Mei Chen

University of Southern California, Los Ángeles, California, United States

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Publications (84)556.64 Total impact

  • 08/2015; DOI:10.1089/wound.2014.0620
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    ABSTRACT: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited disorder characterized by skin fragility, blistering and multiple skin wounds with no currently approved or consistently effective treatment. It is due to mutations in the gene encoding type VII collagen (C7). Using recombinant human C7 (rhC7) purified from human dermal fibroblasts (FB-rhC7), we showed previously that intravenously (IV) injected rhC7 distributed to engrafted RDEB skin, incorporated into its dermal-epidermal junction (DEJ) and reversed the RDEB disease phenotype. Human dermal fibroblasts, however, are not used for commercial production of therapeutic proteins. Therefore, we generated rhC7 from Chinese hamster ovary (CHO) cells. The CHO-derived recombinant type VII collagen (CHO-rhC7), similar to FB-rhC7, was secreted as a correctly folded, disulfide-bonded, helical trimer resistant to protease degradation. CHO-rhC7 bound to fibronectin and promoted human keratinocyte migration in vitro. A single dose of CHO-rhC7, administered IV into new-born C7 null RDEB mice, incorporated into the dermal-epidermal junction of multiple skin sites, tongue and esophagus, restored anchoring fibrils, improved dermal-epidermal adherence and increased the animals' life span. Furthermore, no circulating or tissue-bound anti-C7 antibodies were observed in the mice. These data demonstrate the efficacy of CHO-rhC7 in a preclinical murine model of RDEB.Journal of Investigative Dermatology accepted article preview online, 23 July 2015. doi:10.1038/jid.2015.291.
    Journal of Investigative Dermatology 07/2015; 135(12). DOI:10.1038/jid.2015.291 · 7.22 Impact Factor
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    ABSTRACT: Recessive dystrophic epidermolysis bullosa is a severe, incurable, inherited blistering disease caused by COL7A1 mutations. Emerging evidence suggests hematopoietic progenitor cells (HPCs) can be reprogrammed into skin; HPC-derived cells can restore COL7 expression in COL7-deficient mice. We report two children with recessive dystrophic epidermolysis bullosa treated with reduced-toxicity conditioning and HLA-matched HPC transplantation. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of pediatrics 07/2015; 167(3). DOI:10.1016/j.jpeds.2015.05.051 · 3.79 Impact Factor
  • David T Woodley · Mei Chen ·
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    ABSTRACT: The Journal of Investigative Dermatology publishes basic and clinical research in cutaneous biology and skin disease.
    Journal of Investigative Dermatology 07/2015; 135(7):1705-1707. DOI:10.1038/jid.2015.149 · 7.22 Impact Factor
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    ABSTRACT: Significance: The treatment and care of patients with skin wounds are a major healthcare expenditure. Burn wounds, iatrogenic surgical wounds, venous stasis dermatitis ulcers, diabetic lower limb ulcers, pressure ulcers, and skin wounds from peripheral neuropathies are largely treated with only supportive care. Despite a great deal of research into using growth factors as therapeutic agents, to date, the field has been disappointing. The only biologic agent that is Federal Drug Administration (FDA) approved for promoting skin wound healing is recombinant platelet-derived growth factor (PDGF-BB), but its modest efficacy and expense limit its use clinically. Recent Advances: Acute hypoxia induced by the clotting of dermal blood vessels during the wounding of skin is a major stress factor that leads to the re-programming of basal keratinocytes to initiate re-epithelialization. The laterally migrating keratinocytes secrete extracellular heat shock protein 90 alpha. Heat shock protein 90 alpha (hsp90α) engages low-density lipoprotein receptor-related protein-1 (LRP-1) cellular receptors and works as an autocrine factor to stimulate keratinocyte migration (re-epithelialization) and as a paracrine factor to stimulate the migration of dermal fibroblasts (fibroplasia) and microvascular endothelial cells (neo-vascularization). Hypoxia-triggered extracellular heat shock protein 90 alpha acts as the master regulator of initial skin wound healing. Critical Issues: It is not yet known how the engagement of hsp90α with the LRP-1 receptor leads to increased motility of keratinocytes, fibroblasts, or microvascular endothelial cells. Understanding the sequence of how an acute skin wound via hypoxic stress leads to cellular events that ultimately induce accelerated wound closure provides numerous targets for new wound-healing therapeutic agents. Future Directions: Developing data for an investigational new drug (IND) application to the FDA for a Phase I study using hsp90α in human skin wounds. Identifying the cellular signaling mechanisms by which hsp90α enhances skin cell migration, leading to accelerated wound closure.
    04/2015; 4(4):203-212. DOI:10.1089/wound.2014.0566
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    ABSTRACT: When tissues are injured and blood vessels clotted, the local environment becomes ischemic - lack of adequate supply of oxygen and glucose delivered to the surrounding cells. The heat shock protein-90 (Hsp90) family proteins protect tissues from various environmental insults and participate in the damaged tissue repair. Here we report discovery of a novel ischemia-responsive mechanism by which the two Hsp90 isoforms, Hsp90α and Hsp90β, work together to promote cell motility in wounded skin and accelerate wound closure. We demonstrate that Hsp90α and Hsp90β have distinct and non-exchangeable functions during wound healing. Under hypoxia and lack of serum factors, Hsp90β binds to the cytoplasmic tail of the LDL Receptor-Related Protein-1 (LRP-1) and stabilizes the receptor at the cell surface. Hsp90α, however, is secreted by the cell into extracellular space, where it binds and signals through the LRP-1 receptor to promote cell motility, leading to wound closure. In addition to skin injury, we suggest that this repair mechanism applies broadly to other non-cutaneous injured tissues.
    Journal of Cell Science 03/2015; 128(8). DOI:10.1242/jcs.166363 · 5.43 Impact Factor
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    ABSTRACT: Chronic and non-healing skin wounds represent a significant clinical, economic and social problem worldwide. Currently, there are few effective treatments. Lack of well-defined animal models to investigate wound healing mechanisms and furthermore to identify new and more effective therapeutic agents still remains a major challenge. Pig skin wound healing is close to humans. However, standardized pig wound healing models with demonstrated validity for testing new wound healing candidates are unavailable. Here we report a systematic evaluation and establishment of both acute and diabetic wound healing models in pigs, including wound-creating pattern for drug treatment versus control, measurements of diabetic parameters and the time for detecting delayed wound healing. We find that treatment and control wounds should be on the opposite and corresponding sides of a pig. We demonstrate a strong correlation between duration of diabetic conditions and the length of delay in wound closure. Using these new models, we narrow down the minimum therapeutic entity of secreted Hsp90α to a 27-amino acid peptide, called fragment-8 (F-8). In addition, results of histochemistry and immunohistochemistry analyses reveal more organized epidermis and dermis in Hsp90α-healed wounds than the control. Finally, Hsp90α uses a similar signaling mechanism to promote migration of isolated pig and human keratinocytes and dermal fibroblasts. This is the first report that shows standardized pig models for acute and diabetic wound healing studies and proves its usefulness with both an approved drug and a new therapeutic agent.
    PLoS ONE 12/2014; 9(12):e113956. DOI:10.1371/journal.pone.0113956 · 3.23 Impact Factor
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    ABSTRACT: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have severe, incurable skin fragility, blistering, and multiple skin wounds due to mutations in the gene encoding type VII collagen (C7), the major component of anchoring fibrils mediating epidermal-dermal adherence. Nearly 10-25% of RDEB patients carry nonsense mutations leading to premature stop codons (PTCs) that result in truncated C7. In this study, we evaluated the feasibility of using aminoglycosides to suppress PTCs and induce C7 expression in two RDEB keratinocyte cell lines (Q251X/Q251X and R578X/R906) and two primary RDEB fibroblasts (R578X/R578X and R163X/R1683X). Incubation of these cells with aminoglycosides (geneticin, gentamicin, and paromomycin) resulted in the synthesis and secretion of a full-length C7 in a dose-dependent and sustained manner. Importantly, aminoglycoside-induced C7 reversed the abnormal RDEB cell phenotype and incorporated into the dermal-epidermal junction of skin equivalents. We further demonstrated the general utility of aminoglycoside-mediated readthrough in 293 cells transiently transfected with expression vectors encoding 22 different RDEB nonsense mutations. This is the first study demonstrating that aminoglycosides can induce PTC readthrough and restore functional C7 in RDEB caused by nonsense mutations. Therefore, aminoglycosides may have therapeutic potential for RDEB patients and other inherited skin diseases caused by nonsense mutations.Molecular Therapy (2014); doi:10.1038/mt.2014.140.
    Molecular Therapy 07/2014; 22(10). DOI:10.1038/mt.2014.140 · 6.23 Impact Factor
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    ABSTRACT: Abbreviations: AF, anchoring fibril; C7, type VII collagen; CMP, cartilage matrix protein; DEJ, dermal–epidermal junction; DIF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; Fn3, fibronectin type III-like repeat; IIF, indirect immunofluorescence; NC1, N-terminal noncollagenous domain of type VII collagen; NC2, C-terminal noncollagenous domain of type VII collagen; PTC, premature termination codon; RDEB, recessive dystrophic epidermolysis bullosa; RDEB-I, RDEB inversa; RDEB-O, RDEB generalized other; RDEB-sev,gen, RDEB severe, generalized; TH, triple helical; VWF-A, A domain of von Willebrand factor
    Journal of Investigative Dermatology 11/2013; 134(4). DOI:10.1038/jid.2013.475 · 7.22 Impact Factor
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    ABSTRACT: Normal cells secrete heat shock protein-90alpha (Hsp90α) in response to tissue injury. Tumor cells have managed to constitutively secrete Hsp90α during invasion and metastasis. The sole function of the extracellular Hsp90α (eHsp90α) is to promote cell motility, a critical event for both wound healing and tumor progression. The mechanism of the pro-motility action by eHsp90α, however, remained elusive. A key issue is whether eHsp90α still acts as a chaperone outside the cells or it is a new and bona fide signaling molecule. Here, we provide evidence that eHsp90α utilizes a unique trans-membrane signaling mechanism to promote cell motility and wound healing. First, the subdomain II in the extracellular part of the low-density lipoprotein receptor-related protein-1 (LRP-1) receives eHsp90α signal. Then, the NPVY, but not the NPTY, motif in the cytoplamic tail of LRP-1 connects eHsp90α signaling to serine-473, but not threonine-308, phosphorylation in Akt kinases. Individual knockdown of Akt1, Akt2 or Akt3 revealed the importance of Akt1 and Ak2 in eHsp90α-induced cell motility. Akt gene rescue experiments suggest that Akt1 and Akt2 work in concert, rather than independently, to mediate the eHsp90α pro-motility signaling. Finally, Akt1- and Akt2- knockout mice showed impaired wound healing that cannot be corrected by topical application with eHsp90α protein.
    Molecular and Cellular Biology 10/2013; 33(24). DOI:10.1128/MCB.00559-13 · 4.78 Impact Factor
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    ABSTRACT: Patients with recessive dystrophic epidermolysis bullosa (RDEB) have incurable skin fragility, blistering, and skin wounds due to mutations in the gene that codes for type VII collagen (C7) that mediates dermal-epidermal adherence in human skin. In this study, we evaluated if topically applied human recombinant C7 (rC7) could restore C7 at the dermal-epidermal junction (DEJ) and enhance wound healing. We found that rC7 applied topically onto murine skin wounds stably incorporated into the newly formed DEJ of healed wounds and accelerated wound closure by increasing re-epithelialization. Topical rC7 decreased the expression of fibrogenic transforming growth factor-β2 (TGF-β2) and increased the expression of anti-fibrogenic TGF-β3. These were accompanied by the reduced expression of connective tissue growth factor, fewer α smooth muscle actin (α-SMA)-positive myofibroblasts, and less deposition of collagen in the healed neodermis, consistent with less scar formation. In addition, using a mouse model in which skin from C7 knock out mice was grafted onto immunodeficient mice, we showed that applying rC7 onto RDEB grafts with wounds restored C7 and anchoring fibrils (AFs) at the DEJ of the grafts and corrected the dermal-epidermal separation. The topical application of rC7 may be useful for treating patients with RDEB and patients who have chronic skin wounds.Molecular Therapy (2013); doi:10.1038/mt.2013.87.
    Molecular Therapy 05/2013; 21(7). DOI:10.1038/mt.2013.87 · 6.23 Impact Factor
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    ABSTRACT: Despite extensive investigative studies and clinical trials over the past two decades, we still do not understand why cancer cells are more sensitive to the cellular toxicity of Hsp90 inhibitors than normal cells. We still do not understand why only some cancer cells are sensitive to the Hsp90 inhibitors. Based on studies of the past few years, we argue that the selected sensitivity of cancer cells to Hsp90 inhibitors, such as 17-N-allylamino-17-demethoxygeldanamycin, is due to inhibition of the extracellular Hsp90 (eHsp90) rather than intracellular Hsp90 by these inhibitors. Because not all tumor cells utilize eHsp90 for motility, invasion and metastasis, only the group of "eHsp90-dependent" cancer cells is sensitive to Hsp90 inhibitors. If these notions prove to be true, pharmaceutical agents that selectively target eHsp90 should be more effective on tumor cells and less toxic on normal cells than current inhibitors that nondiscriminatively target both extracellular and intracellular Hsp90.
    International review of cell and molecular biology 02/2013; 303:203-35. DOI:10.1016/B978-0-12-407697-6.00005-2 · 3.42 Impact Factor
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    ABSTRACT: AF, anchoring fibril; C7, type VII collagen; DEJ, dermal–epidermal junction; IV, intravenous; rC7, human recombinant C7; RDEB, recessive dystrophic epidermolysis bullosa
    Journal of Investigative Dermatology 01/2013; 133(7). DOI:10.1038/jid.2013.10 · 7.22 Impact Factor
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    ABSTRACT: When skin is wounded, migration of epidermal keratinocytes at the wound edge initiates within hours, whereas migration of dermal fibroblasts toward the wounded area remains undetectable until several days later. This "cell type traffic" regulation ensures proper healing of the wound, as disruptions of the regulation could either cause delay of wound healing or result in hypertrophic scars. TGFβ3 is the critical traffic controller that selectively halts migration of the dermal, but not epidermal, cells to ensure completion of wound re-epithelialization prior to wound remodeling. However, the mechanism of TGFβ3's anti-motility signaling has never been investigated. We report here that activated TβRII transmits the anti-motility signal of TGFβ3 in full to TβRI, since expression of the constitutively activated TβRI-TD mutant was sufficient to replace TGFβ3 to block PDGF-bb-induced dermal fibroblast migration. Second, the three components of R-Smad complex are all required. Individual downregulation of Smad2, Smad3 or Smad4 prevented TGFβ3 from inhibiting dermal fibroblast migration. Third, Protein Kinase Array allowed us to identify the protein kinase A (PKA) as a specific downstream effector of R-Smads in dermal fibroblasts. Activation of PKA alone blocked PDGF-bb-induced dermal fibroblast migration, just like TGFβ3. Downregulation of PKA's catalytic subunit nullified the anti-motility signaling of TGFβ3. This is the first report on anti-motility signaling mechanism by TGFβ family cytokines. Significance of this finding is not only limited to wound healing but also to other human disorders, such as heart attack and cancer, where the diseased cells have often managed to avoid the anti-motility effect of TGFβ.
    Biology Open 12/2012; 1(12):1169-77. DOI:10.1242/bio.20122246 · 2.42 Impact Factor
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    ABSTRACT: BACKGROUND: Bullous pemphigoid (BP) is an autoimmune blistering disease characterized by autoantibodies specific for the 180-kd BP antigen-2 (BP180) (also termed "type XVII collagen") protein. The BP180 enzyme-linked immunosorbent assay (ELISA) is specific for the immunodominant NC16A domain of the protein. However, we and others have observed patients whose reactivity to BP180 is exclusive of the NC16A domain (referred to henceforth as non-NC16A BP). OBJECTIVE: We sought to determine the incidence of non-NC16A BP and identify regions of reactivity within the BP180 protein. METHODS: Sera from 51 patients who met the clinical and histologic criteria for BP were screened for NC16A reactivity by ELISA. Sera that were negative by ELISA were screened for IgG reactivity to an epidermal extract, recombinant BP180 protein, and subregions of BP180, by immunoblot. Demographic and clinical data were also collected on all patients. RESULTS: Four sera (7.8%) were negative using the BP180 ELISA but positive for IgG reactivity to the extracellular domain of BP180. Further mapping identified 4 regions outside of NC16A recognized by these sera: amino acid (AA) 1280 to 1315, AA 1080 to 1107, AA 1331 to 1404, and AA 1365 to 1413. One of these sera also had IgE specific for NC16A. One patient had an atypical presentation with lesions limited to the lower aspect of the legs and scarring of the nail beds. LIMITATIONS: The small total number of patients with non-NC16A BP limits the identification of demographic or clinical correlates. CONCLUSION: It is significant that 7.8% of sera from patients with new BP react to regions of BP180 exclusively outside of NC16A and, thus, would not be identified using the currently available BP180 ELISA.
    Journal of the American Academy of Dermatology 10/2012; 68(3). DOI:10.1016/j.jaad.2012.09.012 · 4.45 Impact Factor
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    ABSTRACT: Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive cutaneous squamous cell carcinoma (cSCC). Metastasis leading to mortality is greater in RDEB than in other patient groups with cSCC. Here we investigate the dermal component in RDEB using mRNA expression profiling to compare cultured fibroblasts isolated from individuals without cSCC and directly from tumor matrix in RDEB and non-RDEB samples. Although gene expression of RDEB normal skin fibroblasts resembled that of cancer-associated fibroblasts, RDEB cancer-associated fibroblasts exhibited a distinct and divergent gene expression profile, with a large proportion of the differentially expressed genes involved in matrix and cell adhesion. RDEB cancer-associated fibroblasts conferred increased adhesion and invasion to tumor and nontumor keratinocytes. Reduction of COL7A1, the defective gene in RDEB, in normal dermal fibroblasts led to increased type XII collagen, thrombospondin-1, and Wnt-5A, while reexpression of wild type COL7A1 in RDEB fibroblasts decreased type XII collagen, thrombospondin-1, and Wnt-5A expression, reduced tumor cell invasion in organotypic culture, and restricted tumor growth in vivo. Overall, our findings show that matrix composition in patients with RDEB is a permissive environment for tumor development, and type VII collagen directly regulates the composition of matrix proteins secreted by dermal and cancer-associated fibroblasts.
    Cancer Research 05/2012; 72(14):3522-34. DOI:10.1158/0008-5472.CAN-11-2996 · 9.33 Impact Factor
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    Rishu Gupta · David T Woodley · Mei Chen ·
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    ABSTRACT: Epidermolysis bullosa acquisita (EBA) is a rare, acquired, chronic subepidermal bullous disease of the skin and mucosa characterized by autoantibodies to type VII collagen (C7) structures, a major component of anchoring fibrils, which attach the epidermis to the dermis. EBA patients have tissue-bound and circulating antitype C7 autoantibodies that attack type C7 and result in a reduction or perturbation of normally functioning anchoring fibrils. Patients with EBA have skin fragility, blisters, erosions, scars, milia, and nail loss, all features reminiscent of genetic dystrophic epidermolysis bullosa. These immunoglobulin G antitype C7 antibodies are pathogenic, because when they are injected into mice, the mice develop an EBA-like blistering disease. In addition to the classical mechanobullous presentation, EBA also has several other distinct clinical syndromes similar to bullous pemphigoid, Brunsting-Perry pemphigoid, or cicatricial pemphigoid. Although treatment for EBA is often unsatisfactory, some therapeutic success has been achieved with colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin.
    Clinics in dermatology 01/2012; 30(1):60-9. DOI:10.1016/j.clindermatol.2011.03.011 · 2.47 Impact Factor
  • Wei Li · Kathryn O'Brien · David Woodley · Mei Chen ·

    Cellular Trafficking of Cell Stress Proteins in Health and Disease, 1 edited by Brian Henderson, A Graham Pockley, 01/2012: chapter Heat Shock Protein 90 Versus Conventional Growth Factors in Acute and Diabetic Wound Healing: pages 259-277; Springer., ISBN: 978-94-007-4739-5
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    ABSTRACT: Deregulated accumulation of hypoxia-inducible factor-1α (HIF-1α) is a hallmark of many solid tumors. Directly targeting HIF-1α for therapeutics is challenging. Our finding that HIF-1α regulates secretion of heat shock protein-90α (Hsp90α) for cell migration raises the exciting possibility that targeting the secreted Hsp90α from HIF-1α-positive tumors has a better clinical outlook. Using the HIF-1α-positive and metastatic breast cancer cells MDA-MB-231, we show that down-regulation of the deregulated HIF-1α blocks Hsp90α secretion and invasion of the cells. Reintroducing an active, but not an inactive, HIF-1α into endogenous HIF-1α-depleted cells rescues both Hsp90α secretion and invasion. Inhibition of Hsp90α secretion, neutralization of secreted Hsp90α action, or removal of the cell surface LRP-1 receptor for secreted Hsp90α reduces the tumor cell invasion in vitro and lung colonization and tumor formation in nude mice. Furthermore, we localized the tumor-promoting effect to a 115-amino acid region in secreted Hsp90α called F-5. Supplementation with F-5 is sufficient to bypass the blockade of HIF-1α depletion and resumes invasion by the tumor cells under serum-free conditions. Because normal cells do not secrete Hsp90α in the absence of stress, drugs that target F-5 should be more effective and less toxic in treatment of HIF-1α-positive tumors in humans.
    Molecular biology of the cell 12/2011; 23(4):602-13. DOI:10.1091/mbc.E11-06-0575 · 4.47 Impact Factor

Publication Stats

3k Citations
556.64 Total Impact Points


  • 2000-2015
    • University of Southern California
      • • Department of Dermatology
      • • Department of Medicine
      Los Ángeles, California, United States
  • 2002-2013
    • Keck School of Medicine USC
      Los Ángeles, California, United States
    • The Scripps Research Institute
      لا هویا, California, United States
    • Northwestern University
      Evanston, Illinois, United States
  • 2009-2012
    • University of California, Los Angeles
      • Division of Dermatology
      Los Ángeles, California, United States
  • 2007
    • VA Greater Los Angeles Healthcare System
      Los Angeles, California, United States
    • University of North Carolina at Chapel Hill
      • Department of Dermatology
      North Carolina, United States
  • 1999
    • University of Illinois at Chicago
      Chicago, Illinois, United States
  • 1998
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States