Table 2.
Different roles of ECM, cells, and signaling molecules in fetal or adult wound healing
| Wound healing component | Contribution to fetal scarless healing | Contribution to scars in adults |
|---|---|---|
| ECM | ||
| Collagen | Higher expression levels of collagen III for longer and in a weave pattern (200, 201, 202, 248, 249, 250) | Collagen I is dominant (203) |
| Fibrin(ogen) | Forms porous clots made by aligned fibers (14, 40, 69) | Clot and early provisional matrix formation (31) |
| Fn | cFn with EDA, EDB domains is the predominant isoform (57, 58, 62, 311, 312) | Cellular forces can activate the integrin switch toward αvβ3 engagement (50, 53, 54, 55, 56) |
| Hyaluronan | Expressed in wound for up to 3 weeks (205) | Expression ends within 1 week (205). Can stimulate stress fiber formation (209) |
| SPARC | Sequesters PDGF isoforms (68) | Indirectly leads to hydrogen peroxide production by fibroblasts (74), contributes to fibroblasts resisting apoptosis (75, 76) |
| TNC | Expressed earlier and for longer ensuing wound (100, 101) | Implied in organ fibrosis (102); KO attenuates pulmonary and skin fibrosis (107) and suppresses proinflammatory macrophages (108, 109); and activates latent TGF-β1 (97) |
| Thrombospondin | TSP-1 promotes timely resolution of inflammation (82, 84); TSP-2 delays wound healing but contributes to formation of collagen fibrils (86, 87) | TSP-1 activates TGF-β latency-associated complex (78, 79); TSP-1 is highly expressed in hypertrophic scars (85); and TSP-4 is proinflammatory (88) |
| Vitronectin | Not essential for development (92, 93) | Clot formation and complement cascade (90, 91) |
| Cells | ||
| DCs | Subdued inflammation (144) | Necessary for remodeling (143) |
| Fibroblasts | αSMA is constitutively expressed (185); TGF-β isoforms are expressed at lower levels compared with adult fibroblasts (313); higher levels of p-SMAD intracellularly (166); TGF-β1 autoinduction loop is missing (184); altered prostaglandin E2 pathway (314) | Cofilin-1 and profilin-1 are upregulated compared with fetal fibroblasts (315); PDGFRα+ fibroblasts contribute to fibrotic remodeling (279); PDGFRβ+ fibroblasts' subpopulation emerges in fibrosis (278); express prolyl-4-hydroxylase (204); nitrosylation of caspase3 prevents apoptosis (270); emergence of αSMA+ and HAS1+ subpopulation in pulmonary fibrosis samples (281) |
| Macrophages | Tissue remodeling activation (17, 126); fetal macrophages resemble anti-inflammatory activation (127); macrophages expressing arginase compete with fibroblasts l-arginine (132, 133, 134, 135) | Proinflammatory activation (17, 126); sustain myofibroblast activation via cadherin-11 in fibrosis (138); can transition to myofibroblasts in fibrosis (139, 140, 141) |
| Mast cells | Less abundant and degranulate less in scarless wounds (117, 118) | Scar formation via IL-33 secretion (119) and response to HMGB1 (120) |
| Neutrophils | Neonatal NIF inhibits NET formation, controlling inflammation (149, 150) | Release superoxide, hydrogen peroxide, inflammatory cytokines, and proteases (147) |
| Signaling molecules | ||
| BMP | Profibrotic BMP-2 is expressed at lower levels and only in hair follicles (158, 159) | BMP-1 cleaves TSP-1 enhancing TGF-β release promoting myofibroblast activation (157) |
| HGF | Interferes with TGF-β1 signaling (283) | |
| TGF-β | Early upregulation of TGF-β3 isoform (168); exogenous TGF-β1 leads to scar even in fetal wounds (166); TGF-β3/TGF-β1 ratio is higher than in adult wounds (177, 178, 179, 180, 181); TGF-β1 is cleared by 18 h (186) | High levels of TGF-β1 and TGF-β2 isoforms (179); temporally limited upregulation of TGF-β3 (after a week) (167); scar stiffness inhibits LEMD3 antagonism of TGF-β (182) |
| Thy-1 | Fetal fibroblasts express Thy-1 (219); regulates engagement of αvβ3 and αvβ5 (212, 213) | Thy-1–negative fibroblasts localized in fibrotic lesions (204, 214) |
| Wnt | Wnt6 reduces epithelial-to-mesenchymal transition (198) | Responsible for epithelial-to-mesenchymal transition in keloid and dermal scars (189, 190, 191); Wnt3a increases proliferation and collagen I secretion in adult fibroblasts (197) |