Searched for: person:lup03
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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.
PMCID:5333576
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.
PMCID:3423199
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.
PMCID:5510746
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 TÂ 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.
PMCID:5364946
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.
PMCID:3050560
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.
PMCID:3904096
PMID: 24492848
ISSN: 2157-1422
CID: 3131652
Response to Andersen et al.'s "A genome-wide association meta-analysis links hidradenitis suppurativa to common and rare sequence variants causing disruption of the Notch and Wnt/β-catenin signaling pathways." [Letter]
Perez, Olivia D; Lin, Meng-Ju; Pomeranz, Miriam K; Chiu, Ernest S; Lu, Catherine P; Petukhova, Lynn
PMID: 40334920
ISSN: 1097-6787
CID: 5839282
Decoding Tertiary Lymphoid Structures in Hidradenitis Suppurativa: New Mechanistic Insights
Yu, Wei-Wen; Tong, Jie; Lu, Catherine P
PMID: 40152835
ISSN: 1523-1747
CID: 5817512
Skin immune-mesenchymal interplay within tertiarylymphoid structures promotes autoimmunepathogenesis in hidradenitis suppurativa
Yu, Wei-Wen; Barrett, Joy N P; Tong, Jie; Lin, Meng-Ju; Marohn, Meaghan; Devlin, Joseph C; Herrera, Alberto; Remark, Juliana; Levine, Jamie; Liu, Pei-Kang; Fang, Victoria; Zellmer, Abigail M; Oldridge, Derek A; Wherry, E John; Lin, Jia-Ren; Chen, Jia-Yun; Sorger, Peter; Santagata, Sandro; Krueger, James G; Ruggles, Kelly V; Wang, Fei; Su, Chang; Koralov, Sergei B; Wang, Jun; Chiu, Ernest S; Lu, Catherine P
Hidradenitis suppurativa (HS) is a chronic, debilitating inflammatory skin disease characterized by keratinized epithelial tunnels that grow deeply into the dermis. Here, we examined the immune microenvironment within human HS lesions. Multi-omics profiling and multiplexed imaging identified tertiary lymphoid structures (TLSs) near HS tunnels. These TLSs were enriched with proliferative T cells, including follicular helper (Tfh), regulatory (Treg), and pathogenic T cells (IL17A+ and IFNG+), alongside extensive clonal expansion of plasma cells producing antibodies reactive to keratinocytes. HS fibroblasts express CXCL13 or CCL19 in response to immune cytokines. Using a microfluidic system to mimic TLS on a chip, we found that HS fibroblasts critically orchestrated lymphocyte aggregation via tumor necrosis factor alpha (TNF-α)-CXCL13 and TNF-α-CCL19 feedback loops with B and T cells, respectively; early TNF-α blockade suppressed aggregate initiation. Our findings provide insights into TLS formation in the skin, suggest therapeutic avenues for HS, and reveal mechanisms that may apply to other autoimmune settings, including Crohn's disease.
PMID: 39662091
ISSN: 1097-4180
CID: 5762712
Molecular Signature Associated With Acute Rejection in Vascularized Composite Allotransplantation
Cassidy, Michael F; Doudican, Nicole A; Frazzette, Nicholas; Rabbani, Piul S; Carucci, John A; Gelb, Bruce E; Rodriguez, Eduardo D; Lu, Catherine P; Ceradini, Daniel J
BACKGROUND/UNASSIGNED:A deeper understanding of acute rejection in vascularized composite allotransplantation is paramount for expanding its utility and longevity. There remains a need to develop more precise and accurate tools for diagnosis and prognosis of these allografts, as well as alternatives to traditional immunosuppressive regimens. METHODS/UNASSIGNED:Twenty-seven skin biopsies collected from 3 vascularized composite allotransplantation recipients, consisting of face and hand transplants, were evaluated by histology, immunohistochemistry staining, and gene expression profiling. RESULTS/UNASSIGNED:significantly predicted inflammation specific to vascularized composite allografts that required therapeutic intervention. CONCLUSIONS/UNASSIGNED:The mechanism of vascularized composite allograft-specific inflammation and rejection appears to be conserved across different patients and skin on different anatomical sites. A concise gene signature can be utilized to ascertain graft status along with a continuous scale, providing valuable diagnostic and prognostic information to supplement current gold standards of graft evaluation.
PMCID:11415116
PMID: 39310283
ISSN: 2373-8731
CID: 5802822