Faculty Bibliography
Searched for:
school:SOM
Department/Unit:Cell Biology
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14089
In every end there is a beginning-telomeres in male reproduction
PMID: 25108466
ISSN: 0015-0282
CID: 1141522
Activation of melanocyte antioxidant response pathways following exposure to vitiligo-inducing phenols: Implications for vitiligo pathogenesis [Meeting Abstract]
Vitiligo is a common disorder characterized by progressive melanocyte death. Vitiligo can be induced in an occupational setting by exposure to vitiligo-inducing phenols (VIPs) such as 4 tert-butyl phenol (4TBP) and monobenzyl ether of hydroquinone (MBEH). These VIPs are believed to specifically target melanocytes due to their structural similarity to tyrosine and competition for binding to tyrosinase, the rate-limiting enzyme for melanin synthesis. By exposing normal melanocytes to VIPs and using microarray analysis and bioinformatics approaches for gene expression profiling, we identified key signaling pathways that are involved in the melanocyte response to VIP exposure. In particular, we hypothesized that exposure of primary human melanocytes to VIPs would result in oxidative stress that triggers antioxidant responses in order to protect melanocytes from cell death. Following melanocyte exposure to VIPs, HO-1 was upregulated (4TBP exposure: 5.49-fold; MBEH exposure: 25.98- fold). HO-1 is a direct target of Nrf2, a key regulator of the Nrf2- ARE antioxidant response. Activation of Nrf2 and its targets, HO- 1 and NQO1, was confirmed by conventional Western blot analysis and quantitative RT-PCR. We are now characterizing the mechanisms that regulate Nrf2 activation in response to VIPs. Additional antioxidants including SOD2 (4TBP: 10.5-fold; MBEH: 38.5-fold), peroxiredoxin 6 (4TBP: 2.44-fold; MBEH: 15.18-fold), and Nrf2 binding partners, MafK (4TBP: 2.12-fold; MBEH: 2.50- fold) and MafF (4TBP: 2.32-fold; MBEH: 3.16-fold) were also upregulated with VIP exposure and are being investigated further. Several studies have revealed dysfunctional antioxidant responses in melanocytes from patients with vitiligo, however the underlying mechanisms that reduce their efficacy are yet to be determined. We hypothesize that investigation of VIP-induced pathways may lead to the characterization of these mechanisms and provide opportunities for development of targeted therapeutics for the treatment of vitiligo
EMBASE:71656845
ISSN: 1755-1471
CID: 1362922
Noncontact, low-frequency ultrasound therapy enhances neovascularization and wound healing in diabetic mice
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
PMCID:4422103
PMID: 25158717
ISSN: 1529-4242
CID: 1162372
Variation in HSP70 expression contributes to skin color diversity via regulation of melanogenesis [Meeting Abstract]
Differences in epidermal melanin levels result in the wide variation in color associated with ethnic skin diversity. Ethnic differences result from variance in melanogenesis, melanin transfer, and melanosome degradation in the epidermis, but the mechanisms underlying these differences, and their contribution to the regulation of skin color, are not fully understood. In this study, we explored proteins which were differentially expressed between Caucasian- and African American donor skin- derived melanocytes using twodimensional gel electrophoresis and mass spectroscopy. We consequently identified an important role for Heat Shock Protein 70 (Hsp70 encoded by HSPA1A) in skin color determination. In contrast to a previous report suggesting negative regulation of melanogenesis, Hsp70 was found to be more abundant in melanocytes from African American donors compared to those from Caucasian donors, which also reflected protein expression in the skin. In particular, inhibition of Hsp70, using either a specific inhibitor or siRNA targeting, significantly decreased melanin content of African American donor melanocytes, consistent with previous reports that Hsp70 is an Endoplasmic Reticulum (ER) chaperone involved in post-translational modification of tyrosinase. Indeed, inhibition of Hsp70 caused a decrease in tyrosinase protein levels by affecting its maturation. Taken together, our data reveal that Hsp70 plays an essential role in regulation of melanogenesis and thereby contributes to the ethnic diversity of skin color
EMBASE:71656893
ISSN: 1755-1471
CID: 1362912
Control of brain development and homeostasis by local and systemic insulin signalling
Insulin and insulin-like growth factors (IGFs) are important regulators of growth and metabolism. In both vertebrates and invertebrates, insulin/IGFs are made available to various organs, including the brain, through two routes: the circulating systemic insulin/IGFs act on distant organs via endocrine signalling, whereas insulin/IGF ligands released by local tissues act in a paracrine or autocrine fashion. Although the mechanisms governing the secretion and action of systemic insulin/IGF have been the focus of extensive investigation, the significance of locally derived insulin/IGF has only more recently come to the fore. Local insulin/IGF signalling is particularly important for the development and homeostasis of the central nervous system, which is insulated from the systemic environment by the blood-brain barrier. Local insulin/IGF signalling from glial cells, the blood-brain barrier and the cerebrospinal fluid has emerged as a potent regulator of neurogenesis. This review will address the main sources of local insulin/IGF and how they affect neurogenesis during development. In addition, we describe how local insulin/IGF signalling couples neural stem cell proliferation with systemic energy state in Drosophila and in mammals.
PMID: 25200291
ISSN: 1463-1326
CID: 5596142
Barrier properties of cultured retinal pigment epithelium
The principal function of an epithelium is to form a dynamic barrier that regulates movement between body compartments. Each epithelium is specialized with barrier functions that are specific for the tissues it serves. The apical surface commonly faces a lumen, but the retinal pigment epithelium (RPE) appears to be unique by a facing solid tissue, the sensory retina. Nonetheless, there exists a thin (subretinal) space that can become fluid filled during pathology. RPE separates the subretinal space from the blood supply of the outer retina, thereby forming the outer blood-retinal barrier. The intricate interaction between the RPE and sensory retina presents challenges for learning how accurately culture models reflect native behavior. The challenge is heightened by findings that detail the variation of RPE barrier proteins both among species and at different stages of the life cycle. Among the striking differences is the expression of claudin family members. Claudins are the tight junction proteins that regulate ion diffusion across the spaces that lie between the cells of a monolayer. Claudin expression by RPE varies with species and life-stage, which implies functional differences among commonly used animal models. Investigators have turned to transcriptomics to supplement functional studies when comparing native and cultured tissue. The most detailed studies of the outer blood-retinal barrier have focused on human RPE with transcriptome and functional studies reported for human fetal, adult, and stem-cell derived RPE.
PMID: 24731966
ISSN: 0014-4835
CID: 971702
A Randomized Controlled Trial of the embrace(R) Device to Reduce Incisional Scar Formation
BACKGROUND:: Scarring represents a significant biomedical burden in clinical medicine. Mechanomodulation has been linked to scarring through inflammation, but until now a systematic approach to attenuate mechanical force and reduce scarring has not been possible. METHODS:: We conducted a twelve month, prospective, open label, randomized, multi-center clinical trial to evaluate abdominoplasty scar appearance following post-operative treatment with the embrace device to reduce mechanical forces on healing surgical incisions. Incisions from 65 healthy adult subjects were randomized to receive embrace treatment on one half of an abdominoplasty incision and control treatment (surgeon's optimal care methods) on the other half. The primary endpoint for this study was the difference between assessments of the scar appearance for the treated and control sides using the Visual Analogue Scale (VAS) scar score. RESULTS:: Final twelve month study photos were obtained from 36 subjects who completed at least five weeks of dressing application. The mean VAS score for embrace-treated scars (2.90) was significantly improved compared to control-treated scars (3.29) at 12 months (difference = 0.39, 95% confidence interval [0.14, 0.66], p = 0.027). Both subjects and investigators found that embrace-treated scars demonstrated significant improvements in overall appearance at 12 months using the Patient and Observer Scar Assessment Scale (POSAS) evaluation (p = 0.02 and p < 0.001, respectively). No serious adverse events were reported. CONCLUSION:: These results demonstrate that the embrace device significantly reduces scarring following abdominoplasty surgery. To our knowledge, this represents the first level one evidence for post-operative scar reduction.
PMCID:4425293
PMID: 24804638
ISSN: 1529-4242
CID: 971302
Diabetes Irreversibly Depletes Bone Marrow-Derived Mesenchymal Progenitor Cell Subpopulations
Diabetic vascular pathology is largely attributable to impairments in tissue recovery from hypoxia. Circulating progenitor cells have been postulated to play a role in ischemic recovery and deficiencies in these cells have been well described in diabetic patients. Here, we examine bone marrow-derived mesenchymal progenitor cells (BM-MPCs) that have previously been shown to be important for new blood vessel formation, and demonstrate significant deficits in the context of diabetes. Further, we determine that this dysfunction is attributable to intrinsic defects in diabetic BM-MPCs that are not correctable by restoring glucose homeostasis. We identify two transcriptionally distinct subpopulations that are selectively depleted by both type 1 and type 2 diabetes, and these subpopulations have pro-vasculogenic expression profiles, suggesting that they are vascular progenitor cells. These results suggest that the clinically observed deficits in progenitor cells may be attributable to selective and irreversible depletion of progenitor cell subsets in patients with diabetes.
PMCID:4429348
PMID: 24740572
ISSN: 0012-1797
CID: 901232
Capillary Force Seeding of Hydrogels for Adipose-Derived Stem Cell Delivery in Wounds
Effective skin regeneration therapies require a successful interface between progenitor cells and biocompatible delivery systems. We previously demonstrated the efficiency of a biomimetic pullulan-collagen hydrogel scaffold for improving bone marrow-derived mesenchymal stem cell survival within ischemic skin wounds by creating a "stem cell niche" that enhances regenerative cytokine secretion. Adipose-derived mesenchymal stem cells (ASCs) represent an even more appealing source of stem cells because of their abundance and accessibility, and in this study we explored the utility of ASCs for hydrogel-based therapies. To optimize hydrogel cell seeding, a rapid, capillary force-based approach was developed and compared with previously established cell seeding methods. ASC viability and functionality following capillary hydrogel seeding were then analyzed in vitro and in vivo. In these experiments, ASCs were seeded more efficiently by capillary force than by traditional methods and remained viable and functional in this niche for up to 14 days. Additionally, hydrogel seeding of ASCs resulted in the enhanced expression of multiple stemness and angiogenesis-related genes, including Oct4, Vegf, Mcp-1, and Sdf-1. Moving in vivo, hydrogel delivery improved ASC survival, and application of both murine and human ASC-seeded hydrogels to splinted murine wounds resulted in accelerated wound closure and increased vascularity when compared with control wounds treated with unseeded hydrogels. In conclusion, capillary seeding of ASCs within a pullulan-collagen hydrogel bioscaffold provides a convenient and simple way to deliver therapeutic cells to wound environments. Moreover, ASC-seeded constructs display a significant potential to accelerate wound healing that can be easily translated to a clinical setting.
PMCID:4149299
PMID: 25038246
ISSN: 2157-6564
CID: 1075532
Roles for Hedgehog signaling in adult organ homeostasis and repair
The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.
PMCID:4197719
PMID: 25183867
ISSN: 0950-1991
CID: 1180802
