength degradation of the wall, (b) proliferation of the wall, and (c) both strength degradation and proliferation of the wall. A saccular aneurysm shape was not observed when considering only arterial wall degradation up to 90%. However, the saccular shape formed when proliferation of the arterial wall was also taken into consideration. The resultant shape was consistent with clinical observations. Our findings have suggested that a saccular aneurysm may not be formed by degradation of the arterial wall alone, but also require its proliferation.
    Full-text · Article · Jan 2008 · Journal of Biomechanical Science and Engineering
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    ABSTRACT: The primary thrombus formation is a critical phenomenon both physiologically and pathologically. It has been seen that various mechanical factors are involved the regulation of primary thrombus formation through a series of physiological and biochemical processes, including blood flow and intercellular molecular bridges. However, it has not been fully understood how the existence of red blood cells contributes to the process of platelet thrombus formation. We computationally analyzed the motions of platelets in plasma layer above which red blood cells flow assuming a background simple shear flow of a shear rate of 1000 s- 1 using Stokesian dynamics. In the computation, fluid mechanical interactions between platelets and red blood cells were taken into account together with the binding forces via plasma proteins between two platelets and between a platelet and injured vessel wall. The process of the platelets aggregation was significantly dependent on whether red blood cells were present. When red blood cells were absent, the aggregate formed grew more vertically compared to the case with red blood cells. Conversely, when red blood cells were present, the aggregate spread more horizontally because the red blood cells constrained the vertical growth when the height of the aggregate reached the level of the red blood cells. Our results suggest that red blood cells mechanically play a significant role in primary thrombus formation, which accelerates the horizontal spread of the thrombus, and point out the necessity of considering the presence of red blood cells when investigating the mechanism of thrombus formation.
    No preview · Article · Jan 2008 · Thrombosis Research
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    ABSTRACT: We have been investigating the cardiovascular system over micro to macro levels by using conjugated computational mechanics analyzing fluid, solid and bio-chemical interactions. In the present study, we introduce our recent researches on the mass transport to saccular aneurysm, cerebral aneurysm growth based on a hemodynamic hypothesis, malaria-infected red blood cell mechanics using a particle method and primary thrombus formation.
    Full-text · Article · Jan 2008
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    ABSTRACT: It has been pointed out that some mechanical factors play important roles in a series of physiological or biochemical processes during the thrombus formation. Recently, many studies including the authors’ work qualitatively demonstrated how the thrombus is regulated under the influences of the blood flow and the intercellular molecular bridge using computational fluid dynamics techniques[1–4]. They verified the importance of the balance of them in the process of the thrombus formation. However, few studies have taken into account the existence of the other cell constituents than the platelet such as red blood cell (RBC).
    No preview · Conference Paper · Jun 2007

Publication Stats

456 Citations
84.02 Total Impact Points


  • 2002-2015
    • The University of Tokyo
      • • Department of Applied Life Sciences
      • • Department of Chemistry and Biotechnology
      白山, Tōkyō, Japan
  • 2011
    • Hachinohe Institute of Technology
      Aomori, Aomori, Japan
  • 2002-2009
    • Tohoku University
      • • Department of Bioengineering and Robotics
      • • Department of Biomolecular Sciences
  • 2006
    • Texas A&M University
      • Department of Biomedical Engineering
      College Station, Texas, United States
  • 2000-2002
    • Nagoya Institute of Technology
      • Department of Mechanical Engineering
      Nagoya, Aichi, Japan