Role of Periostin in Skin Wound Healing and Pathologic Scar Formation
The skin serves as the primary protective barrier against external injury. While it possesses remarkable regenerative capabilities, the process of wound healing can sometimes result in pathologic scars such as hypertrophic scars and keloids. These scars not only cause physical discomfort but also impose psychological and economic burdens. Periostin, an extracellular matrix (ECM) protein, has emerged as a critical regulator in both physiologic wound healing and pathologic scar formation. This article explores the multifaceted roles of periostin in skin repair and scarring, emphasizing its molecular mechanisms, experimental findings, and therapeutic potential.
Periostin in Normal Skin Wound Healing
Skin wound healing is a dynamic, multistage process involving inflammation, proliferation, and remodeling. Immediately after injury, cytokines, chemokines, and matricellular proteins are secreted in a spatiotemporally regulated manner to recruit repair cells such as macrophages, fibroblasts, and keratinocytes. These cells form granulation tissue, contract the wound, and restore the epithelial barrier. Periostin, a matricellular protein, is upregulated post-injury and peaks around day 7 in murine models. Its expression is closely associated with fibroblasts and is regulated by transforming growth factor-beta 1 (TGF-β1), a cytokine central to wound repair.
Experimental studies using periostin-knockout mice reveal its indispensable role in wound closure. Full-thickness skin wounds in periostin-deficient mice are significantly larger at days 5 and 7 compared to wild-type mice, with reduced α-smooth muscle actin (α-SMA) expression, a marker of myofibroblast differentiation. Myofibroblasts are critical for wound contraction, and their impaired differentiation in the absence of periostin delays healing. Furthermore, periostin knockout mice exhibit prolonged re-epithelialization intervals, highlighting its role in keratinocyte proliferation. Periostin achieves this by cooperating with interleukin-1 alpha (IL-1α) to induce IL-6 production in fibroblasts, activating the nuclear factor kappa beta (NF-κB) pathway. IL-6 then stimulates keratinocyte proliferation, accelerating epithelial regeneration.
Beyond endogenous roles, therapeutic strategies leveraging periostin have shown promise. In diabetic mice, scaffolds containing periostin and connective tissue growth factor (CCN2) enhance wound healing by suppressing persistent neutrophil infiltration, increasing collagen density, and promoting revascularization. Similarly, adipose-derived stem cells (ADSCs) engineered to overexpress periostin exhibit superior survival under hypoxia and enhance paracrine signaling, further accelerating tissue repair.
The Dual Role of Periostin: Timing Matters
While periostin is essential for normal wound healing, its overexpression or dysregulated spatiotemporal expression can disrupt repair. Constitutively overexpressing periostin in transgenic mice paradoxically delays wound closure, underscoring the importance of tightly regulated periostin levels during distinct healing phases. This phenomenon suggests that therapeutic interventions must replicate the natural temporal dynamics of periostin expression rather than simply augmenting its levels.
Periostin in Pathologic Scar Formation
Pathologic scars arise from excessive fibroblast activation, leading to uncontrolled ECM deposition, myofibroblast persistence, and tissue fibrosis. Periostin is markedly overexpressed in hypertrophic scars and keloids compared to normal skin. Screening of subtractive hybridization libraries identified periostin as a gene upregulated in pathologic scars, with expression levels escalating from normal skin to hypertrophic scars to keloids. Hydrocortisone, a scar-inhibiting agent, reduces periostin mRNA in keloid fibroblasts (KFs) by 32% and in hypertrophic scar fibroblasts by 47%, correlating with diminished fibroblast proliferation and ECM secretion.
Mechanisms Driving Scar Pathogenesis
Periostin promotes pathologic scarring through multiple signaling pathways:
- Integrin-αvβ3–PI3K/Akt Pathway: Periostin binds to integrin receptors on KFs, activating phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling. This cascade enhances fibroblast proliferation, collagen synthesis, migration, and invasion. Knockdown of periostin in KFs under hypoxic conditions (2% O₂) reduces these effects, while exogenous periostin restores them.
- RhoA/ROCK Pathway: Periostin interacts with interleukin-4 (IL-4) and IL-13 to create a “vicious cycle” in scar formation. These cytokines upregulate periostin secretion, which in turn activates RhoA/ROCK signaling to stimulate TGF-β1 production. TGF-β1 further amplifies periostin expression, perpetuating fibrosis. Inhibiting RhoA/ROCK disrupts this loop, suggesting a therapeutic target.
- Angiogenesis: Periostin enhances scar resilience under hypoxia by promoting angiogenesis. Conditioned medium from KFs stimulates human umbilical vein endothelial cells (HUVECs) to migrate and form tubules via ERK1/2 and focal adhesion kinase (FAK) pathways. Periostin also upregulates angiogenic factors like vascular endothelial growth factor (VEGF) and angiopoietin-1 in KFs, ensuring nutrient supply to expanding scar tissue.
Therapeutic Implications and Challenges
Targeting periostin offers a dual therapeutic avenue: enhancing its expression to treat chronic wounds and suppressing it to mitigate scarring. For chronic wounds, ADSCs modified to secrete periostin or biocompatible scaffolds releasing periostin and CCN2 have shown efficacy in preclinical models. Conversely, hydrocortisone and RhoA/ROCK inhibitors may attenuate periostin-driven fibrosis in scars.
However, challenges remain. The biphasic role of periostin necessitates precise control over its expression kinetics. Constitutive overexpression disrupts healing, while incomplete suppression may fail to prevent scarring. Additionally, periostin’s interactions with diverse pathways (e.g., TGF-β1, IL-6, angiogenesis) complicate targeted interventions. Further research is needed to elucidate spatiotemporal expression patterns and optimize delivery systems for clinical use.
Future Directions
- Mechanistic Studies: Detailed investigations into how periostin regulates cross-talk between fibroblasts, immune cells, and endothelial cells will clarify its role in tissue remodeling.
- Advanced Models: Humanized mouse models or 3D scar-on-a-chip systems could better replicate human pathophysiology and test therapeutics.
- Clinical Trials: Translational studies evaluating periostin-modulating agents (e.g., monoclonal antibodies, gene therapy) are essential to validate preclinical findings.
In conclusion, periostin is a pivotal mediator of skin repair and fibrosis, with its effects hinging on context-specific expression. Harnessing its regenerative potential while curbing its fibrotic actions holds promise for improving outcomes in wound healing and scar management.
doi.org/10.1097/CM9.0000000000000949
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