Defining Endotypes in Hidradenitis Suppurativa to Improve Treatment

Using spatial transcriptomics to map distinct HS disease endotypes and identify targeted therapeutic strategies for this underserved inflammatory skin disease.
Completed Dermatologic Diseases Other Disease Subtyping Drug Repurposing Experimental Platforms & Models Health Disparities Human Cohorts Population & Patient-Centered Single Cell Technologies Spatial Biology Therapeutic Development Translational & Clinical

Funding Year: 2023

Project Overview

Hidradenitis suppurativa (HS) is a chronic, painful inflammatory skin disease affecting up to 1 in 25 people in the US, disproportionately impacting people of color, with varied symptoms and no universally effective treatments. This project investigates the transcriptional landscape of distinct HS endotypes using digital spatial profiling, hypothesizing that each endotype has unique disease drivers and therapeutic targets. Key findings include six transcriptionally distinct fibroblast populations, a gradient of hormonal activity across tissue conditions, and elevated expression of growth hormone and androgen receptors in pro-inflammatory fibroblast subsets — pointing to hormonal signaling as a potential trigger for dysregulated fibroblast activity and a new avenue for therapeutic targeting.

Impact & Innovation

Mapping HS at single-cell resolution to unlock targeted treatment.

 

By identifying six distinct fibroblast populations and uncovering hormonal signaling as a potential driver of pro-inflammatory activity, this project reframes HS as a heterogeneous disease requiring endotype-specific therapeutic strategies.

  • Reveals transcriptionally distinct fibroblast populations and hormonal signaling pathways as novel mechanistic drivers of HS, opening new targets for both novel and repurposed therapies
  • Supports treatment stratification by endotype, with plans to submit a development grant to advance translational therapy development based on these findings
  • Advances the Consortium’s Shared Mechanisms Across Autoimmune Diseases pillar by connecting fibroblast biology and hormonal dysregulation in HS to broader inflammatory and autoimmune disease mechanisms
Research Approach

A framework designed for discovery

This project applies digital spatial profiling and single-cell transcriptomics to map the transcriptional landscape of distinct HS endotypes, identify disease-driving cell populations and signaling pathways, and pinpoint potential therapeutic targets. The work integrates spatial and cellular resolution to move from endotype characterization toward translational therapy development.

Digital spatial profiling (DSP) using a spatial transcriptomics platform to characterize transcriptional differences between HS endotypes; single-cell and spatial analysis of fibroblast populations, pericytes, endothelial cells, and epithelial cell types; trajectory analysis of fibroblast lineage relationships; and in vitro interrogation of hormone receptor pathway activation and inhibition using patient-derived keratinocytes, fibroblasts, and skin explants.

Lesional and normal skin tissue from HS patients profiled by DSP, single-cell transcriptomic datasets identifying six fibroblast populations and hormone receptor expression gradients across tissue conditions, and in vitro patient-derived cell and tissue models for functional pathway validation.

Identification of transcriptional endotypes, pro-inflammatory fibroblast populations, and hormonal signaling pathways as therapeutic targets in HS, with a translational goal of endotype-based treatment stratification and a planned development grant submission to advance identified therapies toward clinical application.

Investigators & Institutions

Powering the science

Principal Investigator

Anna Eisenstein, MD, PhD, Colton Consortium Member

Assistant Professor, Department of Dermatology, Yale School of Medicine, Yale University

Colton Centers & Institutions

Colton Center for Autoimmunity at Yale University

Research Outputs

From insight to impact

Publications

EGFR-STAT1 pathway drives fibrosis initiation in fibroinflammatory skin diseases

Nature Communications
Odell, AV; Newton, NM; Eisenstein, A; Micevic, G; Flavell, RA; Odell, ID October 2025
Animal ModelsBioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeDisease SubtypingExperimental Platforms & ModelsHuman CohortsMulti-omics IntegrationSingle Cell TechnologiesTherapeutic DevelopmentTranslational & ClinicalDermatologic DiseasesOtherSclerodermaSystemic DiseasesSystemic Sclerosis (Scleroderma)Yale University

LB1037 single-cell and spatial transcriptomics reveal elevated pro-inflammatory fibroblasts and hormonal activity in hidradenitis suppurativa

Journal of Investigative Dermatology
Suresh, A; Hsia, H; Eisenstein, A August 2025
BioinformaticsBiological & MechanisticCytokine SignalingData-Driven & QuantitativeExperimental Platforms & ModelsImmune ProfilingInnate ImmunityMulti-omics IntegrationSingle Cell TechnologiesSpatial BiologyDermatologic DiseasesOtherYale University

Skin damage signals mediate allergic sensitization to spatially unlinked antigen

Science Immunology
Waizman, DA; Brown-Soler, I; Martin, AL; Ma, Y; Zhou, K; Israni-Winger, K; Zhang, C; Medzhitov, R; Launay, P; Michieletto, MF; Henao-Mejia, J; Palm, NW; Craft, J; Eisenstein, A; Wang, A April 2025
Adaptive ImmunityAnimal ModelsBiological & MechanisticCytokine SignalingExperimental Platforms & ModelsImmune ProfilingInnate ImmunityNeuro-Immune InteractionsAllergic & Atopic DiseasesDermatologic DiseasesYale University

Additional Outputs

Suresh A, Hsia H, Odell I, Eisenstein A. Single-cell and spatial transcriptomics reveal elevated pro-inflammatory fibroblasts and hormonal activity in hidradenitis suppurativa. 

  • HS Foundation Danby Grant: $20,000 (Anna Eisenstein, 1 year).
  • Poster presented at the Society for Investigative Dermatology meeting, San Diego, CA, May 2025; abstract to appear in the Journal of Investigative Dermatology.