Michael T Longaker

Stanford Medicine, Stanford, California, United States

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Publications (839)3094.59 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Stem cells and progenitor cells are integral to tissue homeostasis and repair. They contribute to health through their ability to self-renew and commit to specialized effector cells. Recently, defects in a variety of progenitor cell populations have been described in both preclinical and human diabetes. These deficits affect multiple aspects of stem cell biology, including quiescence, renewal, and differentiation, as well as homing, cytokine production, and neovascularization, through mechanisms that are still unclear. More important, stem cell aberrations resulting from diabetes have direct implications on tissue function and seem to persist even after return to normoglycemia. Understanding how diabetes alters stem cell signaling and homeostasis is critical for understanding the complex pathophysiology of many diabetic complications. Moreover, the success of cell-based therapies will depend on a more comprehensive understanding of these deficiencies. This review has three goals: to analyze stem cell pathways dysregulated during diabetes, to highlight the effects of hyperglycemic memory on stem cells, and to define ways of using stem cell therapy to overcome diabetic complications. Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
    American Journal Of Pathology 06/2015; DOI:10.1016/j.ajpath.2015.05.003 · 4.60 Impact Factor
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    ABSTRACT: Adipose tissue contains an abundant source of multipotent mesenchymal cells termed "adipose-derived stromal cells" (ASCs) which hold potential for regenerative medicine. However, the heterogeneity inherent to ASCs harvested using standard methodologies remains largely undefined, particularly in regards to differences across donors. Identifying the subpopulations of ASCs predisposed towards differentiation along distinct lineages holds value for improving graft survival, predictability, and efficiency. Human (h)ASCs from three different donors were independently isolated by density-based centrifugation from adipose tissue and maintained in culture or differentiated along either adipogenic or osteogenic lineages using differentiation media. Undifferentiated and differentiated hASCs were then analyzed for the presence of 242 human surface markers by flow cytometry analysis. By comprehensively characterizing the surface marker profile of undifferentiated hASCs using flow cytometry, we gained novel insight into the heterogeneity underlying protein expression on the surface of cultured undifferentiated hASCs across different donors. Comparing the surface marker profile of undifferentiated hASCs to hASCs that have undergone osteogenic or adipogenic differentiation allowed for the identification of surface markers upregulated and downregulated by osteogenic or adipogenic differentiation. Osteogenic differentiation induced upregulation of CD164 and downregulation of CD49a, CD49b, CD49c, CD49d, CD55, CD58, CD105, and CD166 while adipogenic differentiation induced upregulation of CD36, CD40, CD146, CD164, and CD271 and downregulation of CD49b, CD49c, CD49d, CD71, CD105, and CD166. These results lend support to the notion that hASCs isolated using standard methodologies represent a heterogeneous population and serve as a foundation for future studies seeking to maximize their regenerative potential through FACS-based selection prior to therapy.
    Tissue Engineering Part A 05/2015; DOI:10.1089/ten.TEA.2015.0039 · 4.64 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):30. DOI:10.1097/01.prs.0000465477.92868.67 · 3.33 Impact Factor
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    ABSTRACT: The surgical implantation of materials and devices has dramatically increased over the past decade. This trend is expected to continue with the broadening application of biomaterials and rapid expansion of aging populations. One major factor that limits the potential of implantable materials and devices is the foreign body response, an immunologic reaction characterized by chronic inflammation, foreign body giant cell formation, and fibrotic capsule formation. The English literature on the foreign body response to implanted materials and devices is reviewed. Fibrotic encapsulation can cause device malfunction and dramatically limit the function of an implanted medical device or material. Basic science studies suggest a role for immune and inflammatory pathways at the implant-host interface that drive the foreign body response. Current strategies that aim to modulate the host response and improve construct biocompatibility appear promising. This review article summarizes recent basic science, preclinical, and clinicopathologic studies examining the mechanisms driving the foreign body response, with particular focus on breast implants and synthetic meshes. Understanding these molecular and cellular mechanisms will be critical for achieving the full potential of implanted biomaterials to restore human tissues and organs.
    Plastic and Reconstructive Surgery 05/2015; 135(5):1489-1498. DOI:10.1097/PRS.0000000000001193 · 3.33 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):100. DOI:10.1097/01.prs.0000465588.33184.af · 3.33 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):120-121. DOI:10.1097/01.prs.0000465620.23775.46 · 3.33 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):124-125. DOI:10.1097/01.prs.0000465626.54269.69 · 3.33 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):26. DOI:10.1097/01.prs.0000465469.54750.33 · 3.33 Impact Factor
  • Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):23. DOI:10.1097/01.prs.0000465467.69997.55 · 3.33 Impact Factor
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    Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):104-105. DOI:10.1097/01.prs.0000465594.27346.c8 · 3.33 Impact Factor
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    ABSTRACT: Adipose-derived stromal cells (ASCs) represent a relatively abundant source of multipotent cells, with many potential applications in regenerative medicine. The present study sought to demonstrate the use of RNA sequencing (RNA-Seq) in identifying differentially expressed transcripts, particularly long non-coding RNAs (lncRNAs), associated with adipogenic differentiation to gain a clearer picture of the mechanisms responsible for directing ASC fate toward the adipogenic lineage. Human ASCs were cultured in adipogenic differentiation media and RNA was harvested at Days 0, 1, 3, 5, and 7. Directional RNA-Seq libraries were prepared and sequenced. Paired-end reads were mapped to the human genome reference sequence hg19. Transcriptome assembly was performed and significantly differentially expressed transcripts identified. Gene Ontology (GO) term analysis was then performed to identify coding and non-coding transcripts of interest. Differential expression of several identified lncRNA was verified by quantitative real-time polymerase chain reaction. 2868 significantly differentially expressed transcripts were identified; 207 were non-coding. Enriched GO terms among upregulated coding transcripts notably reflected differentiation toward the adipogenic lineage. Enriched GO terms among downregulated coding transcripts reflected growth arrest. Guilt-by-association analysis revealed non-coding RNA candidates with potential roles in the process of adipogenic differentiation. The precise mechanisms that guide lineage-specific differentiation in multipotent cells are not yet fully understood. Defining lncRNAs associated with adipogenic differentiation allows for potential manipulation of regulatory pathways in novel ways. Thus, we present RNA-Seq as a powerful tool for expanding our understanding of ASCs and for development of novel applications employing these cells in regenerative medicine.
    Plastic and Reconstructive Surgery 05/2015; 135(5S Suppl):87-88. DOI:10.1097/01.prs.0000465570.59626.7f · 3.33 Impact Factor
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    ABSTRACT: Adipose derived stromal cells (ASCs) are a multipotent cell population derived from the stromal vascular fraction of lipoaspirate. Given their relatively broad differentiation potential and paracrine capabilities, ASCs represent a readily accessible, endogenous resource for novel reconstructive strategies. In particular, augmentation of autologous fat grafts with ASCs has already been employed clinically for restoration of soft tissue defects. While fat grafting alone remains highly unpredictable, enrichment of fat with supplemental ASCs, also known as cell-assisted lipotransfer (CAL), has been shown to significantly enhance volume retention. How addition of these cells to fat grafts results in improved outcomes, however, remains poorly understood. Furthermore, the safety of CAL in the setting of prior malignancy and post-radiation wound beds has yet to be fully determined, an important consideration for its use in cancer reconstruction. Thus, further studies to determine the how and why behind the efficacy of CAL are necessary before it can be widely adopted as a safe and reliable surgical technique.
    Discovery medicine 04/2015; 19(105):245-53. · 3.50 Impact Factor
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    ABSTRACT: Cell-assisted lipotransfer has shown much promise as a technique to improve fat graft take. However, the concentration of stromal vascular fraction cells required to optimally enhance fat graft retention remains unknown. Human lipoaspirate was processed for both fat transfer and harvest of stromal vascular fraction (SVF) cells. Cells were then mixed back with fat at varying concentrations ranging from 10,000 to 10 million cells per 200 μl of fat. Fat graft volume retention was assessed via CT scanning over 8 weeks, and then fat grafts were explanted and compared histologically for overall architecture and vascularity. Maximum fat graft retention was seen at a concentration of 10,000 cells per 200 μl of fat. The addition of higher number of cells negatively impacted fat graft retention, with supplementation of 10 million cells producing the lowest final volumes, lower than fat alone. Interestingly, fat grafts supplemented with 10,000 cells showed significantly increased vascularity and decreased inflammation, while fat grafts supplemented with 10 million cells showed significant lipodegeneration compared to fat alone CONCLUSIONS:: Our study demonstrates dose dependence in the number of SVF cells that can be added to a fat graft to enhance retention. While cell-assisted lipotransfer may help promote graft survival, this effect may need to be balanced with the increased metabolic load of added cells that may compete with adipocytes for nutrients during the post-graft period.
    Plastic and Reconstructive Surgery 03/2015; DOI:10.1097/PRS.0000000000001367 · 3.33 Impact Factor
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    ABSTRACT: Nanotechnology represents a major frontier with potential to significantly advance the field of bone tissue engineering. Current limitations in regenerative strategies include impaired cellular proliferation and differentiation, insufficient mechanical strength of scaffolds, and inadequate production of extrinsic factors necessary for efficient osteogenesis. Here we review several major areas of research in nanotechnology with potential implications in bone regeneration: 1) nanoparticle-based methods for delivery of bioactive molecules, growth factors, and genetic material, 2) nanoparticle-mediated cell labeling and targeting, and 3) nano-based scaffold construction and modification to enhance physicochemical interactions, biocompatibility, mechanical stability, and cellular attachment/survival. As these technologies continue to evolve, ultimate translation to the clinical environment may allow for improved therapeutic outcomes in patients with large bone deficits and osteodegenerative diseases. Copyright © 2015. Published by Elsevier Inc.
    Nanomedicine: nanotechnology, biology, and medicine 03/2015; 11(5). DOI:10.1016/j.nano.2015.02.013 · 5.98 Impact Factor
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    ABSTRACT: Postnatal tissue-specific stem/progenitor cells hold great promise to enhance repair of damaged tissues. Many of these cells are retrieved from bone marrow or adipose tissue via invasive procedures. Peripheral blood is an ideal alternative source for the stem/progenitor cells because of its ease of retrieval. We present a coculture system that routinely produces a group of cells from adult peripheral blood. Treatment with these cells enhanced healing of critical-size bone defects in the mouse calvarium, a proof of principle that peripheral blood-derived cells can be used to heal bone defects. From these cells, we isolated a subset of CD45(-) cells with a fibroblastic morphology. The CD45(-) cells were responsible for most of the differentiation-induced calcification activity and were most likely responsible for the enhanced healing process. These CD45(-) fibroblastic cells are plastic-adherent and exhibit a surface marker profile negative for CD34, CD19, CD11b, lineage, and c-kit and positive for stem cell antigen 1, CD73, CD44, CD90.1, CD29, CD105, CD106, and CD140α. Furthermore, these cells exhibited osteogenesis, chondrogenesis, and adipogenesis capabilities. The CD45(-) fibroblastic cells are the first peripheral blood-derived cells that fulfill the criteria of mesenchymal stem cells as defined by the International Society for Cellular Therapy. We have named these cells "blood-derived mesenchymal stem cells." ©AlphaMed Press.
    STEM CELLS TRANSLATIONAL MEDICINE 03/2015; 4(4). DOI:10.5966/sctm.2014-0150 · 3.60 Impact Factor
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    ABSTRACT: Over 100 million patients acquire scars in the industrialized world each year, primarily as a result of elective operations. Although undefined, the global incidence of scarring is even larger, extending to significant numbers of burn and other trauma-related wounds. Scars have the potential to exert a profound psychological and physical impact on the individual. Beyond aesthetic considerations and potential disfigurement, scarring can result in restriction of movement and reduced quality of life. The formation of a scar following skin injury is a consequence of wound healing occurring through reparative rather than regenerative mechanisms. In this article, the authors review the basic stages of wound healing; differences between adult and fetal wound healing; various mechanical, genetic, and pharmacologic strategies to reduce scarring; and the biology of skin stem/progenitor cells that may hold the key to scarless regeneration.
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    ABSTRACT: Bone is a dynamic tissue, with a range of diverse functions, including locomotion, protection of internal organs, and hematopoiesis. Optimum treatment of fractures and/or bone defects requires knowledge of the complex cellular interactions involved with bone healing and remodeling. Emerging data have underscored the importance of osteoclasts in this process, playing a key role both in normal bone turnover and in facilitating bone regeneration. In this review, the authors discuss the basic principles of osteoclast biology, including its cellular origins, its function, and key regulatory mechanisms, in addition to conditions that arise when osteoclast function is altered.
    Plastic &amp Reconstructive Surgery 03/2015; 135(3):808-16. DOI:10.1097/PRS.0000000000000963 · 3.33 Impact Factor
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    ABSTRACT: Mesenchymal stem cells (MSCs) show promise for cellular therapy and regenerative medicine. Human adipose-derived stem cells (hASCs) represent an attractive source of seed cells in bone regeneration. How to effectively improve osteogenic differentiation of hASCs in the bone tissue engineering has become a very important question with profound translational implications. Numerous regulatory pathways dominate osteogenic differentiation of hASCs involving transcriptional factors and signaling molecules. However, how these factors combine with each other to regulate hASCs osteogenic differentiation still remains to be illustrated. The highly conserved developmental proteins TWIST play key roles for transcriptional regulation in mesenchymal cell lineages. This study investigates TWIST1 function in hASCs osteogenesis. Our results show that TWIST1 shRNA silencing increased the osteogenic potential of hASCs in vitro and their skeletal regenerative ability when applied in vivo. We demonstrate that the increased osteogenic capacity observed with TWIST1 knockdown in hASCs is mediated through endogenous activation of BMP and ERK/FGF signaling leading, in turn, to upregulation of TAZ, a transcriptional modulator of mesenchymal stem cells differentiation along the osteoblast lineage. Inhibition either of BMP or ERK/FGF signaling suppressed TAZ upregulation and the enhanced osteogenesis in shTWIST1 hASCs. Co-silencing of both TWIST1 and TAZ abrogated the effect elicited by TWIST1 knockdown thus, identifying TAZ as a downstream mediator through which TWIST1 knockdown enhanced osteogenic differentiation in hASCs. Our functional study contributes to a better knowledge of molecular mechanisms governing the osteogenic ability of hASCs, and highlights TWIST1 as a potential target to facilitate in vivo bone healing. This article is protected by copyright. All rights reserved. © 2014 AlphaMed Press.
    Stem Cells 03/2015; 33(3). DOI:10.1002/stem.1907 · 7.70 Impact Factor
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    ABSTRACT: Introduction: Wound healing can be characterized as underhealing, as in the setting of chronic wounds, or overhealing, occurring with hypertrophic scar formation after burn injury. Topical therapies targeting specific biochemical and molecular pathways represent a promising avenue for improving and, in some cases normalizing, the healing process. Areas covered: A brief overview of both normal and pathological wound healing has been provided, along with a review of the current clinical guidelines and treatment modalities for chronic wounds, burn wounds and scar formation. Next, the major avenues for wound healing drugs, along with drugs currently in development, are discussed. Finally, potential challenges to further drug development, and future research directions are discussed. Expert opinion: The large body of research concerning wound healing pathophysiology has provided multiple targets for topical therapies. Growth factor therapies with the ability to be targeted for localized release in the wound microenvironment are most promising, particularly when they modulate processes in the proliferative phase of wound healing.
    Expert Opinion on Emerging Drugs 02/2015; 20(2):1-12. DOI:10.1517/14728214.2015.1018176 · 3.28 Impact Factor
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    ABSTRACT: Endothelial progenitor cells have been shown to traffic to and incorporate into ischemic tissues, where they participate in new blood vessel formation, a process termed vasculogenesis. Previous investigation has demonstrated that endothelial progenitor cells appear to mobilize from bone marrow to the peripheral circulation after exercise. In this study, the authors investigate potential etiologic factors driving this mobilization and investigate whether the mobilized endothelial progenitor cells are the same as those present at baseline. Healthy volunteers (n = 5) performed a monitored 30-minute run to maintain a heart rate greater than 140 beats/min. Venous blood samples were collected before, 10 minutes after, and 24 hours after exercise. Endothelial progenitor cells were isolated and evaluated. Plasma levels of stromal cell-derived factor-1α significantly increased nearly two-fold immediately after exercise, with a nearly four-fold increase in circulating endothelial progenitor cells 24 hours later. The endothelial progenitor cells isolated following exercise demonstrated increased colony formation, proliferation, differentiation, and secretion of angiogenic cytokines. Postexercise endothelial progenitor cells also exhibited a more robust response to hypoxic stimulation. Exercise appears to mobilize endothelial progenitor cells and augment their function by means of stromal cell-derived factor 1α-dependent signaling. The population of endothelial progenitor cells mobilized following exercise is primed for vasculogenesis with increased capacity for proliferation, differentiation, secretion of cytokines, and responsiveness to hypoxia. Given the evidence demonstrating positive regenerative effects of exercise, this may be one possible mechanism for its benefits.
    Plastic &amp Reconstructive Surgery 02/2015; 135(2):340e-50e. DOI:10.1097/PRS.0000000000000917 · 3.33 Impact Factor

Publication Stats

20k Citations
3,094.59 Total Impact Points


  • 2000–2015
    • Stanford Medicine
      • • Department of Surgery
      • • Division of Plastic and Reconstructive Surgery
      • • Adult Plastic Surgery Clinic
      Stanford, California, United States
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • Albert Einstein College of Medicine
      New York, New York, United States
  • 1997–2015
    • Stanford University
      • • Department of Surgery
      • • Division of Plastic and Reconstructive Surgery
      • • Institute for Stem Cell Biology and Regenerative Medicine
      Palo Alto, California, United States
    • Eastern Virginia Medical School
      Norfolk, Virginia, United States
    • State University of New York Downstate Medical Center
      • Department of Medicine
      Brooklyn, NY, United States
    • The Children's Hospital of Philadelphia
      • Center for Fetal Diagnosis and Treatment
      Philadelphia, Pennsylvania, United States
  • 2011
    • University of Pittsburgh
      • Department of Surgery
      Pittsburgh, Pennsylvania, United States
  • 2000–2009
    • University of California, Los Angeles
      • • Department of Surgery
      • • Dental Research Institute
      • • Division of Plastic Surgery
      Los Ángeles, California, United States
  • 2008
    • University of Texas Medical Branch at Galveston
      Galveston, Texas, United States
  • 2007
    • King's College London
      Londinium, England, United Kingdom
    • University of Texas at Dallas
      Richardson, Texas, United States
    • Harvard University
      Cambridge, Massachusetts, United States
    • Massachusetts Institute of Technology
      • Department of Mechanical Engineering
      Cambridge, MA, United States
  • 2006
    • Fourth Military Medical University
      Xi’an, Liaoning, China
    • Lucile Packard Children’s Hospital at Stanford
      Palo Alto, California, United States
  • 2004
    • Centre Hospitalier Lyon Sud
      Lyons, Rhône-Alpes, France
    • Singapore General Hospital
      • Department of Plastic Surgery
      Tumasik, Singapore
  • 2002
    • University of Utah
      • Huntsman Cancer Institute
      Salt Lake City, UT, United States
  • 1997–2002
    • NYU Langone Medical Center
      • Department of Surgery
      New York, New York, United States
  • 1990–2002
    • Harvard Medical School
      Boston, Massachusetts, United States
    • CSU Mentor
      Long Beach, California, United States
  • 2001
    • Penn State Hershey Medical Center and Penn State College of Medicine
      Hershey, Pennsylvania, United States
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States
    • National University of Singapore
      • Department of Surgery
      Singapore, Singapore
  • 1999–2001
    • University of Connecticut
      • Department of Surgery
      Mansfield City, CT, United States
    • New York University
      • Institute of Reconstructive Plastic Surgery
      New York City, NY, United States
    • Cedars-Sinai Medical Center
      Los Ángeles, California, United States
    • Children's Mercy Hospital
      Kansas City, Missouri, United States
  • 1994–2001
    • American Society of Ophthalmic Plastic and Reconstructive Surgery
      New York, New York, United States
  • 1998–2000
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Texas A&M University - Galveston
      Galveston, Texas, United States
    • Georgetown University
      Washington, Washington, D.C., United States
  • 1994–2000
    • CUNY Graduate Center
      New York, New York, United States
  • 1988–1999
    • University of California, San Francisco
      • • Department of Surgery
      • • Division of Pediatric Surgery
      San Francisco, California, United States
  • 1997–1998
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 1996
    • Philadelphia ZOO
      Filadelfia, Pennsylvania, United States
    • University of Oklahoma
      • Department of Surgery
      Norman, Oklahoma, United States
  • 1995
    • Max Planck Institute of Biochemistry
      München, Bavaria, Germany
  • 1989
    • The University of Manchester
      Manchester, England, United Kingdom