TABLE 1.

Similarities between hypertrophic and keloid scars

Parameter	Hypertrophic and keloid scar	References
In vivo	↑ High‐frequency conductance (skin surface hydration)	[18, 19]
	Persistent ↑ TEWL (SC barrier function)
	Faster SC turnover
Epidermis	↑ But inconsistently, ↑ μm (in all scars), ↑ cell layers	[28, 29],[42],[38, 79]
	Rete ridges ‐ (all scars)	[22, 26, 28, 38, 79]
	↓ Length cuboidal desmosomes	[42]
	Epidermal appendages ‐ (in all scars), displaced	[28, 29],[26, 29]
	↑ K2e	[20]
	↑ K1/K10, normal K10	[20],[79]
	Normal loricrin, filaggrin, SKALP, SPRR2	[79]
	Ki67 ↑, normal Ki67	[20],[38, 79]
	Normal Bcl‐2 +, c‐jun + expression, p53 −	[109]
	Diffuse ↑ TGF‐β1 (in 90%), ↑ S100A12	[110],[111]
Keratinocytes (in vitro)	Normal proliferation rates	[79]
Dermal cells	p53 −; normal Bcl‐2 +, c‐jun +, c‐fos +, Ki67 +; ↑ apoptosis	[109];[112]
	CD34 −, FXIIIa −, S‐100 − (in all scars); TGF‐β1 + (all scars)	[46] c ;[110]
	CD34−/α‐SMA+/p16 + population	[38] b
ECM	↑ Connective tissue; non‐fibrotic PD ‐ (in all scars)	[26, 28, 29];[45]
	Parallel collagen orientation	[30]
	Nodules +, nodules (48%‐50%)	[29, 32],[38, 41]
	Normal collagen synthesis	[21]
	Normal collagen content in μg/mg wet tissue (in all scars)	[113]
	↑ Collagen synthesis (sensitive to tranilast inhibition)	[21, 22, 23, 24]
	↑ Collagen I (in all scars)	[43]
	↑ Fibronectin; ↓ fibrillin‐1 (in all scars), ↓ elastin in superficial dermis	[25, 26, 27];[44]
	↑ Periostin; + hyaluronic acid in RD	[114];[115]
	Normal levels lysyl oxidase (cross‐linking enzyme)	[116]
	Normal active collagenase, no collagen degradation resistance	[117]
	Normal MMP‐9; normal MMP‐2 secretion, ↑ MMP‐2	[118];[113, 118, 119]
	↑ TIMP‐1, ↑ TIMP‐2	[119]
Cellular density	↑	[26, 28, 29]
	↑ ATP and protein levels, ↑ fibroblasts, ↓ fibrocytes	[120]
Vasculature	↓ Vessels, similar pattern of vascularization	[40]
	↑ Blood vessel density	[26, 28, 29]
	↑ Occluded microvessels	[31, 32]
	↑ Endothelin‐1; ↑ HIF‐1α (margin Kscar)	[121];[122]
Immune cells	Variable inflammatory infiltrate +	[41]
	Mast cells +	[123]
	CD68 −	[124]
	↑ FXIIIa + DCs in RD (in all scars)	[125]
	↑ HLA‐DR+/CD1a + DCs	[126]
Fibroblasts	↑ Vimentin	[38]
	↑ Apoptosis; ↑ caspase‐3, ↑ caspase‐9	[127];[128]
	PAR‐1 −, PAR‐2 −	[29]
	↑ DNMT in HsF (90%) and KF (100%)	[129]
Fibroblasts (in vitro)	Normal proliferation (MTT), normal apoptosis rates	[65]
	↑ Type I fibroblast (migratory, small spindle shaped)	[62] a
	↑ Collagen I and III, collagen processing genes	[37]
	↑ Cancer, cellular movement, cellular growth and proliferation, tissue development, connective tissue function, cell death genes
	↓ Cancer, reproductive system disease, tissue development, cell growth and proliferation, cell‐to‐cell signalling genes
	↑ Fibronectin, ↑ fibronectin (in all scars)	[36] a , c ,[25, 27] a
	↑ Transcriptional activity of α1(I) procollagen gene	[73] a
	↑ Collagen I, ↑ PAI‐2, ↓ MMP‐3	[75] a , c
	Fas +, Bcl‐2 +, Bax +; ceramide‐induced apoptosis +	[67, 68] a ;[68] a
	↑ DNMT1, ↑ TGF‐β1, ↓ Smad7; reversible by DNA methylation inhibition	[129]
	↓ Glucose consumption; COX‐1 +, COX‐2 −	[130];[131] a
	↑ Migration, CTGF, PAI‐1, TGF‐β1/2, collagen I, fibronectin, hydroxyproline	[33]
	+ TGF‐β1: ↓ MMP1, ↑ collagen I (similar to NF)	[43]
	+ Sucrose: ↓ collagen I, ↓ collagen I:III ratio	[132] a
	+ Tacrolimus: ↓ NME/NM23 NDK1, heterogenous NRP H3‐2H9	[133]
	+ miR‐188‐5p mimic transfection: ↑ proliferation	[134]
	+ BM‐MSC supernatant: ↓ proliferation, migration, CTGF, PAI‐1, TGF‐β1/2, collagen I, fibronectin, hydroxyproline; ↑ TGF‐β3, decorin	[33]
Fibroblasts (3D)	↑↑ Contraction in collagen gel with TGF‐β2, without TGF‐β2	[34],[35]
	Continued ↑ collagen I and III (normal expression in monolayers)	[135] c
Skin equivalents (in vitro)	↑ Contraction, (↑) dermal thickness, ↑ α‐SMA, ↑ p16, ↓ HAS1, ↓ MMP3	[39]
Myofibroblasts	Predominant cell type	[26, 136]
	↑ Cross‐linking in 3D collagen structure	[136]
	PAR‐1 +, PAR‐2 +; ↑ LH2b	[29];[136]
Nerve cells	Normal nerve fibre density in epidermis (α1‐AR/α‐SMA, α1‐AR/PGP9.5)	[137]
Explants (in vitro)	↓ MMP‐3, collagen fibres composed of thick bundles	[138]
	+ PDT: ↓ collagen I and III	[138]
Other	↑ TGFβRI/II, Smad2/3/4, p‐Smad 2	[139]
	↑ Collagen I and III, fibronectin, α‐SMA
	↑ COX‐1 in dermal cells	[140]
	↓ COX‐2, normal	[140],[141]
	↑ FGF‐2, LTBP‐2	[142]
	↑ SIP1	[43]
	CD34−/ proline‐4‐hydroxylase +, FVIII −, FXIIIa −	[124, 143]
	↑ mTOR	[144]
	↑ Bcl‐2 in basal keratinocytes & in dermis, p53 −	[109]
	Normal p63	[145]
	Mathematical modelling of NO in wound healing: ↑ vascularity, hypoxia, ↑ blood vessel occlusion	[146]

Similar abnormalities in hypertrophic and keloid scars, parameter expression listed as compared to control groups (normal skin and/or normal scar). Table contains all publications in which both mature hypertrophic and keloid scars are studied, and in this table shared abnormalities of hypertrophic and keloid scars are listed. Legend; + (located after parameter): present, normal expression or values; ↑: increased; −: absent; ↓: decreased; ≈: similar to normal skin and/or normal scar.

Abbreviations: ATP, adenosine triphosphate; Bcl‐2, B‐cell lymphoma 2; BM‐MSC, bone marrow‐derived mesenchymal stem cells; COX, cyclo‐oxygenase; DCs, dendritic cells; DNMT1, DNA methyltransferase 1 (catalyses DNA methylation); FGF‐2, (basic) fibroblast growth factor 2; FVIII, factor VIII; FXIIIa, factor XIIIa; HAS1, hyaluronan synthase 1 gene expression; heterogenous NRP H3‐2H9, heterogenous nuclear ribonucleoprotein H3‐2H9 (RNA binding protein, involved in epithelial‐mesenchymal interactions and post‐translational control of collagen I and III expression); HIF‐1α, hypoxia‐inducible factor 1 alpha; HLA, human leucocyte antigen; HsF, hypertrophic scar fibroblasts; IHC, immunohistochemistry; K, keratin; KF, keloid fibroblasts; LH2b, lysyl hydroxylase (collagen cross‐linking); LTBP‐2, latent‐transforming growth factor beta‐binding protein 2; MMP, matrix metalloproteinase; MMP3, matrix metalloproteinase 3 gene expression; mTOR, mammalian target of rapamycin; NF, normal skin fibroblasts; NME/NM23 NDK1, NME/NM23 nucleoside diphosphate kinase 1 (metastasis suppressor gene, involved in cell movement and adhesion); NO, nitric oxide; P4H, proline‐4‐hydroxylase (marker for active collagen synthesis); PAR, protease‐activated receptor; PDT, photodynamic therapy; PGP9.5, protein gene product 9.5 (neuronal marker); p‐Smad, phosphorylated Smad; RD, reticular dermis; SC, stratum corneum; SIP1, Smad interacting protein 1; TEWL, transepidermal water loss; TGF‐β, transforming growth factor beta; TIMP, tissue inhibitor of metalloproteinase. NB any additional information on parameters listed in abbreviations are all derived from cited literature in table; α1‐AR, alpha 1 adrenergic receptor; α‐SMA, alpha smooth muscle actin.

^aExplant fibroblast cell isolation; unless stated otherwise, fibroblasts were isolated via enzymatic digestion;

^bGradient differences between hypertrophic scars and keloids, see also Table 2;

^cResults based on n = 1.