Deok-Ho Kim

University of Washington Seattle, Seattle, Washington, United States

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Publications (96)327.59 Total impact

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    Dataset: c4ib00209a
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    ABSTRACT: Direct intercellular transfer of cellular components is a recently described general mechanism of cell-cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained. Using a cell-cell pair of metastatic melanoma and endothelial cells, known to interact at various stages during cancer progression, we show that cytosolic proteins can indeed be transferred between heterotypic cells. Using precise relative cell patterning we provide evidence that this transfer depends on extent of the interface between heterotypic cell populations. This result is further supported by a mathematical model capturing various experimental conditions. We further demonstrate that cytosolic protein transfer can have important functional consequences for the tumor-stroma interactions, e.g., in heterotypic transfer of constitutively activated BRAF, a common melanoma associated mutation, leading to an enhanced activation of the downstream MAPK pathway. Our results suggest that cytosolic protein transfer can have important consequences for regulation of processes involving physical co-location of heterotypic cell types, particularly in invasive cancer growth.
    Integrative Biology 02/2015; DOI:10.1039/C4IB00209A · 4.00 Impact Factor
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    ABSTRACT: Endothelial physiology is regulated not only by humoral factors but also by mechanical factors such as fluid shear stress and the underlying cellular matrix microenvironment. The purpose of the present study was to examine the effects of matrix topographical cues on the endothelial secretion of cytokines/chemokines in vitro. Human endothelial cells were cultured on nanopatterned polymeric substrates with different ratios of ridge to groove widths (1:1, 1:2, and 1:5) and with different stiffnesses (6.7 MPa and 2.5 GPa) in the presence and absence of 1.0 ng/mL TNF-α. The levels of cytokines/chemokines secreted into the conditioned media were analyzed with a multiplexed bead-based sandwich immunoassay. Of the nano-patterns tested, the 1:1 and 1:2 type-patterns were found to induce the greatest degree of endothelial cell elongation and directional alignment. The 1:2 type nanopatterns lowered the secretion of inflammatory cytokines such as IL-1β, IL-3, IL-4 and MCP-1, compared to unpatterned substrates. Additionally, of the two polymers tested, it was found that the stiffer substrate resulted in significant decreases in the secretion of IL-3, IL-13, IL-4 and MCP-1. These results suggest that substrates with specific extracellular nanotopographical cues or stiffnesses may provide anti-atherogenic effects like those seen with laminar shear stresses by suppressing the endothelial secretion of cytokines and chemokines involved in vascular inflammation and remodeling.
    ACS Applied Materials & Interfaces 02/2015; DOI:10.1021/acsami.5b00554 · 5.90 Impact Factor
  • Biophysical Journal 01/2015; 108(2):295a. DOI:10.1016/j.bpj.2014.11.1607 · 3.83 Impact Factor
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    ABSTRACT: Direct intercellular transfer of cellular components is a recently described general mechanism of cell-cell communication. It is a more non-specific mode of intercellular communication that is not actively controlled by the participating cells. Though membrane bound proteins and small non-protein cytosolic components have been shown to be transferred between cells, the possibility of transfer of cytosolic proteins has not been clearly established, and its mechanism remains unexplained. Using a cell-cell pair of metastatic melanoma and endothelial cells, known to interact at various stages during cancer progression, we show that cytosolic proteins can indeed be transferred between heterotypic cells. Using precise relative cell patterning we provide evidence that this transfer depends on extent of the interface between heterotypic cell populations. This result is further supported by a mathematical model capturing various experimental conditions. We further demonstrate that cytosolic protein transfer can have important functional consequences for the tumor-stroma interactions, e.g., in heterotypic transfer of constitutively activated BRAF, a common melanoma associated mutation, leading to an enhanced activation of the downstream MAPK pathway. Our results suggest that cytosolic protein transfer can have important consequences for regulation of processes involving physical co-location of heterotypic cell types, particularly in invasive cancer growth.
    Integrative Biology 01/2015; · 4.00 Impact Factor
  • Biophysical Journal 01/2015; 108(2):201a. DOI:10.1016/j.bpj.2014.11.1110 · 3.83 Impact Factor
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    ABSTRACT: Most current drug screening assays used to identify new drug candidates are 2D cell-based systems, even though such in vitro assays do not adequately re-create the in vivo complexity of 3D tissues. Inadequate representation of the human tissue environment during a preclinical test can result in inaccurate predictions of compound effects on overall tissue functionality. Screening for compound efficacy by focusing on a single pathway or protein target, coupled with difficulties in maintaining long-term 2D monolayers, can serve to exacerbate these issues when using such simplistic model systems for physiological drug screening applications. Numerous studies have shown that cell responses to drugs in 3D culture are improved from those in 2D, with respect to modeling in vivo tissue functionality, which highlights the advantages of using 3D-based models for preclinical drug screens. In this review, we discuss the development of microengineered 3D tissue models that accurately mimic the physiological properties of native tissue samples and highlight the advantages of using such 3D microtissue models over conventional cell-based assays for future drug screening applications. We also discuss biomimetic 3D environments, based on engineered tissues as potential preclinical models for the development of more predictive drug screening assays for specific disease models.
    Journal of the Association for Laboratory Automation 11/2014; DOI:10.1177/2211068214557813 · 1.50 Impact Factor
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    ABSTRACT: Periostin is a secreted matricellular protein critical for epithelial-mesenchymal transition and carcinoma metastasis. In glioblastoma, it is highly upregulated compared with normal brain, and existing reports indicate potential prognostic and functional importance in glioma. However, the clinical implications of periostin expression and function related to its therapeutic potential have not been fully explored.
    Neuro-Oncology 08/2014; DOI:10.1093/neuonc/nou161 · 5.29 Impact Factor
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    ABSTRACT: The aim of this study is to elucidate the relationship of laryngeal electromyography (LEMG) and computed tomographic (CT) parameters to improve the prognosis of recurrent laryngeal nerve injury. 22 patients clinically suspected of having recurrent laryngeal nerve injury were examined with LEMG and CT studies. Bilateral thyroarytenoid (TA) muscles were examined and findings were interpreted by a single blind technique. Laryngeal CT image analysis of the ventricle dilation symmetry determined TA muscle atrophy. Finally, a follow-up laryngoscopic examination determined improvement of vocal fold movement. Ventricle dilation symmetry and the dichotomized TA muscle atrophy parameter significantly relate to the improvement of vocal fold movement (χ2 = 4.029, P = 0.039, and χ2 = 3.912, P = 0.048, respectively). When the severity of vocal fold impairment was classified as severe TA muscle atrophy or none/discrete MUAP recruitment, it was found to significantly relate with the improvement of vocal fold movement (χ2 = 6.712, P =.010). From this study, image analysis of the ventricle dilation symmetry to determine the severity of TA muscle atrophy shows promise for the improved prognosis of vocal fold immobility.
    Journal of Electromyography and Kinesiology 08/2014; 25(1). DOI:10.1016/j.jelekin.2014.08.004 · 1.73 Impact Factor
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    ABSTRACT: Most cells in the body secrete, or are in intimate contact with extracellular matrix (ECM), which provides structure to tissues and regulates various cellular phenotypes. Cells are well known to respond to biochemical signals from the ECM, but recent evidence has highlighted the mechanical properties of the matrix, including matrix elasticity and nanotopography, as fundamental instructive cues regulating signal transduction pathways and gene transcription. Recent observations also highlight the importance of matrix nanotopography as a regulator of cellular functions, but lack of facile experimental platforms has resulted in a continued negligence of this important microenvironmental cue in tissue culture experimentation. In this review, we present our opinion on the importance of nanotopography as a biological cue, contexts in which it plays a primary role influencing cell behavior, and detail advanced techniques to incorporate nanotopography into the design of experiments, or in cell culture environments. In addition, we highlight signal transduction pathways that are involved in conveying the extracellular matrix nanotopography information within the cells to influence cell behavior.
    Cell adhesion & migration 07/2014; 8(4). DOI:10.4161/cam.29359 · 3.40 Impact Factor
  • Assaf Shapira, Deok-Ho Kim, Tal Dvir
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    ABSTRACT: The ability of the living body to heal and regenerate itself following trauma is astonishing. Numerous events of repair and regeneration occur during our lifetime, most of which we are never aware of. Unfortunately, in some cases, the injury or defect cannot be adequately repaired solely by nature and medical intervention is required.
    Biofabrication 05/2014; 6(2):020301. DOI:10.1088/1758-5082/6/2/020301 · 4.30 Impact Factor
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    ABSTRACT: Purpose To evaluate the efficacy of mesenchymal stem cells (MSCs) encapsulated in self-assembled peptide (SAP) hydrogels in a rat knee model for the prevention of osteoarthritis (OA) progression. Materials and methods Nanostructured KLD-12 SAPs were used as the injectable hydrogels. Thirty-three Sprague Dawley rats were used for the OA model. Ten rats were used for the evaluation of biotin-tagged SAP disappearance. Twenty-three rats were divided into four groups: MSC (n=6), SAP (n=6), SAP-MSC (n=6), and no treatment (n=5). MSCs, SAPs, and SAP-MSCs were injected into the knee joints 3 weeks postsurgery. Histologic examination, immunofluorescent staining, measurement of cytokine levels, and micro-computed tomography analysis were conducted 6 weeks after injections. Behavioral studies were done to establish baseline measurements before treatment, and repeated 3 and 6 weeks after treatment to measure the efficacy of SAP-MSCs. Results Concentration of biotinylated SAP at week 1 was not significantly different from those at week 3 and week 6 (P=0.565). Bone mineral density was significantly lower in SAP-MSC groups than controls (P=0.002). Significant differences in terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling staining between the control group and all other groups were observed. Caspase-8, tissue inhibitor of metalloproteinases 1, and matrix metalloproteinase 9 were diffusely stained in controls, whereas localized or minimal staining was observed in other groups. Modified Mankin scores were significantly lower in the SAP and SAP-MSC groups than in controls (P=0.001 and 0.013). Although not statistically significant, synovial inflammation scores were lower in the SAP (1.3±0.3) and SAP-MSC (1.3±0.2) groups than in controls (2.6±0.2). However, neither the cytokine level nor the behavioral score was significantly different between groups. Conclusion Injection of SAP-MSC hydrogels showed evidence of chondroprotection, as measured by the histologic grading and decreased expression of biochemical markers of inflammation and apoptosis. It also lowered subchondral bone mineral density, which can be increased by OA. This suggests that the SAP-MSC complex may have clinical potential to inhibit OA progression.
    International Journal of Nanomedicine 05/2014; 9 Suppl 1(Suppl 1):141-57. DOI:10.2147/IJN.S54114 · 4.20 Impact Factor
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    International Journal of Nanomedicine 05/2014; 9 Suppl 1(Suppl 1):1-5. DOI:10.2147/IJN.S61212 · 4.20 Impact Factor
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    ABSTRACT: We have examined the effects of surface nanotopography and hyaluronic acid on in vitro chondrogenesis of dental pulp stem cells (DPSCs). UV-assisted capillary force lithography (CFL) was employed to fabricate well-defined, nanostructured scaffolds of composite PEG-GelMA-HA hydrogels that consist of polyethylene glycol dimethacrylate (PEGDMA), methacrylated gelatin (GelMA), and hyaluronic acid (HA). Using this microengineered platform, we first demonstrated that DPSCs formed three-dimensional spheroids, which provide an appropriate environment for in vitro chondrogenic differentiation. We also found that DPSCs cultured on nanopatterned PEG-GelMA-HA scaffolds showed a significant up-regulation of the chondrogenic gene markers (Sox9, Alkaline phosphatase, Aggrecan, Procollagen type II, and Procollagen type X) while down-regulating the pluripotent stem cell gene, Nanog, and epithelial-mesenchymal genes (Twist, Snail, Slug) compared to tissue culture polystyrene-cultured DPSCs. Immunocytochemistry showed more extensive deposition of collagen type II in DPSCs cultured on the nanopatterned PEG-GelMA-HA scaffolds. These findings suggest that nanotopography and HA provide important cues for promoting chondrogenic differentiation of DPSCs.
    Tissue Engineering Part A 04/2014; DOI:10.1089/ten.TEA.2013.0614 · 4.64 Impact Factor
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    ABSTRACT: Although synthetic polymers are desirable in tissue engineering applications for the reproducibility and tunability of their properties, synthetic small diameter vascular grafts lack the capability to endothelialize in vivo. Thus, synthetically fabricated biodegradable tissue scaffolds that reproduce important aspects of the extracellular environment are required to meet the urgent need for improved vascular grafting materials. In this study, we have successfully fabricated well-defined nanopatterned cell culture substrates made of a biodegradable composite hydrogel consisting of poly(ethylene glycol) dimethacrylate (PEGDMA) and gelatin methacrylate (GelMA) by using UV-assisted capillary force lithography. The elasticity and degradation rate of the composite PEG–GelMA nanostructures were tuned by varying the ratios of PEGDMA and GelMA. Human umbilical vein endothelial cells (HUVECs) cultured on nanopatterned PEG–GelMA substrates exhibited enhanced cell attachment compared with those cultured on unpatterned PEG–GelMA substrates. Additionally, HUVECs cultured on nanopatterned PEG-GelM substrates displayed well-aligned, elongated morphology similar to that of native vascular endothelial cells and demonstrated rapid and directionally persistent migration. The ability to alter both substrate stiffness and degradation rate and culture endothelial cells with increased elongation and alignment is a promising next step in recapitulating the properties of native human vascular tissue for tissue engineering applications.
    Biofabrication 04/2014; 6(2):024112. DOI:10.1088/1758-5082/6/2/024112 · 4.30 Impact Factor
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    ABSTRACT: Vascular smooth muscle cells (vSMCs) retain the ability to undergo modulation in their phenotypic continuum, ranging from a mature contractile state to a proliferative, secretory state. vSMC differentiation is modulated by a complex array of microenvironmental cues, which include the biochemical milieu of the cells and the architecture and stiffness of the extracellular matrix. In this study, we demonstrate that by using UV-assisted capillary force lithography (CFL) to engineer a polyurethane substratum of defined nanotopography and stiffness, we can facilitate the differentiation of cultured vSMCs, reduce their inflammatory signature, and potentially promote the optimal functioning of the vSMC contractile and cytoskeletal machinery. Specifically, we found that the combination of medial tissue-like stiffness (11 MPa) and anisotropic nanotopography (ridge width_groove width_ridge height of 800_800_600 nm) resulted in significant upregulation of calponin, desmin, and smoothelin, in addition to the downregulation of intercellular adhesion molecule-1, tissue factor, interleukin-6, and monocyte chemoattractant protein-1. Further, our results allude to the mechanistic role of the RhoA/ROCK pathway and caveolin-1 in altered cellular mechanotransduction pathways via differential matrix nanotopography and stiffness. Notably, the nanopatterning of the stiffer substrata (1.1 GPa) resulted in the significant upregulation of RhoA, ROCK1, and ROCK2. This indicates that nanopatterning an 800_800_600 nm pattern on a stiff substratum may trigger the mechanical plasticity of vSMCs resulting in a hypercontractile vSMC phenotype, as observed in diabetes or hypertension. Given that matrix stiffness is an independent risk factor for cardiovascular disease and that CFL can create different matrix nanotopographic patterns with high pattern fidelity, we are poised to create a combinatorial library of arterial test beds, whether they are healthy, diseased, injured, or aged. Such high-throughput testing environments will pave the way for the evolution of the next generation of vascular scaffolds that can effectively crosstalk with the scaffold microenvironment and result in improved clinical outcomes.
    Tissue Engineering Part A 04/2014; DOI:10.1089/ten.tea.2013.0455 · 4.64 Impact Factor
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    ABSTRACT: Current tissue engineering methods lack the ability to properly recreate scaffold-free, cell dense tissues with physiological structures. Recent studies have shown that the use of nanoscale cues allows for precise control over large area 2D tissue structures without restricting cell growth or cell density. In this study, we developed a simple and versatile platform combining a thermoresponsive nanofabricated substratum (TNFS) incorporating nanotopographical cues and the gel casting method for the fabrication of scaffold-free 3D tissues. Our TNFS allows for the structural control of aligned cell monolayers, which can be spontaneously detached via a change in culture temperature. Utilizing our gel casting method, viable, aligned cell sheets can be transferred without loss of anisotropy or stacked with control over individual layer orientations. Transferred cell sheets and individual cell layers within multilayered tissues robustly retain structural anisotropy, allowing for the fabrication of scaffold-free, 3D tissues with hierarchal control of overall tissue structure.
    ACS Nano 03/2014; 8(5). DOI:10.1021/nn4063962 · 12.03 Impact Factor
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    ABSTRACT: Adult stem cells hold great promise as a source of diverse terminally differentiated cell types for tissue engineering applications. However, due to the complexity of chemical and mechanical cues specifying differentiation outcomes, development of arbitrarily complex geometric and structural arrangements of cells, adopting multiple fates from the same initial stem cell population, has been difficult. Here, we show that the topography of the cell adhesion substratum can be an instructive cue to adult stem cells and topographical variations can strongly bias the differentiation outcome of the cells towards adipocyte or osteocyte fates. Switches in cell fate decision from adipogenic to osteogenic lineages were accompanied by changes in cytoskeletal stiffness, spanning a considerable range in the cell softness/rigidity spectrum. Our findings suggest that human mesenchymal stem cells (hMSC) can respond to the varying density of nanotopographical cues by regulating their internal cytoskeletal network and use these mechanical changes to guide them toward making cell fate decisions. We used this finding to design a complex two-dimensional pattern of co-localized cells preferentially adopting two alternative fates, thus paving the road for designing and building more complex tissue constructs with diverse biomedical applications.
    Biomaterials 03/2014; 35(8):2401-2410. DOI:10.1016/j.biomaterials.2013.11.037 · 8.31 Impact Factor
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    ABSTRACT: Cardiovascular disease remains the leading cause of death worldwide(1). Cardiac tissue engineering holds much promise to deliver groundbreaking medical discoveries with the aims of developing functional tissues for cardiac regeneration as well as in vitro screening assays. However, the ability to create high-fidelity models of heart tissue has proven difficult. The heart's extracellular matrix (ECM) is a complex structure consisting of both biochemical and biomechanical signals ranging from the micro- to the nanometer scale(2). Local mechanical loading conditions and cell-ECM interactions have recently been recognized as vital components in cardiac tissue engineering(3-5). A large portion of the cardiac ECM is composed of aligned collagen fibers with nano-scale diameters that significantly influences tissue architecture and electromechanical coupling(2). Unfortunately, few methods have been able to mimic the organization of ECM fibers down to the nanometer scale. Recent advancements in nanofabrication techniques, however, have enabled the design and fabrication of scalable scaffolds that mimic the in vivo structural and substrate stiffness cues of the ECM in the heart(6-9). Here we present the development of two reproducible, cost-effective, and scalable nanopatterning processes for the functional alignment of cardiac cells using the biocompatible polymer poly(lactide-co-glycolide) (PLGA)(8) and a polyurethane (PU) based polymer. These anisotropically nanofabricated substrata (ANFS) mimic the underlying ECM of well-organized, aligned tissues and can be used to investigate the role of nanotopography on cell morphology and function(10-14). Using a nanopatterned (NP) silicon master as a template, a polyurethane acrylate (PUA) mold is fabricated. This PUA mold is then used to pattern the PU or PLGA hydrogel via UV-assisted or solvent-mediated capillary force lithography (CFL), respectively(15,16). Briefly, PU or PLGA pre-polymer is drop dispensed onto a glass coverslip and the PUA mold is placed on top. For UV-assisted CFL, the PU is then exposed to UV radiation (λ = 250-400 nm) for curing. For solvent-mediated CFL, the PLGA is embossed using heat (120 °C) and pressure (100 kPa). After curing, the PUA mold is peeled off, leaving behind an ANFS for cell culture. Primary cells, such as neonatal rat ventricular myocytes, as well as human pluripotent stem cell-derived cardiomyocytes, can be maintained on the ANFS(2).
    Journal of Visualized Experiments 01/2014; DOI:10.3791/50039
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    ABSTRACT: Inspired by ultrastructural analysis of ex vivo human tissues as well as the physiological importance of structural density, we fabricated nanogrooves with 1:1, 1:3, and 1:5 spacing ratio (width:spacing, width = 550 nm). In response to the nanotopographical density, the adhesion, migration, and differentiation of human mesenchymal stem cells (hMSCs) were sensitively controlled, but the proliferation showed no significant difference. In particular, the osteo- or neurogenesis of hMSCs were enhanced at the 1:3 spacing ratio rather than 1:1 or 1:5 spacing ratio, implying an existence of potentially optimized nanotopographical density for stem cell function. Furthermore, such cellular behaviors were positively correlated with several cell morphological indexes as well as the expression of integrin β1 or N-cadherin. Our findings propose that nanotopographical density may be a key parameter for the design and manipulation of functional scaffolds for stem cell-based tissue engineering and regenerative medicine.
    Scientific Reports 12/2013; 3:3552. DOI:10.1038/srep03552 · 5.08 Impact Factor

Publication Stats

2k Citations
327.59 Total Impact Points

Institutions

  • 2011–2014
    • University of Washington Seattle
      • • Institute for Stem Cell and Regenerative Medicine
      • • Department of Bioengineering
      Seattle, Washington, United States
    • University of California, Berkeley
      Berkeley, California, United States
  • 2012
    • Johns Hopkins Medicine
      • Department of Biomedical Engineering
      Baltimore, MD, United States
    • Seoul National University
      • Department of Biosystems and Biomaterials Science and Engineering
      Seoul, Seoul, South Korea
  • 2008–2011
    • Johns Hopkins University
      • Department of Biomedical Engineering
      Baltimore, Maryland, United States
  • 2003–2006
    • Pusan National University
      Tsau-liang-hai, Busan, South Korea
  • 2001–2006
    • Korea Institute of Science and Technology
      • Sensor System Research Center
      Sŏul, Seoul, South Korea
    • Korea University
      • Department of Electrical Engineering
      Sŏul, Seoul, South Korea
  • 2005
    • Chonnam National University
      Gwangju, Gwangju, South Korea
    • Eawag: Das Wasserforschungs-Institut des ETH-Bereichs
      Duebendorf, Zurich, Switzerland
  • 2004
    • Korea Research Institute of Chemical Technology
      Daiden, Daejeon, South Korea