Bio

Professional Education


  • Master of Public Health, New York Medical College (2010)
  • Master of Science, Georgetown University (2005)
  • Doctor of Medicine, New York Medical College (2010)

Publications

All Publications


  • Dipeptidyl Peptidase-4, Wound Healing, Scarring, and Fibrosis. Plastic and reconstructive surgery Hu, M. S., Longaker, M. T. 2016; 138 (5): 1026-1031

    Abstract

    Scarring and fibrosis are an enormous public health concern, resulting in excessive morbidity and mortality in addition to countless lost health care dollars. Recent advances in cell and developmental biology promise a better understanding of scarring and fibrosis and may translate to new clinical therapies.

    View details for PubMedID 27782998

  • Stem Cells in Bone Regeneration STEM CELL REVIEWS AND REPORTS Walmsley, G. G., Ransom, R. C., Zielins, E. R., Leavitt, T., Flacco, J. S., Hu, M. S., Lee, A. S., Longaker, M. T., Wan, D. C. 2016; 12 (5): 524-529

    Abstract

    Bone has the capacity to regenerate and repair itself. However, this capacity may be impaired or lost depending on the size of the defect or the presence of certain disease states. In this review, we discuss the key principles underlying bone healing, efforts to characterize bone stem and progenitor cell populations, and the current status of translational and clinical studies in cell-based bone tissue engineering. Though barriers to clinical implementation still exist, the application of stem and progenitor cell populations to bone engineering strategies has the potential to profoundly impact regenerative medicine.

    View details for DOI 10.1007/s12015-016-9665-5

    View details for Web of Science ID 000385138500003

    View details for PubMedID 27250635

  • Scarless wound healing: finding the right cells and signals. Cell and tissue research Leavitt, T., Hu, M. S., Marshall, C. D., Barnes, L. A., Lorenz, H. P., Longaker, M. T. 2016; 365 (3): 483-493

    Abstract

    From the moment we are born, every injury to the skin has the potential to form a scar, many of which can impair form and/or function. As such, scar management constitutes a billion-dollar industry. However, effectively promoting scarless wound healing remains an elusive goal. The complex interactions of wound healing contribute to our inability to recapitulate scarless wound repair as it occurs in nature, such as in fetal skin and the oral mucosa. However, many new advances have occurred in recent years, some of which have translated scientific findings from bench to bedside. In vivo lineage tracing has helped establish a variety of novel cellular culprits that may act as key drivers of the fibrotic response. These newly characterized cell populations present further targets for therapeutic intervention, some of which have previously demonstrated promising results in animal models. Here, we discuss several recent studies that identify exciting approaches for diminishing scar formation. Particular attention will also be paid to the canonical Wnt/?-catenin signaling pathway, which plays an important role in both embryogenesis and tissue repair. New insights into the differential effects of Wnt signaling on heterogeneous fibroblast and keratinocyte populations within the skin further demonstrate methods by which wound healing can be re-directed to a more fetal scarless phenotype. Graphical abstract Recent approaches to reducing scar formation. Representation showing novel scientific approaches for decreasing scar formation, including the targeting of pro-fibrotic cell populations based on surface molecule expression (e.g. DPP4(+) fibroblasts, ADAM12(+) pericytes). Modulation of cellular mechanotransduction pathways are another means to reduce scar formation, both at the molecular level or, macroscopically with dressings designed to offload tension, at cutaneous wound sites (ADAM12 a disintegrin and metalloprotease 12, DPP4 dipeptidyl peptidase-4, FAK focal adhesion kinase).

    View details for DOI 10.1007/s00441-016-2424-8

    View details for PubMedID 27256396

  • Expansion and Hepatic Differentiation of Adult Blood-Derived CD34(+) Progenitor Cells and Promotion of Liver Regeneration After Acute Injury STEM CELLS TRANSLATIONAL MEDICINE Hu, M., Li, S., Menon, S., Liu, B., Hu, M. S., Longaker, M. T., Lorenz, H. P. 2016; 5 (6): 723-732

    Abstract

    The low availability of functional hepatocytes has been an unmet demand for basic scientific research, new drug development, and cell-based clinical applications for decades. Because of the inability to expand hepatocytes in vitro, alternative sources of hepatocytes are a focus of liver regenerative medicine. We report a new group of blood-derived CD34(+) progenitor cells (BDPCs) that have the ability to expand and differentiate into functional hepatocyte-like cells and promote liver regeneration. BDPCs were obtained from the peripheral blood of an adult mouse with expression of surface markers CD34, CD45, Sca-1, c-kit, and Thy1.1. BDPCs can proliferate in vitro and differentiate into hepatocyte-like cells expressing hepatocyte markers, including CK8, CK18, CK19, ?-fetoprotein, integrin-?1, and A6. The differentiated BDPCs (dBDPCs) also display liver-specific functional activities, such as glycogen storage, urea production, and albumin secretion. dBDPCs have cytochrome P450 activity and express specific hepatic transcription factors, such as hepatic nuclear factor 1?. To demonstrate liver regenerative activity, dBDPCs were injected into mice with severe acute liver damage caused by a high-dose injection of carbon tetrachloride (CCl4). dBDPC treatment rescued the mice from severe acute liver injury, increased survival, and induced liver regeneration. Because of their ease of access and application through peripheral blood and their capability of rapid expansion and hepatic differentiation, BDPCs have great potential as a cell-based therapy for liver disease.Hematopoietic stem/progenitor cell expansion and tissue-specific differentiation in vitro are challenges in regenerative medicine, although stem cell therapy has raised hope for the treatment of liver diseases by overcoming the scarcity of hepatocytes. This study identified and characterized a group of blood-derived progenitor cells (BDPCs) from the peripheral blood of an adult mouse. The CD34(+) progenitor-dominant BDPCs were rapidly expanded and hepatically differentiated into functional hepatocyte-like cells with our established coculture system. BDPC treatment increased animal survival and produced full regeneration in a severe liver injury mouse model caused by CCl4. BDPCs could have potential for liver cell therapies.

    View details for DOI 10.5966/sctm.2015-0268

    View details for Web of Science ID 000376835500011

    View details for PubMedID 27075766

  • Suction assisted liposuction does not impair the regenerative potential of adipose derived stem cells JOURNAL OF TRANSLATIONAL MEDICINE Duscher, D., Luan, A., Rennert, R. C., Atashroo, D., Maan, Z. N., Brett, E. A., Whittam, A. J., Ho, N., Lin, M., Hu, M. S., Walmsley, G. G., Wenny, R., Schmidt, M., Schilling, A. F., Machens, H., Huemer, G. M., Wan, D. C., Longaker, M. T., Gurtner, G. C. 2016; 14

    Abstract

    Adipose-derived stem cells (ASCs) have been identified as a population of multipotent cells with promising applications in tissue engineering and regenerative medicine. ASCs are abundant in fat tissue, which can be safely harvested through the minimally invasive procedure of liposuction. However, there exist a variety of different harvesting methods, with unclear impact on ASC regenerative potential. The aim of this study was thus to compare the functionality of ASCs derived from the common technique of suction-assisted lipoaspiration (SAL) versus resection.Human adipose tissue was obtained from paired abdominoplasty and SAL samples from three female donors, and was processed to isolate the stromal vascular fraction. Fluorescence-activated cell sorting was used to determine ASC yield, and cell viability was assayed. Adipogenic and osteogenic differentiation capacity were assessed in vitro using phenotypic staining and quantification of gene expression. Finally, ASCs were applied in an in vivo model of tissue repair to evaluate their regenerative potential.SAL specimens provided significantly fewer ASCs when compared to excised fat tissue, however, with equivalent viability. SAL-derived ASCs demonstrated greater expression of the adipogenic markers FABP-4 and LPL, although this did not result in a difference in adipogenic differentiation. There were no differences detected in osteogenic differentiation capacity as measured by alkaline phosphatase, mineralization or osteogenic gene expression. Both SAL- and resection-derived ASCs enhanced significantly cutaneous healing and vascularization in vivo, with no significant difference between the two groups.SAL provides viable ASCs with full capacity for multi-lineage differentiation and tissue regeneration, and is an effective method of obtaining ASCs for cell-based therapies.

    View details for DOI 10.1186/s12967-016-0881-1

    View details for Web of Science ID 000375475200004

    View details for PubMedID 27153799

  • Stem and progenitor cells: advancing bone tissue engineering. Drug delivery and translational research Tevlin, R., Walmsley, G. G., Marecic, O., Hu, M. S., Wan, D. C., Longaker, M. T. 2016; 6 (2): 159-173

    Abstract

    Unlike many other postnatal tissues, bone can regenerate and repair itself; nevertheless, this capacity can be overcome. Traditionally, surgical reconstructive strategies have implemented autologous, allogeneic, and prosthetic materials. Autologous bone-the best option-is limited in supply and also mandates an additional surgical procedure. In regenerative tissue engineering, there are myriad issues to consider in the creation of a functional, implantable replacement tissue. Importantly, there must exist an easily accessible, abundant cell source with the capacity to express the phenotype of the desired tissue, and a biocompatible scaffold to deliver the cells to the damaged region. A literature review was performed using PubMed; peer-reviewed publications were screened for relevance in order to identify key advances in stem and progenitor cell contribution to the field of bone tissue engineering. In this review, we briefly introduce various adult stem cells implemented in bone tissue engineering such as mesenchymal stem cells (including bone marrow- and adipose-derived stem cells), endothelial progenitor cells, and induced pluripotent stem cells. We then discuss numerous advances associated with their application and subsequently focus on technological advances in the field, before addressing key regenerative strategies currently used in clinical practice. Stem and progenitor cell implementation in bone tissue engineering strategies have the ability to make a major impact on regenerative medicine and reduce patient morbidity. As the field of regenerative medicine endeavors to harness the body's own cells for treatment, scientific innovation has led to great advances in stem cell-based therapies in the past decade.

    View details for DOI 10.1007/s13346-015-0235-1

    View details for PubMedID 25990836

  • Cell-Assisted Lipotransfer Improves Volume Retention in Irradiated Recipient Sites and Rescues Radiation-Induced Skin Changes STEM CELLS Luan, A., Duscher, D., Whittam, A. J., Paik, K. J., Zielins, E. R., Brett, E. A., Atashroo, D. A., Hu, M. S., Lee, G. K., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2016; 34 (3): 668-673

    View details for DOI 10.1002/stem.2256

    View details for Web of Science ID 000372552600013

  • Ultrasound-Assisted Liposuction Does Not Compromise the Regenerative Potential of Adipose-Derived Stem Cells STEM CELLS TRANSLATIONAL MEDICINE Duscher, D., Atashroo, D., Maan, Z. N., Luan, A., Brett, E. A., Barrera, J., Khong, S. M., Zielins, E. R., Whittam, A. J., Hu, M. S., Walmsley, G. G., Pollhammer, M. S., Schmidt, M., Schilling, A. F., Machens, H., Huemer, G. M., Wan, D. C., Longaker, M. T., Gurtner, G. C. 2016; 5 (2): 248-257

    Abstract

    Human mesenchymal stem cells (MSCs) have recently become a focus of regenerative medicine, both for their multilineage differentiation capacity and their excretion of proregenerative cytokines. Adipose-derived mesenchymal stem cells (ASCs) are of particular interest because of their abundance in fat tissue and the ease of harvest via liposuction. However, little is known about the impact of different liposuction methods on the functionality of ASCs. Here we evaluate the regenerative abilities of ASCs harvested via a third-generation ultrasound-assisted liposuction (UAL) device versus ASCs obtained via standard suction-assisted lipoaspiration (SAL). Lipoaspirates were sorted using fluorescent assisted cell sorting based on an established surface-marker profile (CD34+/CD31-/CD45-), to obtain viable ASCs. Yield and viability were compared and the differentiation capacities of the ASCs were assessed. Finally, the regenerative potential of ASCs was examined using an in vivo model of tissue regeneration. UAL- and SAL-derived samples demonstrated equivalent ASC yield and viability, and UAL ASCs were not impaired in their osteogenic, adipogenic, or chondrogenic differentiation capacity. Equally, quantitative real-time polymerase chain reaction showed comparable expression of most osteogenic, adipogenic, and key regenerative genes between both ASC groups. Cutaneous regeneration and neovascularization were significantly enhanced in mice treated with ASCs obtained by either UAL or SAL compared with controls, but there were no significant differences in healing between cell-therapy groups. We conclude that UAL is a successful method of obtaining fully functional ASCs for regenerative medicine purposes. Cells harvested with this alternative approach to liposuction are suitable for cell therapy and tissue engineering applications. Significance: Adipose-derived mesenchymal stem cells (ASCs) are an appealing source of therapeutic progenitor cells because of their multipotency, diverse cytokine profile, and ease of harvest via liposuction. Alternative approaches to classical suction-assisted liposuction are gaining popularity; however, little evidence exists regarding the impact of different liposuction methods on the regenerative functionality of ASCs. Human ASC characteristics and regenerative capacity were assessed when harvested via ultrasound-assisted (UAL) versus standard suction-assisted liposuction. ASCs obtained via UAL were of equal quality when directly compared with the current gold standard harvest method. UAL is an adjunctive source of fully functional mesenchymal stem cells for applications in basic research and clinical therapy.

    View details for DOI 10.5966/sctm.2015-0064

    View details for Web of Science ID 000370914400013

    View details for PubMedID 26702129

  • Surveillance of Stem Cell Fate and Function: A System for Assessing Cell Survival and Collagen Expression In Situ TISSUE ENGINEERING PART A Walmsley, G. G., Senarath-Yapa, K., Wearda, T. L., Menon, S., Hu, M. S., Duscher, D., Maan, Z. N., Tsai, J. M., Zielins, E. R., Weissman, I. L., Gurtner, G. C., Lorenz, H. P., Longaker, M. T. 2016; 22 (1-2): 31-40
  • Murine Dermal Fibroblast Isolation by FACS JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Walmsley, G. G., Maan, Z. N., Hu, M. S., Atashroo, D. A., Whittam, A. J., Duscher, D., Tevlin, R., Marecic, O., Lorenz, H. P., Gurtner, G. C., Longaker, M. T. 2016

    View details for DOI 10.3791/53430

    View details for Web of Science ID 000368577400023

  • Mesenchymal Stromal Cells as Cell-Based Therapeutics for Wound Healing STEM CELLS INTERNATIONAL Malhotra, S., Hu, M. S., Marshall, C. D., Leavitt, T., Cheung, A. T., Gonzalez, J. G., Kaur, H., Lorenz, H. P., Longaker, M. T. 2016

    Abstract

    Chronic wounds are a source of substantial morbidity for patients and are a major financial burden for the healthcare system. There are no current therapies that reliably improve nonhealing wounds or reverse pathological scarring. Mesenchymal stromal cells (MSCs) are a promising source of novel cell-based therapies due to the ease of their harvest and their integral role in the native wound repair process. Recent work has addressed the problems of loss of plasticity and off-target delivery through use of modern bioengineering techniques. Here we describe the applications of MSCs harvested from different sources to the wound healing process and recent advances in delivery of MSCs to targeted sites of injury.

    View details for DOI 10.1155/2016/4157934

    View details for Web of Science ID 000373501200001

    View details for PubMedID 26966438

  • Short Hairpin RNA Silencing of PHD-2 Improves Neovascularization and Functional Outcomes in Diabetic Wounds and Ischemic Limbs. PloS one Paik, K. J., Maan, Z. N., Zielins, E. R., Duscher, D., Whittam, A. J., Morrison, S. D., Brett, E. A., Ransom, R. C., Hu, M. S., Wu, J. C., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2016; 11 (3)

    Abstract

    The transcription factor hypoxia-inducible factor 1-alpha (HIF-1?) is responsible for the downstream expression of over 60 genes that regulate cell survival and metabolism in hypoxic conditions as well as those that enhance angiogenesis to alleviate hypoxia. However, under normoxic conditions, HIF-1? is hydroxylated by prolyl hydroxylase 2, and subsequently degraded, with a biological half-life of less than five minutes. Here we investigated the therapeutic potential of inhibiting HIF-1? degradation through short hairpin RNA silencing of PHD-2 in the setting of diabetic wounds and limb ischemia. Treatment of diabetic mouse fibroblasts with shPHD-2 in vitro resulted in decreased levels of PHD-2 transcript demonstrated by qRT-PCR, higher levels of HIF-1? as measured by western blot, and higher expression of the downstream angiogenic genes SDF-1 and VEGF?, as measured by qRT-PCR. In vivo, shPHD-2 accelerated healing of full thickness excisional wounds in diabetic mice compared to shScr control, (14.33 ± 0.45 days vs. 19 ± 0.33 days) and was associated with an increased vascular density. Delivery of shPHD-2 also resulted in improved perfusion of ischemic hind limbs compared to shScr, prevention of distal digit tip necrosis, and increased survival of muscle tissue. Knockdown of PHD-2 through shRNA treatment has the potential to stimulate angiogenesis through overexpression of HIF-1? and upregulation of pro-angiogenic genes downstream of HIF-1?, and may represent a viable, non-viral approach to gene therapy for ischemia related applications.

    View details for DOI 10.1371/journal.pone.0150927

    View details for PubMedID 26967994

  • Fibroblast-Specific Deletion of Hypoxia Inducible Factor-1 Critically Impairs Murine Cutaneous Neovascularization and Wound Healing PLASTIC AND RECONSTRUCTIVE SURGERY Duscher, D., Maan, Z. N., Whittam, A. J., Sorkin, M., Hu, M. S., Walmsley, G. G., Baker, H., Fischer, L. H., Januszyk, M., Wong, V. W., Gurtner, G. C. 2015; 136 (5): 1004-1013
  • High-Throughput Screening of Surface Marker Expression on Undifferentiated and Differentiated Human Adipose-Derived Stromal Cells TISSUE ENGINEERING PART A Walmsley, G. G., Atashroo, D. A., Maan, Z. N., Hu, M. S., Zielins, E. R., Tsai, J. M., Duscher, D., Paik, K., Tevlin, R., Marecic, O., Wan, D. C., Gurtner, G. C., Longaker, M. T. 2015; 21 (15-16): 2281-2291

    Abstract

    Adipose tissue contains an abundant source of multipotent mesenchymal cells termed "adipose-derived stromal cells" (ASCs) that 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 toward differentiation along distinct lineages holds value for improving graft survival, predictability, and efficiency. Human ASCs (hASCs) 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 insights into the heterogeneity underlying protein expression on the surface of cultured undifferentiated hASCs across different donors. Comparison of the surface marker profile of undifferentiated hASCs with hASCs that have undergone osteogenic or adipogenic differentiation allowed for the identification of surface markers that were 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 fluorescence-activated cell sorting-based selection before therapy.

    View details for DOI 10.1089/ten.tea.2015.0039

    View details for Web of Science ID 000359812700014

  • Nanotechnology in bone tissue engineering NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE Walmsley, G. G., McArdle, A., Tevlin, R., Momeni, A., Atashroo, D., Hu, M. S., Feroze, A. H., Wong, V. W., Lorenz, P. H., Longaker, M. T., Wan, D. C. 2015; 11 (5): 1253-1263

    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.Traditionally, the reconstruction of bony defects has relied on the use of bone grafts. With advances in nanotechnology, there has been significant development of synthetic biomaterials. In this article, the authors provided a comprehensive review on current research in nanoparticle-based therapies for bone tissue engineering, which should be useful reading for clinicians as well as researchers in this field.

    View details for DOI 10.1016/j.nano.2015.02.013

    View details for Web of Science ID 000363967100022

  • Emerging drugs for the treatment of wound healing EXPERT OPINION ON EMERGING DRUGS Zielins, E. R., Brett, E. A., Luan, A., Hu, M. S., Walmsley, G. G., Paik, K., Senarath-Yapa, K., Atashroo, D. A., Wearda, T., Lorenz, H. P., Wan, D. C., Longaker, M. T. 2015; 20 (2): 235-246

    Abstract

    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.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.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.

    View details for DOI 10.1517/14728214.2015.1018176

    View details for Web of Science ID 000356118400007

  • Skin fibrosis. Identification and isolation of a dermal lineage with intrinsic fibrogenic potential. Science Rinkevich, Y., Walmsley, G. G., Hu, M. S., Maan, Z. N., Newman, A. M., Drukker, M., Januszyk, M., Krampitz, G. W., Gurtner, G. C., Lorenz, H. P., Weissman, I. L., Longaker, M. T. 2015; 348 (6232)

    Abstract

    Dermal fibroblasts represent a heterogeneous population of cells with diverse features that remain largely undefined. We reveal the presence of at least two fibroblast lineages in murine dorsal skin. Lineage tracing and transplantation assays demonstrate that a single fibroblast lineage is responsible for the bulk of connective tissue deposition during embryonic development, cutaneous wound healing, radiation fibrosis, and cancer stroma formation. Lineage-specific cell ablation leads to diminished connective tissue deposition in wounds and reduces melanoma growth. Using flow cytometry, we identify CD26/DPP4 as a surface marker that allows isolation of this lineage. Small molecule-based inhibition of CD26/DPP4 enzymatic activity during wound healing results in diminished cutaneous scarring. Identification and isolation of these lineages hold promise for translational medicine aimed at in vivo modulation of fibrogenic behavior.

    View details for DOI 10.1126/science.aaa2151

    View details for PubMedID 25883361

  • Identification and isolation of a dermal lineage with intrinsic fibrogenic potential SCIENCE Rinkevich, Y., Walmsley, G. G., Hu, M. S., Maan, Z. N., Newman, A. M., Drukker, M., Januszyk, M., Krampitz, G. W., Gurtner, G. C., Lorenz, H. P., Weissman, I. L., Longaker, M. T. 2015; 348 (6232): 302-?
  • Peripheral Blood-Derived Mesenchymal Stem Cells: Candidate Cells Responsible for Healing Critical-Sized Calvarial Bone Defects STEM CELLS TRANSLATIONAL MEDICINE Li, S., Huang, K., Wu, J., Hu, M. S., Sanyal, M., Hu, M., Longaker, M. T., Lorenz, H. P. 2015; 4 (4): 359-368

    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 CD140?. 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."

    View details for DOI 10.5966/sctm.2014-0150

    View details for Web of Science ID 000351652300017

  • Live Fibroblast Harvest Reveals Surface Marker Shift In Vitro TISSUE ENGINEERING PART C-METHODS Walmsley, G. G., Rinkevich, Y., Hu, M. S., Montoro, D. T., Lo, D. D., McArdle, A., Maan, Z. N., Morrison, S. D., Duscher, D., Whittam, A. J., Wong, V. W., Weissman, I. L., Gurtner, G. C., Longaker, M. T. 2015; 21 (3): 314-321

    Abstract

    Current methods for the isolation of fibroblasts require extended ex vivo manipulation in cell culture. As a consequence, prior studies investigating fibroblast biology may fail to adequately represent cellular phenotypes in vivo. To overcome this problem, we describe a detailed protocol for the isolation of fibroblasts from the dorsal dermis of adult mice that bypasses the need for cell culture, thereby preserving the physiological, transcriptional, and proteomic profiles of each cell. Using the described protocol we characterized the transcriptional programs and the surface expression of 176 CD markers in cultured versus uncultured fibroblasts. The differential expression patterns we observed highlight the importance of a live harvest for investigations of fibroblast biology.

    View details for DOI 10.1089/ten.tec.2014.0118

    View details for Web of Science ID 000350043400009

    View details for PubMedID 25275778

  • Scarless Wound Healing: Chasing the Holy Grail PLASTIC AND RECONSTRUCTIVE SURGERY Walmsley, G. G., Maan, Z. N., Wong, V. W., Duscher, D., Hu, M. S., Zielins, E. R., Wearda, T., Muhonen, E., McArdle, A., Tevlin, R., Atashroo, D. A., Senarath-Yapa, K., Lorenz, H. P., Gurtner, G. C., Longaker, M. T. 2015; 135 (3): 907-917

    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.

    View details for DOI 10.1097/PRS.0000000000000972

    View details for Web of Science ID 000350754700070

    View details for PubMedID 25719706

  • Isolation and Enrichment of Human Adipose-derived Stromal Cells for Enhanced Osteogenesis JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Zielins, E. R., Tevlin, R., Hu, M. S., Chung, M. T., McArdle, A., Paik, K. J., Atashroo, D., Duldulao, C. R., Luan, A., Senarath-Yapa, K., Walmsley, G. G., Wearda, T., Longaker, M. T., Wan, D. C. 2015

    View details for DOI 10.3791/52181

    View details for Web of Science ID 000361532900031

  • Stem Cell-Based Therapeutics to Improve Wound Healing. Plastic surgery international Hu, M. S., Leavitt, T., Malhotra, S., Duscher, D., Pollhammer, M. S., Walmsley, G. G., Maan, Z. N., Cheung, A. T., Schmidt, M., Huemer, G. M., Longaker, M. T., Lorenz, H. P. 2015; 2015: 383581-?

    Abstract

    Issues surrounding wound healing have garnered deep scientific interest as well as booming financial markets invested in novel wound therapies. Much progress has been made in the field, but it is unsurprising to find that recent successes reveal new challenges to be addressed. With regard to wound healing, large tissue deficits, recalcitrant wounds, and pathological scar formation remain but a few of our most pressing challenges. Stem cell-based therapies have been heralded as a promising means by which to surpass current limitations in wound management. The wide differentiation potential of stem cells allows for the possibility of restoring lost or damaged tissue, while their ability to immunomodulate the wound bed from afar suggests that their clinical applications need not be restricted to direct tissue formation. The clinical utility of stem cells has been demonstrated across dozens of clinical trials in chronic wound therapy, but there is hope that other aspects of wound care will inherit similar benefit. Scientific inquiry into stem cell-based wound therapy abounds in research labs around the world. While their clinical applications remain in their infancy, the heavy investment in their potential makes it a worthwhile subject to review for plastic surgeons, in terms of both their current and future applications.

    View details for DOI 10.1155/2015/383581

    View details for PubMedID 26649195

  • A Mouse Fetal Skin Model of Scarless Wound Repair JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Walmsley, G. G., Hu, M. S., Hong, W. X., Maan, Z. N., Lorenz, H. P., Longaker, M. T. 2015

    View details for DOI 10.3791/52297

    View details for Web of Science ID 000361532900047

  • Aging disrupts cell subpopulation dynamics and diminishes the function of mesenchymal stem cells SCIENTIFIC REPORTS Duscher, D., Rennert, R. C., Januszyk, M., Anghel, E., Maan, Z. N., Whittam, A. J., Perez, M. G., Kosaraju, R., Hu, M. S., Walmsley, G. G., Atashroo, D., Khong, S., Butte, A. J., Gurtner, G. C. 2014; 4

    View details for DOI 10.1038/srep07144

    View details for Web of Science ID 000346178900001

  • Positive Selection for Bone Morphogenetic Protein Receptor Type-IB Promotes Differentiation and Specification of Human Adipose-Derived Stromal Cells Toward an Osteogenic Lineage TISSUE ENGINEERING PART A McArdle, A., Chung, M. T., Paik, K. J., Duldulao, C., Chan, C., Rennert, R., Walmsley, G. G., Senarath-Yapa, K., Hu, M., Seo, E., Lee, M., Wan, D. C., Longaker, M. T. 2014; 20 (21-22): 3031-3040
  • Osteoclast Derivation from Mouse Bone Marrow JOVE-JOURNAL OF VISUALIZED EXPERIMENTS Tevlin, R., McArdle, A., Chan, C. K., Pluvinage, J., Walmsley, G. G., Wearda, T., Marecic, O., Hu, M. S., Paik, K. J., Senarath-Yapa, K., Atashroo, D. A., Zielins, E. R., Wan, D. C., Weissman, I. L., Longaker, M. T. 2014

    View details for DOI 10.3791/52056

    View details for Web of Science ID 000349311400041

  • Noncontact, low-frequency ultrasound therapy enhances neovascularization and wound healing in diabetic mice. Plastic and reconstructive surgery Maan, Z. N., Januszyk, M., Rennert, R. C., Duscher, D., Rodrigues, M., Fujiwara, T., Ho, N., Whitmore, A., Hu, M. S., Longaker, M. T., Gurtner, G. C. 2014; 134 (3): 402e-11e

    Abstract

    Chronic wounds are a major source of morbidity for patients and represent a significant health burden. Implementing noninvasive techniques that accelerate healing of these wounds would provide great benefit. Ultrasound appears to be an effective modality for the treatment of chronic wounds in humans. MIST Therapy is a noncontact, low-frequency ultrasound treatment delivered through a saline mist. A variety of mechanisms have been proposed to explain the efficacy of ultrasound therapy, but the underlying molecular and cellular pathways impacted by this technique remain unclear. The in vivo effect of noncontact, low-frequency ultrasound was therefore examined in a humanized excisional wound model.The treatment group received noncontact, low-frequency ultrasound therapy three times per week, whereas the control group received a standard dressing change. Wounds were photographed at regular intervals to calculate healing kinetics. Wound tissue was harvested and processed for histology, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay.The MIST group demonstrated significantly accelerated wound healing, with 17.3 days to wound closure compared with 24 days in the controls (p < 0.05). This improvement became evident by day 9, with healing evidenced by significantly decreased mean wound area relative to original size (68 percent versus 80 percent; p < 0.01). Expression of markers of neovascularization (stromal cell-derived factor 1, vascular endothelial growth factor, and CD31) was also increased in the wound beds of noncontact, low-frequency ultrasound-treated mice compared with controls.Noncontact, low-frequency ultrasound treatment improves neovascularization and wound closure rates in excisional wounds for diabetic mice, likely because of the stimulated release of angiogenic factors.

    View details for DOI 10.1097/PRS.0000000000000467

    View details for PubMedID 25158717

  • The Role of Stem Cells in Aesthetic Surgery: Fact or Fiction? PLASTIC AND RECONSTRUCTIVE SURGERY McArdle, A., Senarath-Yapa, K., Walmsley, G. G., Hu, M., Atashroo, D. A., Tevlin, R., Zielins, E., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2014; 134 (2): 193-200

    Abstract

    Stem cells are attractive candidates for the development of novel therapies, targeting indications that involve functional restoration of defective tissue. Although most stem cell therapies are new and highly experimental, there are clinics around the world that exploit vulnerable patients with the hope of offering supposed stem cell therapies, many of which operate without credible scientific merit, oversight, or other patient protection.We review the potential, as well as drawbacks, for incorporation of stem cells in cosmetic procedures. A review of FDA-approved indications and ongoing clinical trials with adipose stem cells is provided. Furthermore, a "snapshot" analysis of websites using the search terms "stem cell therapy" or "stem cell treatment" or "stem cell facelift" was performed.Despite the protective net cast by regulatory agencies such as the FDA and professional societies such as the American Society of Plastic Surgeons, we are witnessing worrying advertisements for procedures such as stem cell facelifts, stem cell breast augmentations, and even stem cell vaginal rejuvenation. The marketing and promotion of stem cell procedures in aesthetic surgery is not adequately supported by clinical evidence in the majority of cases.Stem cells offer tremendous potential, but the marketplace is saturated with unsubstantiated and sometimes fraudulent claims that may place patients at risk. With plastic surgeons at the forefront of stem cell-based regenerative medicine, it is critically important that we provide an example of a rigorous approach to research, data collection, and advertising of stem cell therapies.

    View details for DOI 10.1097/PRS.0000000000000404

    View details for Web of Science ID 000339777300004

  • Studies in Fat Grafting: Part I. Effects of Injection Technique on In Vitro Fat Viability and In Vivo Volume Retention PLASTIC AND RECONSTRUCTIVE SURGERY Chung, M. T., Paik, K. J., Atashroo, D. A., Hyun, J. S., McArdle, A., Senarath-Yapa, K., Zielins, E. R., Tevlin, R., Duldulao, C., Hu, M. S., Walmsley, G. G., Parisi-Amon, A., Momeni, A., Rimsa, J. R., Commons, G. W., Gurtner, G. C., Wan, D. C., Longaker, M. T. 2014; 134 (1): 29-38
  • Studies in Fat Grafting: Part II. Effects of Injection Mechanics on Material Properties of Fat PLASTIC AND RECONSTRUCTIVE SURGERY Atashroo, D., Raphel, J., Chung, M. T., Paik, K. J., Parisi-Amon, A., McArdle, A., Senarath-Yapa, K., Zielins, E. R., Tevlin, R., Duldulao, C., Walmsley, G. G., Hu, M. S., Momeni, A., Domecus, B., Rimsa, J. R., Greenberg, L., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2014; 134 (1): 39-46
  • Tissue Engineering and Regenerative Repair in Wound Healing ANNALS OF BIOMEDICAL ENGINEERING Hu, M. S., Maan, Z. N., Wu, J., Rennert, R. C., Hong, W. X., Lai, T. S., Cheung, A. T., Walmsley, G. G., Chung, M. T., McArdle, A., Longaker, M. T., Lorenz, H. P. 2014; 42 (7): 1494-1507

    Abstract

    Wound healing is a highly evolved defense mechanism against infection and further injury. It is a complex process involving multiple cell types and biological pathways. Mammalian adult cutaneous wound healing is mediated by a fibroproliferative response leading to scar formation. In contrast, early to mid-gestational fetal cutaneous wound healing is more akin to regeneration and occurs without scar formation. This early observation has led to extensive research seeking to unlock the mechanism underlying fetal scarless regenerative repair. Building upon recent advances in biomaterials and stem cell applications, tissue engineering approaches are working towards a recapitulation of this phenomenon. In this review, we describe the elements that distinguish fetal scarless and adult scarring wound healing, and discuss current trends in tissue engineering aimed at achieving scarless tissue regeneration.

    View details for DOI 10.1007/s10439-014-1010-z

    View details for Web of Science ID 000338995900013

  • Gene expression in fetal murine keratinocytes and fibroblasts JOURNAL OF SURGICAL RESEARCH Hu, M. S., Januszyk, M., Hong, W. X., Walmsley, G. G., Zielins, E. R., Atashroo, D. A., Maan, Z. N., McArdle, A., Takanishi, D. M., Gurtner, G. C., Longaker, M. T., Lorenz, H. P. 2014; 190 (1): 344-357

    Abstract

    Early fetuses heal wounds without the formation of a scar. Many studies have attempted to explain this remarkable phenomenon. However, the exact mechanism remains unknown. Herein, we examine the predominant cell types of the epidermis and dermis-the keratinocyte and fibroblast-during different stages of fetal development to better understand the changes that lead to scarring wound repair versus regeneration.Keratinocytes and fibroblasts were harvested and cultured from the dorsal skin of time-dated BALB/c fetuses. Total RNA was isolated and microarray analysis was performed using chips with 42,000 genes. Significance analysis of microarrays was used to select genes with >2-fold expression differences with a false discovery rate <2. Enrichment analysis was performed on significant genes to identify differentially expressed pathways.By comparing the gene expression profile of keratinocytes from E16 versus E18 fetuses, we identified 24 genes that were downregulated at E16. Analysis of E16 and E18 fibroblasts revealed 522 differentially expressed genes. Enrichment analysis showed the top 20 signaling pathways that were downregulated in E16 keratinocytes and upregulated or downregulated in E16 fibroblasts.Our data reveal 546 differentially expressed genes in keratinocytes and fibroblasts between the scarless and scarring transition. In addition, a total of 60 signaling pathways have been identified to be either upregulated or downregulated in these cell types. The genes and pathways recognized by our study may prove to be essential targets that may discriminate between fetal wound regeneration and adult wound repair.

    View details for DOI 10.1016/j.jss.2014.02.030

    View details for Web of Science ID 000338444700051

    View details for PubMedID 24726057

  • Mechanotransduction and fibrosis JOURNAL OF BIOMECHANICS Duscher, D., Maan, Z. N., Wong, V. W., Rennert, R. C., Januszyk, M., Rodrigues, M., Hu, M., Whitmore, A. J., Whittam, A. J., Longaker, M. T., Gurtner, G. C. 2014; 47 (9): 1997-2005

    Abstract

    Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

    View details for DOI 10.1016/j.jbiomech.2014.03.031

    View details for Web of Science ID 000338621900009

  • Diabetes impairs the angiogenic potential of adipose-derived stem cells by selectively depleting cellular subpopulations STEM CELL RESEARCH & THERAPY Rennert, R. C., Sorkin, M., Januszyk, M., Duscher, D., Kosaraju, R., Chung, M. T., Lennon, J., Radiya-Dixit, A., Raghvendra, S., Maan, Z. N., Hu, M. S., Rajadas, J., Rodrigues, M., Gurtner, G. C. 2014; 5

    View details for DOI 10.1186/scrt468

    View details for Web of Science ID 000338465500001

  • Epidermal or Dermal Specific Knockout of PHD-2 Enhances Wound Healing and Minimizes Ischemic Injury PLOS ONE Zimmermann, A. S., Morrison, S. D., Hu, M. S., Li, S., Nauta, A., Sorkin, M., Meyer, N. P., Walmsley, G. G., Maan, Z. N., Chan, D. A., Gurtner, G. C., Giaccia, A. J., Longaker, M. T. 2014; 9 (4)
  • Abstract 8: SDF-1 Regulates Adipose Niche Homeostasis and Adipose Derived Stromal Cell Function. Plastic and reconstructive surgery Maan, Z. N., Rennert, R. C., Duscher, D., Januszyk, M., Paik, K., Chung, M. T., Paik, K., Fujiwara, T., Rodrigues, M., Ho, N., Baker, H., Perez, M., Hu, M., Sorkin, M., Longaker, M. T., Gurtner, G. C. 2014; 133 (3): 15-16

    View details for DOI 10.1097/01.prs.0000444941.23852.ce

    View details for PubMedID 25942119

  • Abstract 151: short hairpin RNA interference therapy for diabetic murine wound closure and hindlimb ischemia. Plastic and reconstructive surgery Paik, K. J., Rennert, R., Chung, M. T., Sorkin, M., Duscher, D., Atashroo, D., Chen, H., Morrison, S. D., Zimmermann, A., Nauta, A., Ko, S., Tevlin, R., Zielins, E., Hu, M. S., McArdle, A., Walmsley, G., Senarath-Yapa, K., Hong, W. X., Garza, R. M., Duldulao, C., Wearda, T., Momeni, A., Wu, J. C., Gurtner, G. C., Longaker, M. T., Wan, D. C. 2014; 133 (3): 167-168

    View details for DOI 10.1097/01.prs.0000444979.14443.08

    View details for PubMedID 25942261

  • Abstract 161: identification of cell-intrinsic mechanisms and differentially regulated genetic pathways responsible for the age-related functional decline in aged skeletal stem cells. Plastic and reconstructive surgery McArdle, A., Chan, C., Seita, J., Senarath-Yapa, K., Hu, M., Walmsley, G. G., Zielins, E., Atashroo, D., Tevlin, R., Weissman, I., Longaker, M. T. 2014; 133 (3): 178-?

    View details for DOI 10.1097/01.prs.0000444990.75431.f1

    View details for PubMedID 25942271

  • Induced Pluripotent Stem Cells in Regenerative Medicine and Disease Modeling CURRENT STEM CELL RESEARCH & THERAPY Walmsley, G. G., Hyun, J., McArdle, A., Senarath-Yapa, K., Hu, M. S., Chung, M. T., Wong, V. W., Longaker, M. T., Wan, D. C. 2014; 9 (2): 73-81

    Abstract

    In 2006, Dr. Yamanaka created the induced pluripotent stem cell (iPSC) by reprogramming adult fibroblasts back to an immature, pluripotent state. Effectively bypassing the ethical constraints of human embryonic stem cells, iPSCs have expanded the horizons of regenerative medicine by offering a means to derive autologous patient-matched cells and tissues for clinical transplantation. However, persisting safety concerns must be addressed prior to their widespread clinical application. In this review, we discuss the history of iPSCs, derivation strategies, and current research involving gene therapy and disease modeling. We review the potential of iPSCs for improving a range of cell-based therapies and obstacles to their clinical implementation.

    View details for Web of Science ID 000331890000001

    View details for PubMedID 24359141

  • Abstract 140: identification, characterization, and prospective isolation of a fibroblast lineage contributing to dermal development, cutaneous scarring, radiation fibrosis, and cancer stroma. Plastic and reconstructive surgery Walmsley, G. G., Rinkevich, Y., Hu, M. S., McArdle, A., Maan, Z. N., Lorenz, H. P., Weissman, I. L., Longaker, M. T. 2014; 133 (3): 157-?

    View details for DOI 10.1097/01.prs.0000444968.20280.4d

    View details for PubMedID 25942251

  • Abstract 135: improved engraftment of autologous skin grafts in diabetic mice with adipose-derived stem cells. Plastic and reconstructive surgery Hu, M., Hong, W. X., Senarath-Yapa, K., Zimmermann, A., Chung, M., Esquivel, M., McArdle, A., Walmsley, G., Maan, Z., Garza, R., Lorenz, H. P., Longaker, M. 2014; 133 (3): 151-?

    View details for DOI 10.1097/01.prs.0000444962.89785.8e

    View details for PubMedID 25942246

  • Wound healing: an update REGENERATIVE MEDICINE Zielins, E. R., Atashroo, D. A., Maan, Z. N., Duscher, D., Walmsley, G. G., Marecic, O., Hu, M., Senarath-Yapa, K., McArdle, A., Tevlin, R., Wearda, T., Paik, K. J., Duldulao, C., Hong, W. X., Gurtner, G. C., Longaker, M. T. 2014; 9 (6): 817-830

    View details for DOI 10.2217/RME.14.54

    View details for Web of Science ID 000345620600012

  • Biological therapies for the treatment of cutaneous wounds: Phase III and launched therapies EXPERT OPINION ON BIOLOGICAL THERAPY Rennert, R. C., Rodrigues, M., Wong, V. W., Duscher, D., Hu, M., Maan, Z., Sorkin, M., Gurtner, G. C., Longaker, M. T. 2013; 13 (11): 1523-1541

    Abstract

    Normal wound healing mechanisms can be overwhelmed in the setting of complex acute and chronic tissue injury. Biological therapies are designed to augment and/or restore the body's natural wound healing abilities. There are a variety of available and emerging technologies utilizing this approach that have demonstrated the ability to augment wound healing.In this review, the clinical data on launched and emerging biological therapies for wound healing applications are summarized. The methodologies discussed include biological skin equivalents, growth factors/small molecules and stem cell-based therapies.While many products possess convincing clinical data demonstrating their efficacy in comparison to standard treatment options, more robust, controlled studies are needed to determine the relative value among established and emerging biological therapies. Future bioengineering and stem cell-based approaches are of particular interest due to the simultaneous correction of multiple deficiencies present in the nonhealing wound.

    View details for DOI 10.1517/14712598.2013.842972

    View details for Web of Science ID 000325712100007

    View details for PubMedID 24093722

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