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Spatiotemporal antagonism in mesenchymal-epithelial signaling in sweat versus hair fate decision

Lu, Catherine P; Polak, Lisa; Keyes, Brice E; Fuchs, Elaine
The gain of eccrine sweat glands in hairy body skin has empowered humans to run marathons and tolerate temperature extremes. Epithelial-mesenchymal cross-talk is integral to the diverse patterning of skin appendages, but the molecular events underlying their specification remain largely unknown. Using genome-wide analyses and functional studies, we show that sweat glands are specified by mesenchymal-derived bone morphogenetic proteins (BMPs) and fibroblast growth factors that signal to epithelial buds and suppress epithelial-derived sonic hedgehog (SHH) production. Conversely, hair follicles are specified when mesenchymal BMP signaling is blocked, permitting SHH production. Fate determination is confined to a critical developmental window and is regionally specified in mice. In contrast, a shift from hair to gland fates is achieved in humans when a spike in BMP silences SHH during the final embryonic wave(s) of bud morphogenesis.
PMID: 28008008
ISSN: 1095-9203
CID: 2964062

Identification of stem cell populations in sweat glands and ducts reveals roles in homeostasis and wound repair

Lu, Catherine P; Polak, Lisa; Rocha, Ana Sofia; Pasolli, H Amalia; Chen, Shann-Ching; Sharma, Neha; Blanpain, Cedric; Fuchs, Elaine
Sweat glands are abundant in the body and essential for thermoregulation. Like mammary glands, they originate from epidermal progenitors. However, they display few signs of cellular turnover, and whether they have stem cells and tissue-regenerative capacity remains largely unexplored. Using lineage tracing, we here identify in sweat ducts multipotent progenitors that transition to unipotency after developing the sweat gland. In characterizing four adult stem cell populations of glandular skin, we show that they display distinct regenerative capabilities and remain unipotent when healing epidermal, myoepithelial-specific, and lumenal-specific injuries. We devise purification schemes and isolate and transcriptionally profile progenitors. Exploiting molecular differences between sweat and mammary glands, we show that only some progenitors regain multipotency to produce de novo ductal and glandular structures, but that these can retain their identity even within certain foreign microenvironments. Our findings provide insight into glandular stem cells and a framework for the further study of sweat gland biology.
PMID: 22770217
ISSN: 1097-4172
CID: 2964042

Stem Cell Lineage Infidelity Drives Wound Repair and Cancer

Ge, Yejing; Gomez, Nicholas C; Adam, Rene C; Nikolova, Maria; Yang, Hanseul; Verma, Akanksha; Lu, Catherine Pei-Ju; Polak, Lisa; Yuan, Shaopeng; Elemento, Olivier; Fuchs, Elaine
Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement-granting privileges associated with both fates-is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.
PMID: 28434617
ISSN: 1097-4172
CID: 3131662

Impaired Epidermal to Dendritic T Cell Signaling Slows Wound Repair in Aged Skin

Keyes, Brice E; Liu, Siqi; Asare, Amma; Naik, Shruti; Levorse, John; Polak, Lisa; Lu, Catherine P; Nikolova, Maria; Pasolli, Hilda Amalia; Fuchs, Elaine
Aged skin heals wounds poorly, increasing susceptibility to infections. Restoring homeostasis after wounding requires the coordinated actions of epidermal and immune cells. Here we find that both intrinsic defects and communication with immune cells are impaired in aged keratinocytes, diminishing their efficiency in restoring the skin barrier after wounding. At the wound-edge, aged keratinocytes display reduced proliferation and migration. They also exhibit a dampened ability to transcriptionally activate epithelial-immune crosstalk regulators, including a failure to properly activate/maintain dendritic epithelial T cells (DETCs), which promote re-epithelialization following injury. Probing mechanism, we find that aged keratinocytes near the wound edge don't efficiently upregulate Skints or activate STAT3. Notably, when epidermal Stat3, Skints, or DETCs are silenced in young skin, re-epithelialization following wounding is perturbed. These findings underscore epithelial-immune crosstalk perturbations in general, and Skints in particular, as critical mediators in the age-related decline in wound-repair.
PMID: 27863246
ISSN: 1097-4172
CID: 2964052

Skin stem cells orchestrate directional migration by regulating microtubule-ACF7 connections through GSK3β

Wu, Xiaoyang; Shen, Qing-Tao; Oristian, Daniel S; Lu, Catherine P; Zheng, Qinsi; Wang, Hong-Wei; Fuchs, Elaine
Homeostasis and wound healing rely on stem cells (SCs) whose activity and directed migration are often governed by Wnt signaling. In dissecting how this pathway integrates with the necessary downstream cytoskeletal dynamics, we discovered that GSK3β, a kinase inhibited by Wnt signaling, directly phosphorylates ACF7, a > 500 kDa microtubule-actin crosslinking protein abundant in hair follicle stem cells (HF-SCs). We map ACF7's GSK3β sites to the microtubule-binding domain and show that phosphorylation uncouples ACF7 from microtubules. Phosphorylation-refractile ACF7 rescues overall microtubule architecture, but phosphorylation-constitutive mutants do not. Neither mutant rescues polarized movement, revealing that phospho-regulation must be dynamic. This circuitry is physiologically relevant and depends upon polarized GSK3β inhibition at the migrating front of SCs/progeny streaming from HFs during wound repair. Moreover, only ACF7 and not GSKβ-refractile-ACF7 restore polarized microtubule-growth and SC-migration to ACF7 null skin. Our findings provide insights into how this conserved spectraplakin integrates signaling, cytoskeletal dynamics, and polarized locomotion of somatic SCs.
PMID: 21295697
ISSN: 1097-4172
CID: 2964032

Sweat gland progenitors in development, homeostasis, and wound repair

Lu, Catherine; Fuchs, Elaine
The human body is covered with several million sweat glands. These tiny coiled tubular skin appendages produce the sweat that is our primary source of cooling and hydration of the skin. Numerous studies have been published on their morphology and physiology. Until recently, however, little was known about how glandular skin maintains homeostasis and repairs itself after tissue injury. Here, we provide a brief overview of sweat gland biology, including newly identified reservoirs of stem cells in glandular skin and their activation in response to different types of injuries. Finally, we discuss how the genetics and biology of glandular skin has advanced our knowledge of human disorders associated with altered sweat gland activity.
PMID: 24492848
ISSN: 2157-1422
CID: 3131652

Novel evidence of androgen receptor immunoreactivity in skin tunnels of hidradenitis suppurativa: assessment of sex and individual variability [Letter]

Yu, W; Barrett, J; Liu, P; Parameswaran, A; Chiu, E S; Lu, C P
PMID: 34047363
ISSN: 1365-2133
CID: 5003622

Epidermal SIRT1 modulates mechanical allodynia in diabetic neuropathy [Meeting Abstract]

Ho, C -Y; Holler, J; Salimian, M; Remark, J; Kevas, Y; Lu, C; Chandrasekaran, K; Russell, J
Introduction: Diabetic neuropathy (DN) is a debilitating disorder characterized by sensory loss and pain. Although common, DN has no effective treatment. A notable pathologic finding of DN is loss of sensory apparatus in the skin, causing sensory abnormalities and pain. Given that diabetic patients frequently develop skin complications, we hypothesize that skin microenvironment is important for the pathogenesis of DN.
Method(s): Our investigation focused on a skin molecule epidermal sirtuin 1 (SIRT1), which is an NAD + -dependent deacetylase known to regulate metabolism and senescence. To address the role of epidermal SIRT1 in neuroprotection against DN, we created a tamoxifeninducible epidermal SIRT1 knockout (KO) and a doxycycline-inducible epidermal SIRT1 overexpression (OE) mouse model. The KO and control mice were placed on high-fat diets (HFDs), and were subsequently assessed by behavioral, morphologic and transcriptome analyses. SIRT1 overexpression was induced in mice after three months of HFDs.
Result(s): The DN phenotype was greatly exacerbated by depletion of epidermal SIRT1, as mice developed extreme mechanical allodynia after HFD. There was also evidence of large-fiber neuropathy, including loss of Meissner corpuscles, tail sensory nerve conduction defects and degeneration of large-diameter axons, while small nerve fibers and the corresponding nociception were largely intact. The phenotype could not be rescued by treatment with the NAD+ precursor nicotinamide riboside. In comparison, induction of epidermal SIRT1 overexpression alleviated the diabetic mechanical allodynia in mice. One potential mechanism of achieving epidermal SIRT1-mediated neuroprotection is increasing the expression of epidermal brainderived neurotrophic factor (BDNF), which could preserve the morphologic and functional integrity of Meissner corpuscles.
Conclusion(s): Our data suggest an important role of epidermal SIRT1 in maintaining skin sensory apparatus and preventing mechanical allodynia in the setting of diabetes. The findings also highlight epidermal SIRT1 as a promising therapeutic target for DN due to easy accessibility of SIRT1 in skin keratinocytes
ISSN: 1529-8027
CID: 5026232

565 Epidermal remodeling and immunogenicity within sinus tracts in hidradenitis suppurativa at the single-cell resolution [Meeting Abstract]

Lin, M; Marohn, M; Yu, W; Mendoza, C; Remark, J; Khodadadi-Jamayran, A; Chiu, E; Lu, C P
Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease affecting human apocrine sweat gland-bearing skin regions. The overall prevalence of HS ranges from 0.05-4.1% with higher occurrence among females and African Americans, and strong associations with smoking and obesity. One unique feature of HS is the development of highly immunogenic keratinized sinus tracts that grow deeply in the dermis which further complicate HS pathogenesis and treatment. Using single cell transcriptomic analyses, we finely dissected different epidermal cell types in the HS lesional skin and revealed significant dysregulation of skin barrier function in the sinus tracts. We demonstrated that sinus tract keratinocytes exhibit dual cell fates of surface epidermis and skin appendages, and derived from progenitors in infundibulum of the apocrine-pilosebaceous unit. By analyzing ligand-receptor expressions between different skin appendages and immune cells, we highlighted Th17 and TNF responses at early and late stages during HS progression, respectively. Our work provides unprecedented understanding of pathological epidermal remodeling in human inflammatory diseases and important implications for therapeutics.
ISSN: 1523-1747
CID: 4857682

030 Defining adaptive and innate immune cell profiles in Hidradenitis Suppurativa at the single cell resolution [Meeting Abstract]

Yu, W; Marohn, M; Lin, M; Barrett, J; Chiu, E; Lu, C P
Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease lacking effective therapeutic options due to little understanding of the complex immune response within the lesional skin. Using single-cell transcriptomic analyses, we examined the signature changes in each immune cell types during HS progression, as well as in silico ligand-receptor predictions between different immune cell types to construct the interaction network that contribute to HS pathogenesis. Our results revealed a predominant Th17 response, as well as a distinct regulatory T cells existing in the lesional skin. We found that M1-polarized macrophages likely facilitate chemotaxis and IL1B responses in perilesional skin, while regulate lymphocyte activation and tissue remodeling in the lesional skin. In addition, we identified a significant increase of CCR7 expressing dendritic cells, as well as activated stromal fibroblasts expressing CCR7-ligand CCL19, which together support the organization of tertiary lymphoid organ (TLO)-like aggregates that contribute to persistent local inflammation. Importantly, we demonstrated a dense infiltration of plasma cells near sinus tracts, and that clonal expansion of the plasma cells frequently exists in HS patients. Together, our work provides a comprehensive understanding of immune responses and cytokine networks defining disease chronicity in HS, as well as significant implications for future therapeutics.
ISSN: 1523-1747
CID: 4857672