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185


Catalase, a therapeutic target in the reversal of estrogen-mediated aging

Elliot, Sharon J; Catanuto, Paola; Pereira-Simon, Simone; Xia, Xiaomei; Pastar, Irena; Thaller, Seth; Head, Cheyanne R; Stojadinovic, Olivera; Tomic-Canic, Marjana; Glassberg, Marilyn K
Despite increasing interest in the reversal of age-related processes, there is a paucity of data regarding the effects of post-menopausal associated estrogen loss on cellular function. We studied human adipose derived-mesenchymal stem cell (hASCs) isolated from women under 45 years old (pre-menopause, pre-hASC) or older than 55 years old (post-menopause, post-hASC). In this study, we provide proof of concept that the age-related ineffective functionality of ASCs can be reversed to improve their ability in promoting tissue repair. We found reduced estrogen receptor expression, decreased estrogen receptor activation, and reduced sensitivity to 17β-estradiol in post-hASCs. This correlated with decreased antioxidants (catalase and SOD expression) and increased oxidative stress compared to pre-hASCs. Increasing catalase expression in post-hASCs restored ER expression and their functional capacity to promote tissue repair as shown in human skin ex vivo wound healing and in vivo mouse model of lung injury. Our results suggest that the consequences of 17β-estradiol decline on function of hASCs may be reversible by changing the oxidative stress/antioxidant composition.
PMID: 34174444
ISSN: 1525-0024
CID: 4925962

Intracellular escape strategies of Staphylococcus aureus in persistent cutaneous infections

Huitema, Leonie; Phillips, Taylor; Alexeev, Vitali; Tomic-Canic, Marjana; Pastar, Irena; Igoucheva, Olga
Pathogenic invasion of Staphylococcus aureus is a major concern in patients with chronic skin diseases like atopic dermatitis (AD), epidermolysis bullosa (EB), or chronic diabetic foot and venous leg ulcers, and can result in persistent and life threatening chronic non-healing wounds. S. aureus is generally recognized as extracellular pathogens. However, S. aureus can also invade, hide, and persist in skin cells to contribute to wound chronicity. The intracellular life cycle of S. aureus is currently incompletely understood, although published studies indicate that its intracellular escape strategies play an important role in persistent cutaneous infections. This review provides current scientific knowledge about the intracellular life cycle of S. aureus in skin cells, which can be classified into professional and non-professional antigen presenting cells, and its strategies to escape adaptive defense mechanisms. First, we discuss phenotypic switch of S. aureus, which affects intracellular routing and degradation. This review also evaluates potential intracellular escape mechanism of S. aureus to avoid intracellular degradation and antigen presentation, preventing an immune response. Furthermore, we discuss potential drug targets that can interfere with the intracellular life cycle of S. aureus. Taken together, this review aims to increase scientific understanding about the intracellular life cycle of S. aureus into skin cells and its strategies to evade the host immune response, information that is crucial to reduce pathogenic invasion and life threatening persistence of S. aureus in chronic cutaneous infections.
PMID: 33179358
ISSN: 1600-0625
CID: 4665392

Epigenetic regulation of cellular functions in wound healing

Pastar, Irena; Marjanovic, Jelena; Stone, Rivka C; Chen, Vivien; Burgess, Jamie L; Mervis, Joshua S; Tomic-Canic, Marjana
Stringent spatiotemporal regulation of the wound healing process involving multiple cell types is associated with epigenetic mechanisms of gene regulation, such as DNA methylation, histone modification and chromatin remodeling, as well as non-coding RNAs. Here we discuss the epigenetic changes that occur during wound healing and the rapidly expanding understanding of how these mechanisms affect healing resolution in both acute and chronic wound milieu. We provide a focused overview of current research into epigenetic regulators that contribute to wound healing by specific cell type. We highlight the role of epigenetic regulators in the molecular pathophysiology of chronic wound conditions. The understanding of how epigenetic regulators can affect cellular functions during normal and impaired wound healing could lead to novel therapeutic approaches, and we outline questions that can provide guidance for future research on epigenetic-based interventions to promote healing. Dissecting the dynamic interplay between cellular subtypes involved in wound healing and epigenetic parameters during barrier repair will deepen our understanding of how to improve healing outcomes in patients affected by chronic non-healing wounds.
PMID: 33690920
ISSN: 1600-0625
CID: 4809352

Cellular reprogramming of diabetic foot ulcer fibroblasts triggers pro-healing miRNA-mediated epigenetic signature

Pastar, Irena; Marjanovic, Jelena; Liang, Liang; Stone, Rivka C; Kashpur, Olga; Jozic, Ivan; Head, Cheyanne R; Smith, Avi; Gerami-Naini, Behzad; Garlick, Jonathan A; Tomic-Canic, Marjana
Diabetic foot ulcers (DFUs), a prevalent complication of diabetes, constitute a major medical challenge with a critical need for development of cell-based therapies. We previously generated induced pluripotent stem cells (iPSCs) from dermal fibroblasts derived from the DFU patients, location-matched skin of diabetic patients and normal healthy donors and re-differentiated them into fibroblasts. To assess the epigenetic microRNA (miR) regulated changes triggered by cellular reprogramming, we performed miRs expression profiling. We found let-7c, miR-26b-5p, -29c-3p, -148a-3p, -196a-5p, -199b-5p and -374a-5p suppressed in iPSC-derived fibroblasts in vitro and in 3D dermis-like self-assembly tissue, whereas their corresponding targets involved in cellular migration were upregulated. Moreover, targets involved in organization of extracellular matrix were induced after fibroblast reprogramming. PLAT gene, the crucial fibrinolysis factor, was upregulated in iPSC-derived fibroblasts and was confirmed as a direct target of miR-196a-5p. miR-197-3p and miR-331-3p were found upregulated specifically in iPSC-derived diabetic fibroblasts, while their targets CAV1 and CDKN3 were suppressed. CAV1, an important negative regulator of wound healing, was confirmed as a direct miR-197-3p target. Together, our findings demonstrate that iPSC reprogramming is an effective approach for erasing the diabetic non-healing miR-mediated epigenetic signature and promoting a pro-healing cellular phenotype.
PMID: 34114688
ISSN: 1600-0625
CID: 4900332

Glucocorticoid-mediated induction of caveolin-1 disrupts cytoskeletal organization, inhibits cell migration and re-epithelialization of non-healing wounds

Jozic, Ivan; Abujamra, Beatriz Abdo; Elliott, Michael H; Wikramanayake, Tongyu C; Marjanovic, Jelena; Stone, Rivka C; Head, Cheyanne R; Pastar, Irena; Kirsner, Robert S; Andreopoulos, Fotios M; Musi, Juan P; Tomic-Canic, Marjana
Although impaired keratinocyte migration is a recognized hallmark of chronic wounds, the molecular mechanisms underpinning impaired cell movement are poorly understood. Here, we demonstrate that both diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) exhibit global deregulation of cytoskeletal organization in genomic comparison to normal skin and acute wounds. Interestingly, we found that DFUs and VLUs exhibited downregulation of ArhGAP35, which serves both as an inactivator of RhoA and as a glucocorticoid repressor. Since chronic wounds exhibit elevated levels of cortisol and caveolin-1 (Cav1), we posited that observed elevation of Cav1 expression may contribute to impaired actin-cytoskeletal signaling, manifesting in aberrant keratinocyte migration. We showed that Cav1 indeed antagonizes ArhGAP35, resulting in increased activation of RhoA and diminished activation of Cdc42, which can be rescued by Cav1 disruption. Furthermore, we demonstrate that both inducible keratinocyte specific Cav1 knockout mice, and MβCD treated diabetic mice, exhibit accelerated wound closure. Taken together, our findings provide a previously unreported mechanism by which Cav1-mediated cytoskeletal organization prevents wound closure in patients with chronic wounds.
PMID: 34145387
ISSN: 2399-3642
CID: 4917892

Notch1 signaling determines the plasticity and function of fibroblasts in diabetic wounds

Shao, Hongwei; Li, Yan; Pastar, Irena; Xiao, Min; Prokupets, Rochelle; Liu, Sophia; Yu, Kerstin; Vazquez-Padron, Roberto I; Tomic-Canic, Marjana; Velazquez, Omaida C; Liu, Zhao-Jun
Fibroblasts play a pivotal role in wound healing. However, the molecular mechanisms determining the reparative response of fibroblasts remain unknown. Here, we identify Notch1 signaling as a molecular determinant controlling the plasticity and function of fibroblasts in modulating wound healing and angiogenesis. The Notch pathway is activated in fibroblasts of diabetic wounds but not in normal skin and non-diabetic wounds. Consistently, wound healing in the FSP-1
PMID: 33109684
ISSN: 2575-1077
CID: 4647162

Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

Sawaya, Andrew P; Stone, Rivka C; Brooks, Stephen R; Pastar, Irena; Jozic, Ivan; Hasneen, Kowser; O'Neill, Katelyn; Mehdizadeh, Spencer; Head, Cheyanne R; Strbo, Natasa; Morasso, Maria I; Tomic-Canic, Marjana
Diabetic foot ulcers (DFUs) are a life-threatening disease that often result in lower limb amputations and a shortened lifespan. However, molecular mechanisms contributing to the pathogenesis of DFUs remain poorly understood. We use next-generation sequencing to generate a human dataset of pathogenic DFUs to compare to transcriptional profiles of human skin and oral acute wounds, oral as a model of "ideal" adult tissue repair due to accelerated closure without scarring. Here we identify major transcriptional networks deregulated in DFUs that result in decreased neutrophils and macrophages recruitment and overall poorly controlled inflammatory response. Transcription factors FOXM1 and STAT3, which function to activate and promote survival of immune cells, are inhibited in DFUs. Moreover, inhibition of FOXM1 in diabetic mouse models (STZ-induced and db/db) results in delayed wound healing and decreased neutrophil and macrophage recruitment in diabetic wounds in vivo. Our data underscore the role of a perturbed, ineffective inflammatory response as a major contributor to the pathogenesis of DFUs, which is facilitated by FOXM1-mediated deregulation of recruitment of neutrophils and macrophages, revealing a potential therapeutic strategy.
PMID: 32938916
ISSN: 2041-1723
CID: 4593212

Topical L-thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

Paus, Ralf; Ramot, Yuval; Kirsner, Robert S; Tomic-Canic, Marjana
Topical hormone therapy with natural or synthetic ligands of nuclear hormone receptors such as glucocorticoids, vitamin D analogues and retinoids has a long and highly successful tradition in dermatology. Yet the dermatological potential of thyroid hormone receptor (TR) agonists has been widely ignored, despite abundant clinical, cell and molecular biology, mouse in vivo, and human skin and hair follicle organ culture data amply documenting a role of TR-mediated signalling in skin physiology and pathology. Here, we review this evidence, with emphasis on wound healing and hair growth, and specifically highlight the therapeutic potential of repurposing topical L-thyroxine (T4) for selected applications in future dermatological therapy. We underscore the known systemic safety and efficacy profile of T4 in clinical medicine, and the well-documented impact of thyroid hormones on, for example, human epidermal and hair follicle physiology, hair follicle epithelial stem cells and pigmentation, keratin expression, mitochondrial energy metabolism and wound healing. On this background, we argue that short-term topical T4 treatment deserves careful further preclinical and clinical exploration for repurposing as a low-cost, effective, and widely available dermatotherapeutic, namely in the management of skin ulcers and telogen effluvium, and that its predictable adverse effects are well-manageable.
PMID: 32682336
ISSN: 1600-0625
CID: 4529172

Skin Microbiota and its Interplay with Wound Healing

Tomic-Canic, Marjana; Burgess, Jamie L; O'Neill, Katelyn E; Strbo, Natasa; Pastar, Irena
The skin microbiota is intimately coupled with cutaneous health and disease. Interactions between commensal microbiota and the multiple cell types involved in cutaneous wound healing regulate the immune response and promote barrier restoration. This dialog between host cells and the microbiome is dysregulated in chronic wounds. In this review, we first describe how advances in sequencing approaches and analysis have been used to study the chronic wound microbiota, and how these findings underscored the complexity of microbial communities and their association with clinical outcomes in patients with chronic wound disorders. We also discuss the mechanistic insights gathered from multiple animal models of polymicrobial wound infections. In addition to the well-described role of bacteria residing in polymicrobial biofilms, we also discuss the role of the intracellular bacterial niche in wound healing. We describe how, in contrast to pathogenic species capable of subverting skin immunity, commensals are essential for the regulation of the cutaneous immune system and provide protection from intracellular pathogens through modulation of the antimicrobial molecule, Perforin-2. Despite recent advances, more research is needed to shed light on host-microbiome crosstalk in both healing and nonhealing chronic wounds to appropriately guide therapeutic developments.
PMID: 32914215
ISSN: 1179-1888
CID: 4589562

A Bioengineered Living Cell Construct Activates Metallothionein/Zinc/MMP8 and Inhibits TGFβ to Stimulate Remodeling of Fibrotic Venous Leg Ulcers

Stone, Rivka C; Stojadinovic, Olivera; Sawaya, Andrew P; Glinos, George D; Lindley, Linsey E; Pastar, Irena; Badiavas, Evangelos; Tomic-Canic, Marjana
Venous leg ulcers (VLU) represent a major clinical unmet need, impairing quality of life for millions worldwide. The bioengineered living cell construct (BLCC) is the only FDA-approved therapy demonstrating efficacy in healing chronic VLU, yet its in vivo mechanisms of action are not well understood. Previously, we reported a BLCC-mediated acute wounding response at the ulcer edge; in this study we elucidated the BLCC-specific effects on the epidermis-free ulcer bed. We conducted a randomized controlled clinical trial (ClinicalTrials.gov NCT01327937) enrolling 30 subjects with non-healing VLUs, and performed genotyping, genomic profiling and functional analysis on wound bed biopsies obtained at baseline and one week after treatment with BLCC plus compression or compression therapy (control). The VLU bed transcriptome featured processes of chronic inflammation and was strikingly enriched for fibrotic/fibrogenic pathways and gene networks. BLCC application decreased expression of pro-fibrotic TGFß1 gene targets and increased levels of TGFß inhibitor decorin. Surprisingly, BLCC upregulated metallothioneins and fibroblast-derived MMP8 collagenase, and promoted endogenous release of MMP-activating zinc to stimulate anti-fibrotic remodeling, a novel mechanism of cutaneous wound healing. By activating a remodeling program in the quiescent VLU bed, BLCC application shifts nonhealing to healing phenotype. As VLU bed fibrosis correlates with poor clinical healing, findings from this study identify the chronic VLU as a fibrotic skin disease and are first to support the development and application of anti-fibrotic therapies as a successful treatment approach. This article is protected by copyright. All rights reserved.
PMID: 31674093
ISSN: 1524-475x
CID: 4162792