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Peer-reviewedCC BYFrontiers in cell and developmental biology

Engrailed-1 in eccrine sweat gland development and regeneration: from evolutionary innovation to therapeutic perspectives.

  • Lei Zhang1
  • Zizhen Zhang2
  • Jiaqi Cheng3
  • Junhong Zhao4
  • Yanyi Xing5
  • Xiang Liu5
  • Lihong Peng3
  • Sixun Wu5
  • Haihong Li5
5 affiliations
  1. 1Department of Psychiatry and Clinical Psychology, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
  2. 2The First School of Clinical Medicine, Hubei University of Medicine, Shiyan, Hubei, China.
  3. 3Department of Burns and Plastic Surgery, The Second Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong, China.
  4. 4Department of Wound Repair and Dermatologic Surgery, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.
  5. 5Department of Burns and Plastic Surgery, Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China.
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Abstract

Functional regeneration of eccrine sweat glands (ESGs) remains a major unmet need in burns and trauma, where extensive skin loss leads to permanent anhidrosis, life-threatening hyperthermia, and impaired quality of life. Here we synthesize evidence pointing to the homeodomain transcription factor Engrailed-1 (EN1) as a central regulator that coordinates ESG development across four interconnected biological functions: (1) establishing a permissive ventral limb field by repressing the WNT7A-LMX1B dorsalization pathway; (2) executing a binary fate switch that suppresses the hair follicle program while activating a pro-glandular program; (3) functioning as a quantitative rheostat whose expression levels determine ESG density-a mechanism potentiated by primate-specific enhancers such as ECE18; and (4) being required for the establishment of a transient eccrine niche (EDEN) that provides mesenchymal support during gland morphogenesis in mouse models. Drawing on this framework, we propose a tiered pathogenesis-regeneration model (Tiers 1-4) mapping to distinct EN1 failures: Tier 1 (ventral field loss) points to bioengineered glabrous skin substitutes; Tier 2 (lineage specification failure) guides strategies to redirect progenitor fate; Tier 3 (aborted morphogenesis) highlights the need for EDEN-like niche reconstruction; and Tier 4 (compromised adult integrity) suggests approaches to reinforce the mechanical anchor of existing glands through EN1-mediated regulation of epidermal isoform of Bullous Pemphigoid Antigen 1 (BPAG1e), a proposed function inferred from in vitro evidence but untested in vivo. This multi-tiered model offers a conceptual framework for functional ESG restoration while addressing translational gaps between embryonic programs and adult tissue competency-a framework that remains speculative and requires rigorous validation in human tissues, as many mechanisms are supported primarily by mouse studies.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026engrailed1,
  title = {{Engrailed-1 in eccrine sweat gland development and regeneration: from evolutionary innovation to therapeutic perspectives.}},
  author = {Lei Zhang and Zizhen Zhang and Jiaqi Cheng and Junhong Zhao and Yanyi Xing and Xiang Liu and Lihong Peng and Sixun Wu and Haihong Li},
  journal = {Frontiers in cell and developmental biology},
  year = {2026},
  month = oct,
  doi = {10.3389/fcell.2026.1917336},
  url = {https://europepmc.org/article/MED/42903334},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Engrailed-1 in eccrine sweat gland development and regeneration: from evolutionary innovation to therapeutic perspectives.
AU  - Lei Zhang
AU  - Zizhen Zhang
AU  - Jiaqi Cheng
AU  - Junhong Zhao
AU  - Yanyi Xing
AU  - Xiang Liu
AU  - Lihong Peng
AU  - Sixun Wu
AU  - Haihong Li
PY  - 2026
DA  - 2026/10/01
JO  - Frontiers in cell and developmental biology
DO  - 10.3389/fcell.2026.1917336
UR  - https://europepmc.org/article/MED/42903334
AB  - Functional regeneration of eccrine sweat glands (ESGs) remains a major unmet need in burns and trauma, where extensive skin loss leads to permanent anhidrosis, life-threatening hyperthermia, and impaired quality of life. Here we synthesize evidence pointing to the homeodomain transcription factor Engrailed-1 (EN1) as a central regulator that coordinates ESG development across four interconnected biological functions: (1) establishing a permissive ventral limb field by repressing the WNT7A-LMX1B dorsalization pathway; (2) executing a binary fate switch that suppresses the hair follicle program while activating a pro-glandular program; (3) functioning as a quantitative rheostat whose expression levels determine ESG density-a mechanism potentiated by primate-specific enhancers such as ECE18; and (4) being required for the establishment of a transient eccrine niche (EDEN) that provides mesenchymal support during gland morphogenesis in mouse models. Drawing on this framework, we propose a tiered pathogenesis-regeneration model (Tiers 1-4) mapping to distinct EN1 failures: Tier 1 (ventral field loss) points to bioengineered glabrous skin substitutes; Tier 2 (lineage specification failure) guides strategies to redirect progenitor fate; Tier 3 (aborted morphogenesis) highlights the need for EDEN-like niche reconstruction; and Tier 4 (compromised adult integrity) suggests approaches to reinforce the mechanical anchor of existing glands through EN1-mediated regulation of epidermal isoform of Bullous Pemphigoid Antigen 1 (BPAG1e), a proposed function inferred from in vitro evidence but untested in vivo. This multi-tiered model offers a conceptual framework for functional ESG restoration while addressing translational gaps between embryonic programs and adult tissue competency-a framework that remains speculative and requires rigorous validation in human tissues, as many mechanisms are supported primarily by mouse studies.
SN  - 2296-634X
ER  -