Yi Liu

Molecular and Cellular Biology Program, Seattle, Washington, United States

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Publications (60)258.94 Total impact

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    ABSTRACT: The interplay between osteoblasts and osteoclasts has a crucial role in maintaining bone homeostasis. In this study, we reveal that osteoblasts are capable of inducing osteoclast apoptosis by FAS ligand (FASL)/FAS signaling. Conditional knockout of FASL in osteoblasts results in elevated osteoclast numbers and activity, along with reduced bone mass, suggesting that osteoblastproduced FASL is required to maintain physiological bone mass. More interestingly, we show that osteoblasts from ovariectomized (OVX) osteoporotic mice exhibit decreased FASL expression that results from the IFN-γ- and TNF-α-activated NF-κB pathway, leading to reduced osteoclast apoptosis and increased bone resorption. Systemic administration of either IFN-γ or TNF-α ameliorates the osteoporotic phenotype in OVX mice and rescues FASL expression in osteoblasts. In addition, ovariectomy induces more significant bone loss in FASL conditional knockout mice than in control group with increased osteoclast activity in which the levels of RANKL and OPG remain unchanged. Taken together, this study suggests that osteoblast-induced osteoclast apoptosis via FASL/FAS signaling is a previously unrecognized mechanism that has an important role in the maintenance of bone mass in both physiological conditions and OVX osteoporosis.
    Cell Death and Differentiation 03/2015; · 8.39 Impact Factor
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    ABSTRACT: This study sought to investigate dimensional changes to the alveolar bone following extraction and application of novel devices used for obturation of socket orifice (socket cap) and space maintenance in sockets with facial dehiscence (socket cage). Six Macaca fascicularis had six teeth each removed according to the following intervention groups (groups A-C intact alveolar bone; D-E facial dehiscence): negative control (A); socket obturated with cap (B); filled with anorganic bovine bone mineral (ABBM) + socket cap (C); dehiscence negative control (D); socket cap + socket cage (E); ABBM + socket cap + socket cage (F). Serial CBCT scans at preoperatively, 6 and 12 weeks following intervention were compared to quantify linear alveolar bone alterations. Without therapeutic intervention, intact sockets exhibited significant reduction in width at the crestal 2 mm of the ridge crest within 6 weeks. Compared with the negative control sites which lost up to 52% of crestal bone width, sites treated with socket cap + ABBM lost at most 4% of bone width at the crestal 2 mm. Similar results were seen in the dehiscence groups, with the combination of socket cap + socket cage + ABBM maintaining the greatest socket width and height dimensions. Results from the current non-human primate study suggest that the socket cap and socket cage devices, when used in conjunction with xenograft proved effective in minimizing post-extraction socket width loss and height seen in both intact sockets and sockets with facial dehiscence defects. © 2015 The Authors. Clinical Oral Implants Research Published by John Wiley & Sons Ltd.
    Clinical Oral Implants Research 02/2015; DOI:10.1111/clr.12521 · 3.12 Impact Factor
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    ABSTRACT: Dental pulp stem cells (DPSCs) possess self-renewal capability, multi-lineage differentiation potential, and can generate a dentin-pulp-like tissue in vivo, which is promising for tooth regeneration. To enlarge the cells resource of DPSCs and explore the feasibility of DPSCs-mediated immune therapy, it is prerequisite to investigate the immunological properties of DPSCs and the underlying mechanisms. Human DPSCs and peripheral blood mononuclear cells were isolated and cultured. Then we used lymphocytes proliferation assays, cytokines detection, Transwell cultures, neutralization experiments, and flow cytometry to examine the in vitro immune characteristics of DPSCs. We found that DPSCs failed to stimulate allogeneic T cells proliferation and suppressed T cells proliferation, B cells proliferation, and mixed lymphocyte reaction. In addition, DPSCs could up-regulate IL-10, down-regulate the production of IL-2, IL-17, and IFN-γ, and did not affect the production of IL-6. Monoclonal antibody against transforming growth factor-β1 restored the T cells proliferation inhibited by DPSCs. Moreover, the population of regulatory T cells increased significantly and T-helper 17 cells decreased significantly in peripheral blood mononuclear cells co-cultured with DPSCs. These data confirmed that DPSCs are low immunogenic, could inhibit the proliferation of lymphocytes, regulate the production of cytokines in vitro, and the secretion of transforming growth factor-β1 may be involved in this event.
    Human Cell 01/2015; DOI:10.1007/s13577-014-0106-y · 1.74 Impact Factor
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    ABSTRACT: ATP plays central roles in cancer metabolism and the Warburg effect. Intratumoral ATP concentrations are up to 104 times higher than those of interstitial ATP in normal tissues. However, extracellular ATP is not known to enter cancer cells. Here we report that human A549 lung cancer cells internalized extracellular ATP by macropinocytosis as demonstrated by colocalization of a nonhydrolyzable fluorescent ATP and a macropinocytosis tracer high-molecular-weight dextran, as well as by a macropinocytosis inhibitor study. Extracellular ATP also induced increase of intracellular ATP levels, without involving transcription and translation at significant levels, and cancer cells’ resistance to ATP-competitor anticancer drugs, likely through the mechanism of ATP internalization. These findings, described for the first time, have profound implications in ATP-sharing among cancer cells in tumors and highlight a novel anticancer target.
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    ABSTRACT: Mesenchymal stem cell-based regenerative medicine is a promising approach for functional tissue reconstruction. A recent study showed that host immune cells regulated bone marrow mesenchymal stem cell (BMMSC)-mediated tissue regeneration. However, it is unknown whether systemic infusion of BMMSCs, which induces immune tolerance, affects cell-based tissue regeneration. In this study, we showed that BMMSCs possessed an immunomodulatory function in vitro. Moreover, systemic infusion of BMMSCs reduced IFN- and TNF- levels in the implantation sites via upregulation of regulatory T cells (Tregs), resulting in marked enhancement of cell-based bone regeneration, but with only limited contribution by BMMSC homing. Furthermore, we showed that systemic BMMSC infusion significantly improved cell-based repair of critical-sized calvarial defects in a murine model. These results suggested a new approach to enhance cell-based bone regeneration.
    Tissue Engineering Part A 08/2014; 21(3-4). DOI:10.1089/ten.TEA.2013.0673 · 4.70 Impact Factor
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    ABSTRACT: ATP plays central roles in cancer metabolism and the Warburg effect. Intratumoral ATP concentrations are up to 10(4) times higher than those of interstitial ATP in normal tissues. However, extracellular ATP is not known to enter cancer cells. Here we report that human A549 lung cancer cells internalized extracellular ATP by macropinocytosis as demonstrated by colocalization of a nonhydrolyzable fluorescent ATP and a macropinocytosis tracer high-molecular-weight dextran. Extracellular ATP also induced increase of intracellular ATP levels and cancer cells' resistance to ATP-competitor anticancer drugs, likely through the mechanism of ATP internalization. These findings, described for the first time, have profound implications in ATP-sharing among cancer cells in tumors and highlight a novel anticancer target.
    Cancer Letters 06/2014; DOI:10.1016/j.canlet.2014.06.008 · 5.02 Impact Factor
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    ABSTRACT: Bone marrow mesenchymal stem cells (BMMSCs) have been used to treat a variety of autoimmune diseases in clinics. However, the therapeutic effects are largely dependent on the immunomodulatory capacity of culture-expanded BMMSCs. In the present study, we show that aspirin (ASA)-treated BMMSCs have significantly improved immunomodulatory function, as indicated by upregulation of regulatory T cells (Tregs) and downregulation of Th17 cells via the 15d-PGJ2/PPARγ/TGF-β1 pathway. Furthermore, the therapeutic effect of ASA-pretreated BMMSCs was confirmed in a dextran sodium sulfate (DSS)-induced experimental colitis mouse model, in which systemic infusion of ASA-pretreated BMMSCs significantly ameliorated disease activity index (DAI) and colonic inflammation, along with an increased number of Tregs and decreased number of Th17 cells. Taken together, our results suggest that aspirin treatment is a feasible strategy to promote BMMSC-based immunomodulation.
    Stem cells and development 04/2014; 23(17). DOI:10.1089/scd.2014.0081 · 4.20 Impact Factor
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    ABSTRACT: Mesenchymal stem cell (MSC)-based regenerative medicine represents a promising frontier for bone reconstruction. Significant efforts have been devoted to clarifying the capacities of MSCs to repair or reconstruct bone tissue. This review provides a concise summary of current knowledge pertaining to the possible mechanisms of MSC action in the regeneration of bone, with particular focus on the interplay between donor MSCs and host immune response in the process of new bone regeneration. This article is protected by copyright. All rights reserved.
    Oral Diseases 04/2014; 20(7). DOI:10.1111/odi.12248 · 2.40 Impact Factor
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    ABSTRACT: Gaseous signaling molecules such as hydrogen sulfide (H2S) are produced endogenously and mediate effects through diverse mechanisms. H2S is one such gasotransmitters that regulates multiple signaling pathways in mammalian cells, and abnormal H2S metabolism has been linked to defects in bone homeostasis. Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S in order to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca(2+) influx because of reduced sulfhydration of cysteine residues on multiple Ca(2+) TRP channels. This decreased Ca(2+) flux downregulates PKC/Erk-mediated Wnt/β-catenin signaling which controls osteogenic differentiation of BMMSCs. Consistently, H2S-deficient mice display an osteoporotic phenotype that can be rescued by small molecules that release H2S. These results demonstrate that H2S regulates BMMSCs and that restoring H2S levels via nontoxic donors may provide treatments for diseases such as osteoporosis that can arise from H2S deficiencies.
    Cell stem cell 04/2014; DOI:10.1016/j.stem.2014.03.005 · 22.15 Impact Factor
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    ABSTRACT: In the oral maxillofacial region, there are significant demands for repairing severe tissue defects caused by congenital malformations, oncologic resection, post-traumatic loss, and pathologic degenerative destruction such as periodontitis. Mesenchymal stem cells (MSCs) are adult stem cells whose multipotency has been investigated for therapeutic applications. This review highlights the main MSCs involved in the tissue regeneration of oral maxillofacial region and recent advances in dental MSC-based tissue regeneration and treatments in this region. MSCs isolated from oral maxillofacial sources have higher proliferation rates and are more capable of forming bone and dental tissues. Large animal models of oral diseases or defects were established and treated with MSCs. Miniature pigs or dogs more closely mimic disease in humans and provide a useful means for translating research into clinical applications. MSCs exert other beneficial effects, including immunomodulation and paracrine processes. The immunoregulatory properties of MSCs facilitate their application to oral diseases and tissue regeneration. Besides autologous MSCs being an excellent cell source for tissue engineering and regenerative medicine, allogeneic MSC-based treatment also provides a safe and effective therapeutic modality, the use of allogeneic MSCs in highly standardized clinical trials could lead to a better understanding of their real-life applications, which sheds light on potential clinical applications for treating oral diseases.
    Histology and histopathology 03/2014; · 2.24 Impact Factor
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    ABSTRACT: A series of novel 9-O-acetyl-4'-substituted 16-membered macrolides derived from josamycin has been designed and synthesized by cleavage of the mycarose of josamycin and subsequent modification of the 4'-hydroxyl group. These derivatives were evaluated for their in vitro antibacterial activities against a panel of Staphylococcus aureus and Staphylococcus epidermidis. 15 (4'-O-(3-Phenylpropanoyl)-9-O-acetyl-desmycarosyl josamycin) and 16 (4'-O-butanoyl-9-O-acetyl-desmycarosyl josamycin) exhibited comparable activities to josamycin against S. aureus (MSSA) and S. epidermidis (MSSE).
    Bioorganic & medicinal chemistry letters 12/2013; DOI:10.1016/j.bmcl.2013.12.029 · 2.33 Impact Factor
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    ABSTRACT: Abnormal stem cell function makes a known contribution to many malignant tumors, but the role of stem cells in benign tumors is not well understood. Here, we show that ossifying fibroma (OF) contains a stem cell population that resembles mesenchymal stem cells (OFMSCs) and is capable of generating OF-like tumor xenografts. Mechanistically, OFMSCs show enhanced TGF-β signaling that induces aberrant proliferation and deficient osteogenesis via Notch and BMP signaling pathways, respectively. The elevated TGF-β activity is tightly regulated by JHDM1D-mediated epigenetic regulation of thrombospondin-1 (TSP1), forming a JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. Inhibition of TGF-β signaling in OFMSCs can rescue their abnormal osteogenic differentiation and elevated proliferation rate. Furthermore, chronic activation of TGF-β can convert normal MSCs into OF-like MSCs via establishment of this JHDM1D/TSP1/TGF-β/SMAD3 autocrine loop. These results reveal that epigenetic regulation of TGF-β signaling in MSCs governs the benign tumor phenotype in OF and highlight TGF-β signaling as a candidate therapeutic target.
    Cell stem cell 11/2013; 13(5):577-89. DOI:10.1016/j.stem.2013.08.010 · 22.15 Impact Factor
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    ABSTRACT: A series of new 4″-O-desosaminyl clarithromycin derivatives were designed and synthesized. The efficient synthesis routes of 6-deoxy-desosamine donors 8 and 11 were developed and the methodology of glycosylation of clarithromycin 4″-OH with desosamine was studied. The activities of the target compounds were tested against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed activities against macrolide sensitive pathogens, and compounds 19 and 22 displayed significant improvement of activities against sensitive pathogens and two strains of MRSE, which verified the importance of desosamine in the interaction of macrolide and its receptor, and offered valuable information of the SAR of macrolide 4″-OH derivatives.
    Bioorganic & medicinal chemistry letters 10/2013; 23(23). DOI:10.1016/j.bmcl.2013.09.083 · 2.33 Impact Factor
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    ABSTRACT: A practicable method of introducing a side chain to the C-4' position of 5-O-desosamine in the 14-membered ketolides was developed. And using this method, a series of novel modified 5-O-mycaminose ketolides were synthesized. These ketolides containing 5-O-4'-carbamate mycaminose were evaluated for their in vitro antibacterial activities against some respiratory pathogens. 15b and 18e showed comparable activity to telithromycin and clarithromycin.
    European Journal of Medicinal Chemistry 08/2013; 69C:174-181. DOI:10.1016/j.ejmech.2013.08.023 · 3.43 Impact Factor
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    ABSTRACT: An inflammatory microenvironment may cause organ degenerative diseases and malignant tumors. However, the precise mechanisms of inflammation-induced diseases are not fully understood. Here we show that the proinflammatory cytokines interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α) synergistically impair self-renewal and differentiation of mesenchymal stem cells (MSCs) via nuclear factor κB (NFκB)--mediated activation of Mothers against decapentaplegic homolog 7 (SMAD7) in ovariectomized (OVX) mice. More interestingly, a long-term elevated levels of IFN-γ and TNF-α result in significantly increased susceptibility to malignant transformation in MSCs through NFκB--mediated upregulation of the oncogenes c-Fos and c-Myc. Depletion of either IFN-γ or TNF-α in OVX mice abolishes MSC impairment and the tendency toward malignant transformation with no NFκB--mediated oncogene activation. Systemic administration of aspirin, which significantly reduces the levels of IFN-γ and TNF-α, results in blockage of MSC deficiency and tumorigenesis by inhibition of NF-κB/SMAD7 and NFκB/c-FOS and c-MYC pathways in OVX mice. In summary, this study reveals that inflammation factors, such as IFN-γ and TNF-α, synergistically induce MSC deficiency via NFκB/SMAD7 signaling and tumorigenesis via NFκB--mediated oncogene activation.
    Stem Cells 07/2013; 31(7). DOI:10.1002/stem.1388 · 7.70 Impact Factor
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    ABSTRACT: Type 2 diabetes (T2D) has become an epidemic worldwide while Type 1 diabetes (T1D) remains a great medical challenge. IR signaling activators could alleviate hyperglycemia, reduce the burden on the pancreas and contribute to prevention and treatment of both types of diabetes. Previously we reported the synthesis and identification of a natural anti-diabetic compound α-penta-galloyl-glucose (α-PGG). Subsequent studies led to the identification of an α-PGG derivative, 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ). Here we report that 6Cl-TGQ not only induced rapid and long-lasting glucose uptake comparable to insulin in adipocytes, but also reduced high blood glucose levels to near normal and significantly decreased plasma insulin levels and improved glucose tolerance performance in high fat diet (HFD)-induced T2D mice when administered orally at 5mg/kg once every other day. Moreover, a single gavage of 6Cl-TGQ at 10mg/kg induced rapid and sharp decline of blood glucose in streptozotocin (STZ)-induced T1D mice. Our studies further indicated that 6Cl-TGQ activated the IR signaling in cell models and insulin-responsive tissues of mice. 6Cl-TGQ-induced Akt phosphorylation was completely blocked by IR and PI3K inhibitors, while the induced glucose uptake was blocked by the same compounds and a Glut4 inhibitor. Receptor binding studies indicated that 6Cl-TGQ bound to IR with a higher affinity than α-PGG. Importantly, 6Cl-TGQ, unlike insulin, selectively induced phosphorylation of IR without activating IGF1R or its signaling and did not increase cancer cell proliferation. These results indicate that 6Cl-TGQ is a potent orally efficacious compound with low carcinogenic potential and may contribute to the prevention and treatment of T1D and T2D.
    Journal of Molecular Endocrinology 04/2013; DOI:10.1530/JME-12-0171 · 3.62 Impact Factor
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    ABSTRACT: Bisphosphonates (BPs), which are used to treat a variety of clinical disorders, have the side effect of jawbone necrosis. Currently, there is no reliable treatment for bisphosphonates-related osteonecrosis of the jaw (BRONJ) due to a lack of understanding of its pathogenesis. To investigate the pathogenesis of BRONJ and observe the treatment effect of bone marrow mesenchymal stem cell (BMMSC) transplantation, we established a pre-clinical animal model of BRONJ in miniature pigs (minipigs). After treatment with zoledronic acid, the clinical and radiographic manifestations of BRONJ could be observed in minipigs after first premolar extraction. The biological and immunological properties of BMMSCs were impaired in the BP-treated minipigs. Moreover, the ratio of Foxp3-positive regulatory T cells (Tregs) in peripheral blood decreased, and IL-17 increased in the serum of BP-treated minipigs. After allogeneic BMMSC transplantation via intravenous infusion, mucosal healing and bone reconstruction were observed, IL-17 levels were reduced, and Treg cells were elevated. In summary, we established a clinically relevant BRONJ model in minipigs and tested a promising allogeneic BMMSC-based therapy, which may have potential clinical applications for treating BRONJ.
    Stem cells and development 03/2013; DOI:10.1089/scd.2012.0615 · 4.20 Impact Factor
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    ABSTRACT: Our previous proof-of-concept study showed the feasibility of regenerating dental stem cell-based bioengineered tooth root (bio-root) structure in large animal model. Here, we used allogeneic dental mesenchymal stem cells to regenerate bio-root, and then installed a crown on the bio-root to restore tooth function. Root shape hydroxyapatite tricalcium phosphate (HA/TCP) scaffold containing dental pulp stem cells (DPSCs) was covered by Vc-induced periodontal ligament stem cell (PDLSC) sheet and implanted into a newly generated jaw bone implant socket. Six months after implantation, a pre-fabricated porcelain crown was cemented to the implant and subjected to tooth function. Clinical, radiological, histological, ultrastructural, systemic immunological evaluations and mechanical properties were analyzed for dynamic changes in bio-root structure. The regenerated bio-root exhibited characteristics of a normal tooth after 6 months of use, including dentinal tubule-like and functional periodontal ligament-like structures. No immunological response to the bio-roots was observed. We developed a standard stem cell procedure for bio-root regeneration to restore adult tooth function. This study is the first to successfully regenerate a functional bio-root structure for artificial crown restoration by using allogeneic dental stem cells and Vc-induced cell sheet, and assess recipient immune response in a pre-clinical model.
    Stem cells and development 01/2013; DOI:10.1089/scd.2012.0688 · 4.20 Impact Factor
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    ABSTRACT: Bone marrow mesenchymal stem cells (MSCs) comprise a heterogeneous population of postnatal progenitor cells with profound immunomodulatory properties, such as upregulation of Foxp3(+) regulatory T cells (Tregs) and downregulation of Th17 cells. However, it is unknown whether different MSC subpopulations possess the same range of immunomodulatory function. Here, we show that a subset of single colony-derived MSCs producing IL-17 is different from bulk MSC population in that it cannot upregulate Tregs, downregulate Th17 cells, or ameliorate disease phenotypes in a colitis mouse model. Mechanistically, we reveal that IL-17, produced by these MSCs, activates the NFκB pathway to downregulate TGF-β production in MSCs, resulting in abolishment of MSC-based immunomodulation. Furthermore, we show that NFκB is able to directly bind to TGF-β promoter region to regulate TGF-β expression in MSCs. Moreover, these IL-17(+) MSCs possess anti-Candida albicans growth effects in vitro and therapeutic effect in C. albicans-infected mice. In summary, this study shows that MSCs contain an IL-17(+) subset capable of inhibiting C. albicans growth, but attenuating MSC-based immunosuppression via NFκB-mediated downregulation of TGF-β.Cell Research advance online publish 25 December 2012; doi:10.1038/cr.2012.179.
    Cell Research 12/2012; DOI:10.1038/cr.2012.179 · 11.98 Impact Factor

Publication Stats

2k Citations
258.94 Total Impact Points


  • 2013–2014
    • Molecular and Cellular Biology Program
      Seattle, Washington, United States
    • Peking Union Medical College Hospital
      Peping, Beijing, China
  • 2011–2014
    • Ohio University
      • Department of Biological Sciences
      Athens, Ohio, United States
  • 2010–2014
    • Capital Medical University
      Peping, Beijing, China
  • 2009–2014
    • University of Southern California
      • Center for Craniofacial Molecular Biology
      Los Angeles, California, United States
  • 2012
    • Chinese Academy of Medical Sciences
      Peping, Beijing, China
    • University of Minnesota Twin Cities
      • School of Dentistry
      Minneapolis, Minnesota, United States
  • 2004–2012
    • Università degli Studi di Genova
      • Dipartimento di Medicina sperimentale (DIMES)
      Genova, Liguria, Italy
  • 2008
    • University of Maryland, Baltimore
      • Department of Endodontics, Prosthodontics and Operative Dentistry
      Baltimore, MD, United States