V J Dzau

Washington DC VA Medical Center, Washington, Washington, D.C., United States

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Publications (488)3810.71 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: High-resolution tracking of stem cells remains a challenging task. An ultra-bright contrast agent with extended intracellular retention is suitable for in vivo high-resolution tracking of stem cells following the implantation. Here, a plasmonic-active nanoplatform was developed for tracking mesenchymal stromal cells (MSCs) in mice. The nanoplatform consisted of TAT peptide-functionalized gold nanostars (TAT-GNS) that emit ultra-bright two-photon photoluminescence capable of tracking MSCs under high-resolution optical imaging. In vitro experiment showed TAT-GNS-labeled MSCs retained a similar differentiability to that of non-labeled MSCs controls. Due to their star shape, TAT-GNS exhibited greater intracellular retention than that of commercial Q-Tracker. In vivo imaging of TAT-GNS-labeled MSCs five days following intra-arterial injections in mice kidneys showed possible MSCs implantation in juxta-glomerular (JG) regions, but non-specifically in glomeruli and afferent arterioles as well. With future design to optimize GNS labeling specificity and clearance, plasmonic-active nanoplatforms may be a useful intracellular tracking tool for stem cell research.
    Journal of Biophotonics 10/2015; DOI:10.1002/jbio.201500173 · 4.45 Impact Factor
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    ABSTRACT: Recent evidence indicates that the vasculature contains mesenchymal stem cells (MSCs). We hypothesized that angiotensin II (Ang II) type 2 receptors (AT2Rs) play a role in the osteogenesis of MSCs and may have a role in vascular calcification. Human MSCs were differentiated into osteoblasts. Expression of AT2R was significantly increased during osteogenesis, whereas the expression of Ang II type 1 receptors was not significantly changed. Incubation with the AT2R blocker PD123319 with or without Ang II significantly inhibited calcium deposition, whereas type 1 receptor blocker valsartan had no significant effect. PD123319 inhibited extracellular signal-regulated kinase (ERK) phosphorylation in the osteogenic process, whereas valsartan had no effect. Furthermore, PD123319 combined with Ang II also inhibited acute ERK phosphorylation in MSCs induced by insulin. In conclusion, AT2R is upregulated during osteogenesis. Blockade of AT2R inhibits osteogenesis and ERK phosphorylation of human MSCs. These results provide a novel insight into the pathophysiology of calcific vascular disease. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.
    Journal of the American Society of Hypertension (JASH) 06/2015; 9(7). DOI:10.1016/j.jash.2015.06.006 · 2.61 Impact Factor
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    ABSTRACT: Wnt signaling has recently emerged as an important regulator of cardiac progenitor cell proliferation and differentiation, but the exact mechanisms by which Wnt signaling modulates these effects are not known. Understanding these mechanisms is essential for advancing our knowledge of cardiac progenitor cell biology and applying this knowledge to enhance cardiac therapy. Here, we explored the effects of Sfrp2, a canonical Wnt inhibitor, in adult cardiac progenitor cell (CPC) differentiation and investigated the molecular mechanisms involved. Our data show that Sfrp2 treatment can promote differentiation of CPCs after ischemia-reperfusion injury. Treatment of CPCs with Sfrp2 inhibited CPC proliferation and primed them for cardiac differentiation. Sfrp2 binding to Wnt6 and inhibition of Wnt6 canonical pathway was essential for the inhibition of CPC proliferation. This inhibition of Wnt6 canonical signaling by Sfrp2 was important for activation of the non-canonical Wnt/Planar Cell Polarity (PCP) pathway through JNK, which in turn induced expression of cardiac transcription factors and CPC differentiation. Taken together, these results demonstrate a novel role of Sfrp2 and Wnt6 in regulating the dynamic process of CPC proliferation and differentiation, as well as providing new insights into the mechanisms of Wnt signaling in cardiac differentiation. Copyright © 2015. Published by Elsevier Ltd.
    Journal of Molecular and Cellular Cardiology 06/2015; 85. DOI:10.1016/j.yjmcc.2015.06.003 · 4.66 Impact Factor
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    ABSTRACT: The human heart has a limited capacity to regenerate lost or damaged cardiomyocytes after cardiac insult. Instead, myocardial injury is characterized by extensive cardiac remodeling by fibroblasts, resulting in the eventual deterioration of cardiac structure and function. Cardiac function would be improved if these fibroblasts could be converted into cardiomyocytes. MicroRNAs (miRNAs), small noncoding RNAs that promote mRNA degradation and inhibit mRNA translation, have been shown to be important in cardiac development. Using this information, various researchers have used miRNAs to promote the formation of cardiomyocytes through several approaches. Several miRNAs acting in combination promote the direct conversion of cardiac fibroblasts into cardiomyocytes. Moreover, several miRNAs have been identified that aid the formation of inducible pluripotent stem cells and miRNAs also induce these cells to adopt a cardiac fate. MiRNAs have also been implicated in resident cardiac progenitor cell differentiation. In this review, we discuss the current literature as it pertains to these processes, as well as discussing the therapeutic implications of these findings. © 2015 American Heart Association, Inc.
    Circulation Research 05/2015; 116(10):1700-1711. DOI:10.1161/CIRCRESAHA.116.304377 · 11.02 Impact Factor
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    ABSTRACT: Personalised medicine has generated global policy interest in the past few years. In 2012, the European Union established the European Alliance for Personalised Medicine with the aim to accelerate the development, delivery, and uptake of personalised health care, broadly defined. In the same year, the UK's Medical Research Council and National Institute for Health Research funded the National Phenome Centre to deliver broad access to a world-class capability in metabolic phenotyping for biomarker discovery and validation, improved patient stratification, and early identification of drug efficacy and safety.
    The Lancet 05/2015; DOI:10.1016/S0140-6736(15)60722-X · 45.22 Impact Factor
  • Conrad P Hodgkinson · Victor J Dzau
    Circulation Research 03/2015; 116(7):1109-1111. DOI:10.1161/CIRCRESAHA.115.305852 · 11.02 Impact Factor
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    ABSTRACT: Despite the importance of juxtaglomerular cell recruitment in the pathophysiology of cardiovascular diseases, the mechanisms that underlie renin production under conditions of chronic stimulation remain elusive. We have previously shown that CD44+ mesenchymal-like cells (CD44+ cells) exist in the adult kidney. Under chronic sodium deprivation, these cells are recruited to the juxtaglomerular area and differentiate to new renin-expressing cells. Given the proximity of macula densa to the juxtaglomerular area and the importance of macula densa released prostanoids in renin synthesis and release, we hypothesized that chronic sodium deprivation induces macula densa release of prostanoids, stimulating renal CD44+ cell activation and differentiation. CD44+ cells were isolated from adult kidneys and cocultured with the macula densa cell line, MMDD1, in normal or low-sodium medium. Low sodium stimulated prostaglandin E2 production by MMDD1 and induced migration of CD44+ cells. These effects were inhibited by addition of a cyclooxygenase 2 inhibitor (NS398) or an E-prostanoid receptor 4 antagonist (AH23848) to MMDD1 or CD44+ cells, respectively. Addition of prostaglandin E2 to CD44+ cells increased cell migration and induced renin expression. In vivo activation of renal CD44+ cells during juxtaglomerular recruitment was attenuated in wild-type mice subjected to salt restriction in the presence of cyclooxygenase 2 inhibitor rofecoxib. Similar results were observed in E-prostanoid receptor 4 knockout mice subjected to salt restriction. These results show that the prostaglandin E2/E-prostanoid receptor 4 pathway plays a key role in the activation of renal CD44+ mesenchymal stromal cell-like cells during conditions of juxtaglomerular recruitment; highlighting the importance of this pathway as a key regulatory mechanism of juxtaglomerular recruitment. © 2015 American Heart Association, Inc.
    Hypertension 03/2015; 65(5). DOI:10.1161/HYPERTENSIONAHA.114.04611 · 6.48 Impact Factor
  • Victor J Dzau · Harvey V Fineberg
    JAMA The Journal of the American Medical Association 01/2015; 313(2):143-4. DOI:10.1001/jama.2014.17660 · 35.29 Impact Factor
  • T. Unger · U.M. Steckelings · V.J. Dzau
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    ABSTRACT: Since its discovery, 25 years ago, the angiotensin AT2 receptor (AT2R) has puzzled the scientific community because of its distinct -localization, regulation, signaling pathways, and biological effects separating it clearly from the classical features of the renin-angiotensin system (RAS) mediated by the angiotensin AT1 receptor. Intensive research over the years has revealed major characteristics of the AT2R as a modulatory player involved in antiproliferation, anti-inflammation, natriuresis, neuroregeneration, and apoptosis, that is, -biological programs that can counterbalance pathological processes and enable recovery from disease. The AT2R has thus mutated from an "-enigmatic" receptor to a significant member of the "protective arm" of the RAS. The recent development of novel, small molecule- and peptide-derived AT2R agonists offers a therapeutic potential in humans with a variety of clinical indications.
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    ABSTRACT: Rationale: A major goal for the treatment of heart tissue damaged by cardiac injury is to develop strategies for restoring healthy heart muscle through the regeneration and repair of damaged myocardium. We recently demonstrated that administration of a specific combination of microRNAs (miR combo) into the infarcted myocardium leads to direct in vivo reprogramming of noncardiac myocytes to cardiac myocytes. However, the biological and functional consequences of such reprogramming are not yet known. Objective: The aim of this study was to determine whether noncardiac myocytes directly reprogrammed using miRNAs in vivo develop into mature functional cardiac myocytes in situ, and whether reprogramming leads to improvement of cardiac function. Methods and results: We subjected fibroblast-specific protein 1-Cre mice/tandem dimer Tomato (tdTomato) mice to cardiac injury by permanent ligation of the left anterior descending coronary artery and injected lentiviruses encoding miR combo or a control nontargeting miRNA. miR combo significantly increased the number of reprogramming events in vivo. Five to 6 weeks after injury, morphological and physiological properties of tdTomato(-) and tdTomato(+) cardiac myocyte-like cells were analyzed ex vivo. tdTomato(+) cells expressed cardiac myocyte markers, sarcomeric organization, excitation-contraction coupling, and action potentials characteristic of mature ventricular cardiac myocytes (tdTomato(-) cells). Reprogramming was associated with improvement of cardiac function, as analyzed by serial echocardiography. There was a time delayed and progressive improvement in fractional shortening and other measures of ventricular function, indicating that miR combo promotes functional recovery of damaged myocardium. Conclusions: The findings from this study further validate the potential use of miRNA-mediated reprogramming as a therapeutic approach to promote cardiac regeneration after myocardial injury.
    Circulation Research 10/2014; 116(3). DOI:10.1161/CIRCRESAHA.116.304510 · 11.02 Impact Factor
  • Victor J Dzau · Philip A Pizzo
    JAMA The Journal of the American Medical Association 10/2014; 312(15):1507-1508. DOI:10.1001/jama.2014.12986 · 35.29 Impact Factor
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    ABSTRACT: Rationale: Cardiac progenitor cells (CPCs) are thought to differentiate into the major cell types of the heart: cardiomyocytes, smooth muscle cells, and endothelial cells. We have recently identified ABI family, member 3 (NESH) binding protein (Abi3bp) as a protein important for mesenchymal stem cell biology. Because CPCs share several characteristics with mesenchymal stem cells, we hypothesized that Abi3bp would similarly affect CPC differentiation and proliferation. Objective: To determine whether Abi3bp regulates CPC proliferation and differentiation. Methods and results: In vivo, genetic ablation of the Abi3bp gene inhibited CPC differentiation, whereas CPC number and proliferative capacity were increased. This correlated with adverse recovery after myocardial infarction. In vitro, CPCs, either isolated from Abi3bp knockout mice or expressing an Abi3bp shRNA construct, displayed a higher proliferative capacity and, under differentiating conditions, reduced expression of both early and late cardiomyocyte markers. Abi3bp controlled CPC differentiation via integrin-β1, protein kinase C-ζ, and v-akt murine thymoma viral oncogene homolog. Conclusions: We have identified Abi3bp as a protein important for CPC differentiation and proliferation.
    Circulation Research 10/2014; 115(12). DOI:10.1161/CIRCRESAHA.115.304216 · 11.02 Impact Factor
  • Tilanthi Jayawardena · Maria Mirotsou · Victor J Dzau
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    ABSTRACT: The therapeutic administration of microRNAs represents an innovative reprogramming strategy with which to advance cardiac regeneration and personalized medicine. Recently, a distinct set of microRNAs was found capable of converting murine fibroblasts to cardiomyocyte-like cells in vitro. Further treatment with JAK inhibitor I significantly enhanced the efficiency of the microRNA-mediated reprogramming (Jayawardena et al., Circ Res 110(11):1465-1473, 2012). This novel technique serves as an initial tool for switching the cell fate of cardiac fibroblasts toward the cardiomyocyte lineage using microRNAs. As the budding field of reprogramming biology develops, we hope that a thorough examination of the chemical, physical, and temporal parameters determining reprogramming efficiency and maturation will enable a better understanding of the mechanisms governing cardiac cell fate and provide new approaches for drug discovery and therapy for cardiovascular diseases.
    Methods in molecular biology (Clifton, N.J.) 04/2014; 1150:263-72. DOI:10.1007/978-1-4939-0512-6_18 · 1.29 Impact Factor
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    ABSTRACT: Despite advances in the treatment of acute tissue ischemia significant challenges remain in effective cytoprotection from ischemic cell death. It has been documented that injected stem cells, such as mesenchymal stem cells (MSCs), can confer protection to ischemic tissue through the release of paracrine factors. The study of these factors is essential for understanding tissue repair and the development of new therapeutic approaches for regenerative medicine. We have recently shown that a novel factor secreted by MSCs, which we called HASF (Hypoxia and Akt induced Stem cell Factor), promotes cardiomyocyte proliferation. In this study we show that HASF has a cytoprotective effect on ischemia induced cardiomyocyte death. We assessed whether HASF could potentially be used as a therapeutic agent to prevent the damage associated with myocardial infarction. In vitro treatment of cardiomyocytes with HASF protein resulted in decreased apoptosis; TUNEL positive nuclei were fewer in number, and caspase activation and mitochondrial pore opening were inhibited. Purified HASF protein was injected into the heart immediately following myocardial infarction. Heart function was found to be comparable to sham operated animals one month following injury and fibrosis was significantly reduced. In vivo and in vitro HASF activated protein kinase C ε (PKCε). Inhibition of PKCε blocked the HASF effect on apoptosis. Furthermore, the beneficial effects of HASF were lost in mice lacking PKCε. Collectively these results identify HASF as a protein of significant therapeutic potential, acting in part through PKCε.
    Journal of Molecular and Cellular Cardiology 11/2013; 66. DOI:10.1016/j.yjmcc.2013.11.010 · 4.66 Impact Factor
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    ABSTRACT: With a changing health care landscape and a growing gap between the excess costs of fulfilling academic health centers' missions and the available funding, the integrity of those missions is in jeopardy. Profound changes are needed in AHCs' organization and operations. Academic health centers (AHCs) have long led the advancement of science and medicine by pursuing missions of clinical care, research, and education. AHCs have been places where important fundamental and translational research is performed and medical innovations are created and tested. Given the dramatic changes ahead in health care and deteriorating research funding, can this record of achievement continue, or do AHCs in the United States face a growing risk of extinction?(1) Despite their substantial societal value, these centers have an uncertain future. The health care landscape is changing rapidly owing to the Affordable Care Act, state budget deficits, and ...
    New England Journal of Medicine 09/2013; 369(11):991-3. DOI:10.1056/NEJMp1302374 · 55.87 Impact Factor
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    ABSTRACT: There is a real need for innovation in health care delivery, as well as in medicine, to address related challenges of access, quality, and affordability through new and creative approaches. Health care environments must foster innovation, not just allowing it but actively encouraging it to happen anywhere and at every level in health care and medicine-from the laboratory, to the operating room, bedside, and clinics. This paper reviews the essential elements and environmental factors important for health-related innovation to flourish in academic health systems.The authors maintain that innovation must be actively cultivated by teaching it, creating "space" for and supporting it, and providing opportunities for its implementation. The authors seek to show the importance of these three fundamental principles and how they can be implemented, highlighting examples from across the country and their own institution.Health innovation cannot be relegated to a second-class status by the urgency of day-to-day operations, patient care, and the requirements of traditional research. Innovation needs to be elevated to a committed endeavor and become a part of an organization's culture, particularly in academic health centers.
    Academic medicine: journal of the Association of American Medical Colleges 08/2013; 88(10). DOI:10.1097/ACM.0b013e3182a32fc2 · 2.93 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) transplanted into injured myocardium promote repair through paracrine mechanisms. We have previously shown that MSCs overexpressing AKT1 (Akt-MSCs) exhibit enhanced properties for cardiac repair. In this study, we investigated the relevance of Abi3bp towards MSC biology. Abi3bp formed extracellular deposits with expression controlled by Akt1 and ubiquitin-mediated degradation. Abi3bp knockdown/knockout stabilized focal adhesions and promoted stress-fiber formation. Furthermore, MSCs from Abi3bp knockout mice displayed severe deficiencies in osteogenic and adipogenic differentiation. Knockout or stable knockdown of Abi3bp increased MSC and Akt-MSC proliferation, promoting S-phase entry via cyclin-d1, ERK1/2 and Src. Upon Abi3bp binding to integrin-β1 Src associated with paxillin which inhibited proliferation. In vivo, Abi3bp knockout increased MSC number and proliferation in bone marrow, lung, and liver. In summary, we have identified a novel extracellular matrix protein necessary for the switch from proliferation to differentiation in MSCs.
    Stem Cells 08/2013; 31(8). DOI:10.1002/stem.1416 · 6.52 Impact Factor
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    ABSTRACT: Rationale: The regenerative capacity of the heart is markedly diminished shortly after birth, coinciding with overall withdrawal of cardiomyocytes from cell cycle. Consequently, the adult mammalian heart has limited capacity to regenerate after injury. The discovery of factors that can induce cardiomyocyte proliferation is, therefore, of high interest and has been the focus of extensive investigation throughout the past years. Objective: We have recently identified C3orf58 as a novel hypoxia and Akt induced stem cell factor (HASF) secreted from mesenchymal stem cells, which can promote cardiac repair through cytoprotective mechanisms. Here, we tested the hypothesis that HASF can also contribute to cardiac regeneration by stimulating cardiomyocyte division and proliferation. Methods and results: Neonatal ventricular cardiomyocytes were stimulated in culture for 7 days with purified recombinant HASF protein. Compared with control untreated cells, HASF-treated neonatal cardiomyocytes exhibited 60% increase in DNA synthesis as measured by bromodeoxyuridine incorporation. These results were confirmed by immunofluorescence confocal microscopy showing a 50% to 100% increase in the number of cardiomyocytes in the mitotic and cytokinesis phases. Importantly, in vivo cardiac overexpression of HASF in a transgenic mouse model resulted in enhanced level of DNA synthesis and cytokinesis in neonatal and adult cardiomyocytes. These proliferative effects were modulated by a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway as revealed by the use of phosphoinositide 3-kinase -pathway-specific inhibitors and silencing of the Cdk7 gene. Conclusions: Our studies support the hypothesis that HASF induces cardiomyocyte proliferation via a phosphoinositide 3-kinase-protein kinase B-cycle-dependent kinase 7 pathway. The implications of this finding may be significant for cardiac regeneration biology and therapeutics.
    Circulation Research 06/2013; 113(4). DOI:10.1161/CIRCRESAHA.113.301075 · 11.02 Impact Factor
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    ABSTRACT: The renin-angiotensin-aldosterone system (RAAS) regulates BP and salt-volume homeostasis. Juxtaglomerular (JG) cells synthesize and release renin, which is the first and rate-limiting step in the RAAS. Intense pathologic stresses cause a dramatic increase in the number of renin-producing cells in the kidney, termed JG cell recruitment, but how this occurs is not fully understood. Here, we isolated renal CD44(+) mesenchymal stem cell (MSC)-like cells and found that they differentiated into JG-like renin-expressing cells both in vitro and in vivo. Sodium depletion and captopril led to activation and differentiation of these cells into renin-expressing cells in the adult kidney. In summary, CD44(+) MSC-like cells exist in the adult kidney and can differentiate into JG-like renin-producing cells under conditions that promote JG cell recruitment.
    Journal of the American Society of Nephrology 06/2013; 24(8). DOI:10.1681/ASN.2012060596 · 9.34 Impact Factor
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    ABSTRACT: Rationale: Regeneration of damaged cardiac tissue after injury presents a daunting challenge in cardiovascular medicine. Recent developments in reprogramming of somatic cells directly to cells of other lineages have raised the possibility of using this approach for cardiac regenerative therapy. Our group recently demonstrated successful miRNA mediated cardiac reprogramming in vitro and in vivo using a combination of miRNAs 1, 133, 206 and 499. Although, the molecular mechanisms underlying miRNA mediated fibroblast reprogramming to cardiomyocytes are yet unknown, accumulating evidence suggest that reprogramming acts through distinct phases and that histone modifications play an important role in these processes. Objective: Identify key genes involved in initiating miRNA mediated reprogramming via histone modifications. Methods and Results: For this, we analyzed the expression levels of 81 different genes involved in chromatin modification 4 days after miRNA transfection using PCR arrays. This analysis revealed that 6 of the 81 tested genes showed differential gene expression (-1.5-fold and p <0.02). JAK inhibitor-1 treatment, known for increasing reprogramming efficiency, further enhanced gene expression changes in 5 of these 6 genes. Setdb2, an H3K9 methyltransferase, was one of the most down-regulated targets 4 days after miRNA transfection (-1.4 fold, p<0.001). This effect was enhanced further when miRNAs were combined with the JAK inhibitor-1 (-2.6 fold, p<0.001). Silencing of Setdb2 using siRNAs further accentuated miRNA cardiac reprogramming as measured by cardiac transcription factor expression at 3 days and 6 days post treatment. Similar trends were observed by FACS analysis detecting increased percentage of αMHC-positive cells in siRNA treated fibroblasts compared to control treated only with the miRNA combination. Interestingly, our data showed that Setdb2 silencing alone was sufficient to initiate cardiac reprogramming, suggesting that Setdb2 might play a crucial role in defining cardiac cell fate. Conclusion: In conclusion our results indicate that Setdb2 down-regulation plays an important role in the direct reprogramming of fibroblasts to cardiomyocyte-like cells.
    BCVS 2013, Las Vegas, NV; 05/2013

Publication Stats

35k Citations
3,810.71 Total Impact Points


  • 2015
    • Washington DC VA Medical Center
      Washington, Washington, D.C., United States
  • 2014
    • The Washington Institute
      Washington, Washington, D.C., United States
  • 2005–2013
    • Duke University
      • Department of Medicine
      Durham, North Carolina, United States
    • Duke University Medical Center
      • • Department of Medicine
      • • Division of Cardiology
      Durham, North Carolina, United States
  • 1985–2007
    • Harvard University
      Cambridge, Massachusetts, United States
  • 1982–2007
    • Harvard Medical School
      • Department of Medicine
      Boston, MA, United States
  • 1982–2005
    • Brigham and Women's Hospital
      • • Department of Medicine
      • • Division of Cardiovascular Medicine
      Boston, Massachusetts, United States
  • 2004
    • University of Glasgow
      • Institute of Cardiovascular and Medical Sciences
      Glasgow, Scotland, United Kingdom
    • Queen's University
      • Department of Physiology
      Kingston, Ontario, Canada
    • Morehouse School of Medicine
      Atlanta, Georgia, United States
    • University of California, San Francisco
      • Division of Adult Cardiothoracic Surgery
      San Francisco, CA, United States
  • 2003
    • University of Kuopio
      Kuopio, Northern Savo, Finland
  • 2001
    • University of Toronto
      • Department of Laboratory Medicine and Pathobiology
      Toronto, Ontario, Canada
  • 1999
    • Justus-Liebig-Universität Gießen
      Gieben, Hesse, Germany
  • 1991–1997
    • Stanford University
      • • Division of Cardiovascular Medicine
      • • Falk Cardiovascular Research Center
      Stanford, California, United States
    • Joslin Diabetes Center
      Boston, Massachusetts, United States
    • Universität Heidelberg
      • Department of Clinical Pharmacology
      Heidelburg, Baden-Württemberg, Germany
  • 1990–1997
    • Stanford Medicine
      • • Falk Cardiovascular Research Center
      • • Division of Cardiovascular Medicine
      Stanford, California, United States
  • 1996
    • Osaka University
      Suika, Ōsaka, Japan
  • 1995
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 1993
    • Osaka City University
      • Graduate School of Medicine
      Ōsaka, Ōsaka, Japan
  • 1992
    • University of Florida
      Gainesville, Florida, United States
  • 1989
    • National Institute for Biological Standards and Control
      Potters Bar, England, United Kingdom
  • 1987–1989
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 1980–1986
    • Massachusetts General Hospital
      • Department of Medicine
      Boston, Massachusetts, United States