Dermatologies
Abstract
Hair loss is a debilitating condition associated with the depletion of dermal papilla cells (DPCs), which can be replenished by dermal sheath cells (DSCs). Hence, strategies aimed at increasing the population of DPCs and DSCs hold great promise for the treatment of hair loss. In this study, we demonstrated that introducing exogenous DPCs and DSCs (hair follicle mesenchymal stem cells) could effectively migrate and integrate into the dermal papilla and dermal sheath niches, leading to enhanced hair growth and prolonged anagen phases. However, the homing rates of DPCs and DSCs were influenced by various factors, including recipient mouse depilation, cell passage number, cell dose, and immune rejection. Through in vitro and in vivo experiments, we further discovered that the CXCL13/CXCR5 pathway mediated the homing of DPCs and DSCs into hair follicle niches. This study underscores the potential of cell-based therapies for hair loss by targeted delivery of DPCs and DSCs to their respective niches, and sheds light on the intriguing concept that isolated mesenchymal stem cells can home back to their original niche microenvironment.
Authors
Kaitao Li, Fang Liu, Ye He, Qian Qu, Pingping Sun, Lijuan Du, Jin Wang, Ruosi Chen, Yuyang Gan, Danlan Fu, Zhexiang Fan, Bingcheng Liu, Zhiqi Hu, Yong Miao
Abstract
Aged skin is prone to viral infections, but the mechanisms responsible for this immunosenescent immune risk are unclear. We observed that aged murine and human skin expressed reduced antiviral proteins (AVPs) and circadian regulators including Bmal1 and Clock. Bmal1 and Clock were found to control rhythmic AVP expression in skin and such circadian-control of AVPs was diminished by disruption of immune cell interleukin 27 signaling and deletion of Bmal1/Clock genes in mouse skins, as well as siRNA-mediated knockdown of CLOCK in human primary keratinocytes. We found that treatment of circadian enhancing agents, nobiletin and SR8278, reduced infection of herpes simplex virus 1 (HSV1) in epidermal explants and human keratinocytes in a BMAL1/CLOCK-dependent manner. Circadian enhancing treatment also reversed susceptibility of aging murine skin and human primary keratinocytes to viral infection. These findings reveal an evolutionarily conserved and age-sensitive circadian regulation of cutaneous antiviral immunity, underscoring circadian restoration as an antiviral strategy in aging populations.
Authors
Stephen Kirchner, Vivian Lei, Paul T. Kim, Meera Patel, Jessica L. Shannon, David Corcoran, Dalton Hughes, Diana K. Waters, Kafui Dzirasa, Detlev Erdmann, Jörn Coers, Amanda S. MacLeod, Jennifer Y. Zhang
Abstract
Malignant T lymphocyte proliferation in mycosis fungoides (MF) is largely restricted to the skin, implying that malignant cells are dependent on their specific cutaneous tumor microenvironment (TME), including interactions with non-malignant immune and stromal cells, cytokines, and other immunomodulatory factors. To explore these interactions, we performed a comprehensive transcriptome analysis of the TME in advanced-stage MF skin tumors by single-cell RNA sequencing. Our analysis identified cell-type compositions, cellular functions, and cell-cell interactions in the MF TME that were distinct from those from healthy skin and benign dermatoses. While patterns of gene expression were common amongst patient samples, high transcriptional diversity was also observed in immune and stromal cells, with dynamic interactions and crosstalk between these cells and malignant T lymphocytes. This heterogeneity mapped to processes such as cell trafficking, matrix interactions, angiogenesis, immune functions, and metabolism that affect cancer cell growth, migration and invasion, as well as anti-tumor immunity. By comprehensively characterizing the transcriptomes of immune and stromal cell within the cutaneous microenvironment of individual MF tumors, we have identified patterns of dysfunction common to all tumors that represents a resource for identifying candidates with therapeutic potential as well as patient-specific heterogeneity that has important implications for personalized disease management.
Authors
Alyxzandria M. Gaydosik, Connor J. Stonesifer, Tracy Tabib, Robert Lafyatis, Larisa J. Geskin, Patrizia Fuschiotti
Abstract
Mutation of the ATP2A2 gene encoding sarco-endoplasmic reticulum calcium ATPase 2 (SERCA2) was linked to Darier disease more than two decades ago; however, there remain no targeted therapies for this disorder causing recurrent skin blistering and infections. Since Atp2a2 knockout mice do not phenocopy its pathology, we established a human tissue model of Darier disease to elucidate its pathogenesis and identify potential therapies. Leveraging CRISPR/Cas9, we generated human keratinocytes lacking SERCA2, which replicated features of Darier disease, including weakened intercellular adhesion and defective differentiation in organotypic epidermis. To identify pathogenic drivers downstream of SERCA2 depletion, we performed RNA sequencing and proteomic analysis. SERCA2-deficient keratinocytes lacked desmosomal and cytoskeletal proteins required for epidermal integrity and exhibited excess MAP kinase signaling, which modulates keratinocyte adhesion and differentiation. Immunostaining patient biopsies substantiated these findings with lesions showing keratin deficiency, cadherin mis-localization, and ERK hyper-phosphorylation. Dampening ERK activity with MEK inhibitors rescued adhesive protein expression and restored keratinocyte sheet integrity despite SERCA2 depletion or chemical inhibition. In sum, coupling multi-omic analysis with human organotypic epidermis as a pre-clinical model, we found that SERCA2 haploinsufficiency disrupts critical adhesive components in keratinocytes via ERK signaling and identified MEK inhibition as a treatment strategy for Darier disease.
Authors
Shivam A. Zaver, Mrinal K. Sarkar, Shaun Egolf, Jonathan Zou, Afua Tiwaa, Brian C. Capell, Johann E. Gudjonsson, Cory L. Simpson
Abstract
Cutaneous lupus erythematosus (CLE) is a disfiguring autoimmune skin disease characterized by an inflammatory infiltrate rich in T cells, which are strongly implicated in tissue damage. How these cells adapt to the skin environment and promote tissue inflammation and damage is not known. In lupus nephritis, we have previously identified an inflammatory gene program in kidney-infiltrating T cells that is dependent on hypoxia-inducible factor-1 (HIF-1), a transcription factor critical for the cellular and developmental response to hypoxia as well as inflammation-associated signals. In our current studies using a mouse model of lupus skin disease, we find that skin-infiltrating CD4+ and CD8+ T cells also express high levels of HIF-1. Skin-infiltrating T cells demonstrate a strong cytotoxic signature at the transcript and protein level, and HIF-1 inhibition abrogates skin and systemic disease in association with decreased T cell cytotoxic activity. We also demonstrate in human CLE tissue that the T cell rich inflammatory infiltrate exhibits increased amounts of HIF-1 and a cytotoxic signature. Granzyme B-expressing T cells are concentrated at sites of skin tissue damage in CLE, suggesting relevance of this pathway to human disease.
Authors
Alicia J. Little, Ping-Min Chen, Matthew D. Vesely, Rahanna N. Khan, Jacob Fiedler, James Garritano, Fahrisa M. Islam, Jennifer M. McNiff, Joseph E. Craft
Abstract
Keratin (K) and other intermediate filament (IF) protein mutations at conserved arginines disrupt keratin filaments into aggregates and cause human epidermolysis bullosa simplex (EBS; K14-R125C) or predispose to mouse liver injury (K18-R90C). The challenge for more than 70 IF-associated diseases is the lack of clinically utilized IF-targeted therapies. We used high-throughput drug screening to identify compounds that normalized mutation-triggered keratin filament disruption. Parthenolide, a plant sesquiterpene lactone, dramatically reversed keratin filament disruption and protected cells and mice expressing K18-R90C from apoptosis. K18-R90C became hyperacetylated compared with K18-WT and treatment with parthenolide normalized K18 acetylation. Parthenolide upregulated the NAD-dependent SIRT2, and increased SIRT2-keratin association. SIRT2 knockdown or pharmacologic inhibition blocked the parthenolide effect, while site-specific Lys-to-Arg mutation of keratin acetylation sites normalized K18-R90C filaments. Treatment of K18-R90C–expressing cells and mice with nicotinamide mononucleotide had a parthenolide-like protective effect. In 2 human K18 variants that associate with human fatal drug-induced liver injury, parthenolide protected K18-D89H– but not K8-K393R–induced filament disruption and cell death. Importantly, parthenolide normalized K14-R125C–mediated filament disruption in keratinocytes and inhibited dispase-triggered keratinocyte sheet fragmentation and Fas-mediated apoptosis. Therefore, keratin acetylation may provide a novel therapeutic target for some keratin-associated diseases.
Authors
Jingyuan Sun, Pei Li, Honglian Gui, Laure Rittié, David B. Lombard, Katrin Rietscher, Thomas M. Magin, Qing Xie, Li Liu, M. Bishr Omary
Abstract
Darier, Hailey-Hailey, and Grover’s diseases are rare acantholytic skin diseases. While these diseases have different underlying causes, they share defects in cell-cell adhesion in the epidermis and desmosome organization. To better understand the underlying mechanisms leading to disease in these conditions we performed RNA-seq on lesional skin samples from patients. The transcriptomic profiles of Darier, Hailey-Hailey, and Grover’s disease were found to share a remarkable overlap, which did not extend to other common inflammatory skin diseases. Analysis of enriched pathways showed a shared upregulation in keratinocyte differentiation, and a decrease in cell adhesion and actin organization pathways in Darier, Hailey-Hailey, and Grover’s disease. Direct comparison to atopic dermatitis and psoriasis showed that the downregulation in actin organization pathways was a unique feature in the acantholytic skin diseases. Further, upstream regulator analysis suggested that a decrease in SRF/MRTF activity was responsible for the downregulation of actin organization pathways. Staining for MRTFA in lesional skin samples showed a decrease in nuclear MRTFA in patient skin compared to normal skin. These findings highlight the significant level of similarity in the transcriptome of Darier, Hailey-Hailey, and Grover’s disease, and identify decreases in actin organization pathways as a unique signature present in these conditions.
Authors
Quinn R. Roth-Carter, Hope E. Burks, Ziyou Ren, Jennifer L. Koetsier, Lam C. Tsoi, Paul W. Harms, Xianying Xing, Joseph Kirma, Robert M. Harmon, Lisa M. Godsel, Abbey L. Perl, Johann E. Gudjonsson, Kathleen J. Green
Abstract
Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and identify therapeutically targetable pathways by performing single-cell and spatial RNA-sequencing on lesional and non-lesional skin biopsies of a PSM patient 12-months apart and 6 healthy controls. We then validated using immunostaining and in vitro approaches.Fibrotic skin was characterized by prominent type-II IFN response, accompanied by infiltrating myeloid, B-cells, and T-cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Further, cell-cell interaction analyses revealed cDC2B dendritic cells as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type-II IFN responses. This work identified key pathogenic circuits between T-cells, cDC2Bs, and myofibroblasts, and suggests JAK1/2 inhibition is a potential therapeutic option in PSM.
Authors
Enze Xing, Feiyang Ma, Rachael Wasikowski, Allison C. Billi, Mehrnaz Gharaee-Kermani, Jennifer Fox, Craig Dobry, Amanda Victory, Mrinal Sarkar, Xianying Xing, Olesya Plazyo, Henry W. Chen, Grant C. Barber, Heidi Jacobe, Pei-Suen Tsou, Robert L. Modlin, John Varga, J. Michelle Kahlenberg, Lam C. Tsoi, Johann E. Gudjonsson, Dinesh Khanna
Abstract
Cutaneous T cell lymphoma (CTCL) is a disfiguring and incurable disease characterized by skin-homing malignant T cells surrounded by immune cells that promote CTCL growth through an immunosuppressive tumor microenvironment (TME). Preliminary data from our phase I clinical trial of anti–programmed cell death ligand 1 (anti–PD-L1) combined with lenalidomide in patients with relapsed/refractory CTCL demonstrated promising clinical efficacy. In the current study, we analyzed the CTCL TME, which revealed a predominant PD-1+ M2-like tumor-associated macrophage (TAM) subtype with upregulated NF-κB and JAK/STAT signaling pathways and an aberrant cytokine and chemokine profile. Our in vitro studies investigated the effects of anti–PD-L1 and lenalidomide on PD-1+ M2-like TAMs. The combinatorial treatment synergistically induced functional transformation of PD-1+ M2-like TAMs toward a proinflammatory M1-like phenotype that gained phagocytic activity upon NF-κB and JAK/STAT inhibition, altered their migration through chemokine receptor alterations, and stimulated effector T cell proliferation. Lenalidomide was more effective than anti–PD-L1 in downregulation of the immunosuppressive IL-10, leading to decreased expression of both PD-1 and PD-L1. Overall, PD-1+ M2-like TAMs play an immunosuppressive role in CTCL. Anti–PD-L1 combined with lenalidomide provides a therapeutic strategy to enhance antitumor immunity by targeting PD-1+ M2-like TAMs in the CTCL TME.
Authors
Zhen Han, Xiwei Wu, Hanjun Qin, Yate-Ching Yuan, Daniel Schmolze, Chingyu Su, Jasmine Zain, Lilach Moyal, Emmilia Hodak, James F. Sanchez, Peter P. Lee, Mingye Feng, Steven T. Rosen, Christiane Querfeld
Abstract
Multi-organ fibrosis in systemic sclerosis (SSc) accounts for substantial mortality and lacks effective therapies. Lying at the crossroad of transforming growth factor-β (TGF-β) and toll-like receptor (TLR) signaling, TGF-β-activated kinase 1 (TAK1) might have a pathogenic role in SSc. We therefore sought to evaluate the TAK1 signaling axis in patients with SSc, and investigate pharmacological TAK1 blockade using a novel drug-like selective TAK1 inhibitor, HS-276. Inhibiting TAK1 abrogated TGF-β1 stimulation of collagen synthesis and myofibroblasts differentiation in healthy skin fibroblasts, and ameliorated constitutive activation of SSc skin fibroblasts. Moreover, treatment with HS-276 prevented dermal and pulmonary fibrosis and reduced the expression of profibrotic mediators in bleomycin-treated mice. Importantly, initiating HS-276 treatment even after fibrosis was already established prevented its progression in affected organs. Together, these findings implicate TAK1 in the pathogenesis of SSc, and identify targeted TAK1 inhibition using a small molecule as a potential strategy for the treatment of SSc and other fibrotic diseases.
Authors
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Scott A. Scarneo, Philip F. Hughes, M. Asif Amin, Pei-Suen Tsou, Dinesh Khanna, Timothy A.J. Haystead, Swati Bhattacharyya, John Varga
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