Key Takeaways & Executive Findings
- •• • ANGPTL4 knockout in EpSCs reduces cyclin E2/A2/B1 and Cdk1 expression while increasing Cdkn2a and Cdkn2b, leading to cell cycle arrest; this identifies ANGPTL4 as a critical regulator of EpSC proliferation, with potential for targeted therapies to enhance epidermal regeneration in chronic wounds. • • PRL8a6 mediates ANGPTL4-induced EpSC proliferation by decreasing G1 phase population and increasing S and G2 phase populations, as shown by cell cycle analysis; this provides a specific molecular target for accelerating wound re-epithelialization, potentially reducing healing time in clinical settings. • • Knockdown of either Angptl4 or Prl8a6 in periwound tissues impairs EpSC proliferation and delays wound healing in vivo, with Prl8a6 mRNA levels positively correlated with Angptl4 mRNA during healing; this validates the ANGPTL4-PRL8a6 axis as a therapeutic pathway for wound repair. • • PRL8a6 is expressed in EpSCs and regulates proliferation under resting conditions and during wound re-epithelialization, representing the first report of its role in EpSCs; this opens new avenues for manipulating stem cell behavior in skin homeostasis and repair.
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Abstract
Angiopoietin-like 4 (ANGPTL4) is elevated in wound tissue and contributes to wound healing, but the mechanisms remain unclear. This study demonstrates that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during murine wound healing. Increased Angptl4 expression positively correlates with elevated levels of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1, each of which induces Angptl4 in EpSCs. RNA sequencing of EpSCs from wild-type and Angptl4 knockout (Angptl4–/–) mice reveals altered expression of cell cycle and proliferation genes, including decreased cyclin E2/A2/B1 and cyclin-dependent kinase 1 (Cdk1), increased Cdk inhibitor 2a (Cdkn2a) and Cdkn2b, and reduced prolactin (PRL) family members Prl2a1, Prl8a1, Prl8a9, and Prl8a6. Mechanistically, ANGPTL4 stimulates EpSC proliferation via PRL8a6-mediated upregulation of cyclins A2/E2/B1 and Cdk1, downregulation of Cdkn2a, and acceleration of G1 to S and G2 phase progression. In vivo, Prl8a6 mRNA is upregulated by ANGPTL4 in mouse periwound tissue during healing. Knockdown of Angptl4 or Prl8a6 impairs EpSC proliferation and delays re-epithelialization. These findings establish that after skin injury, proinflammatory cytokines and growth factors stimulate Angptl4 in EpSCs, and ANGPTL4 promotes EpSC proliferation by increasing Prl8a6, thereby accelerating wound re-epithelialization.
1. Introduction
Epidermal stem cells (EpSCs) are indispensable for skin homeostasis and wound repair. In the basal layer, EpSCs self-renew and differentiate into keratinocytes to maintain tissue integrity. After injury, EpSCs in periwound tissue proliferate, migrate to the wound site, and differentiate to regenerate the epidermis. Despite the clinical importance of efficient re-epithelialization, the endogenous regulatory mechanisms governing EpSC proliferation remain incompletely understood. Current therapeutic approaches for chronic wounds often fail due to insufficient EpSC activation, leading to delayed healing and increased infection risk. Thus, elucidating the molecular drivers of EpSC proliferation is critical for developing targeted interventions.
Angiopoietin-like 4 (ANGPTL4) is upregulated in wound tissue and contributes to healing, but its role in EpSC proliferation and the underlying mechanisms are unclear. This study addresses this gap by investigating ANGPTL4 expression in EpSCs during wound healing, identifying microenvironmental factors that induce Angptl4, and delineating the downstream signaling pathway involving prolactin family member PRL8a6. Using Angptl4 knockout mice and RNA sequencing, we demonstrate that ANGPTL4 promotes EpSC proliferation via PRL8a6-mediated cell cycle acceleration. These findings provide a mechanistic basis for targeting the ANGPTL4-PRL8a6 axis to enhance epidermal regeneration and improve wound healing outcomes.
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Siyuan Yu, Pengxiang Ji, Ting Du, Zuohua Liu, Yuan Yang, Zhenkun Lv, Lei Xu, Qianheng Jin, Weijuan Gong, Yingying Le, Yi Fu, Ruixing Hou (2025). Angptl4 is upregulated by microenvironmental factors during the wound healing process and promotes epidermal stem cell proliferation via PRL8a6. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025145
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Frequently Asked Questions
What is the specific mechanism by which ANGPTL4 promotes epidermal stem cell proliferation?
ANGPTL4 upregulates PRL8a6, which in turn increases cyclins A2/E2/B1 and Cdk1 while decreasing Cdkn2a, accelerating cell cycle progression from G1 to S and G2 phases. This was demonstrated by RNA sequencing of Angptl4–/– EpSCs showing decreased cyclin E2/A2/B1 and Cdk1, and increased Cdkn2a and Cdkn2b, and by functional studies where PRL8a6 mediated these effects.
How does knockdown of Angptl4 or Prl8a6 affect wound healing in vivo?
Knockdown of either Angptl4 or Prl8a6 in periwound tissues impairs EpSC proliferation, decreases epidermal regeneration, and delays wound healing. Prl8a6 mRNA levels are positively correlated with Angptl4 mRNA during healing, and Angptl4 knockdown significantly reduces Prl8a6 mRNA, confirming the in vivo relevance of the ANGPTL4-PRL8a6 axis.
What are the upstream factors that induce Angptl4 expression in epidermal stem cells?
Proinflammatory cytokines and growth factors including tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1 each induce Angptl4 expression in mouse EpSCs. Their increased levels in periwound tissue positively correlate with elevated Angptl4 during wound healing.
Is PRL8a6 expression specific to epidermal stem cells and what is its role under resting conditions?
PRL8a6 is expressed in EpSCs and regulates their proliferation under resting conditions. This is the first report of PRL8a6 in EpSCs. It mediates ANGPTL4-induced proliferation by modulating cell cycle regulators, decreasing G1 phase and increasing S and G2 phase populations, thereby maintaining EpSC homeostasis.
What are the potential clinical implications of targeting the ANGPTL4-PRL8a6 pathway for wound healing?
Targeting this pathway could enhance EpSC proliferation and accelerate re-epithelialization in chronic wounds. Since knockdown of Angptl4 or Prl8a6 delays healing, therapeutic strategies to upregulate ANGPTL4 or PRL8a6, or to mimic their downstream effects on cyclins and Cdkn2a, may improve wound closure. However, further studies are needed to assess safety and efficacy in human patients.
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