Table 1.
In vitro and ex vivo studies on the effect of human keratinocytes on dermal fibroblasts.
| Ref | Type of cells or samples | Type of stimuli | Identified mediators | Experimental outcome |
|---|---|---|---|---|
| Dufour et al. (13) | NEK, HDF, SScF; K-CM; HD full skin explant |
TGF-β, IL-17A | IL-1; TGF-β | Keratinocytes enhance IL-6, IL-8, and MCP-1, production by HDF and SScF. Keratinocytes enhance ECM turnover by enhancing MMP-1 and decreasing col-I. IL-17A increases these effects TGF-β reduces these effects |
| Fernando et al. (14) | HaCaT, HDF; HaCaT-CM |
Particulate matter (PM) fucosterol |
Increase of inflammatory responses (TNFα, IL-1β, IL-6, MMP1, MMP2, elastase, PGE2) in fibroblasts treated with media from HaCaT exposed to CPM. Fucosterol reduced these effects | |
| Zhao et al. (15) | HaCaT; HDF; EE Transwell coculture Hypertrophic scar biopsies |
Dehydration | HaCaT dehydration increases col-I and αSMA expression by HDF. HMGB1 KO in HaCaT decreases HDF activation induced by dehydration. Cytoplasm accumulation of HMGB1 in hypertophic scar |
|
| McCoy et al. (16) | SScK, NEK; HDF; K-CM |
Not-TGF-β | SScK more than NEK enhance col-I and αSMA expression by HDF Microarray data on differences between SScK and NEK |
|
| Carr et al. (17) | NEK, HDF, HaCaT Transwell coculture K-CM |
Differentiated and undifferentiated NEK | IL-1 | NEK enhances G-CSF production by HDF Undifferentiated NEK have stronger effect than differentiated NEK |
| Brembilla et al. (18) | NEK, HDF, SScF K-CM |
IL-22, TNFα | NEK and SScK promote HDF production of MMP-1, MCP-1, and IL-8. IL22 + TNFα enhances this effect |
|
| Zhong et al. (19) | HaCaT, foreskin K, foreskin F; Differentiated-K Transwell coculture Epidermal explant HD, keloids, hypertrophic scars biopsies |
Low humidity/reduced hydration | S100A8/A9 | S100A8/A9 is more expressed in epidermis from keloids and hypertrophic scars than HD HaCaT dehydration increases col-I and αSMA expression by HDF. Effect mediated by epidermal S100A8/A9, which expression is induced by reduced hydration |
| Huang et al. (20) | HaCaT, foreskin K, HDF Keratinocyte-derived microvesicles (K-MV) |
Keratinocyte-derived microvesicles (K-MV) | K-MV enhance in HDF the expression of TGF-β-induced genes and of MMP-1, MMP-3, THBS1, IL-6, lumican; enhance HDF migration and matrix contraction, enhance HDF-dependent angiogenesis Decrease in HDF the expression of cadherin-2 |
|
| Gauglitz et al. (21) | HDF keloid and normal skin biopsies 2D-culture |
S100A7 S100A15 |
Compared to healthy skin reduced expression of S100A7 and S100A15 in keloids epidermis with reciprocal expression of COL1A1, COL1A2, COL3A1. S100A7 and S100A15 on HDF decrease COL1A1, COL1A2 and COL3A1, TGF-β1, TGF-β2, TGF-β3, laminin-β2 and α-SMA and HDF proliferation |
|
| Xu et al. (22) | HaCaT, foreskin k, foreskin F; Differentiated-K Transwell coculture Epidermal explants |
Reduced hydration | ENaC, COX2, PGE2 | HaCaT dehydration increases col-I and αSMA expression by HDF. Effects mediated by ENaC, COX2, PGE2 |
| Arai et al. (23) | Foreskin-K, foreskin-F; EE DE (decellularized dermis) Skin equivalent EE-CM |
IL-1α, IL-1β |
PGE2 detected only in skin equivalent. PGE2 expressed by DD enhances keratinocytes proliferation EE-CM increases COX2, IL-6, and GM-CSF and decrease KGF expression in HDF |
|
| Nikitorowicz-Buniak et al. (24) | HD and SSc skin, HDF, SScF; HD, SSc epidermal and dermal explants; HD, SSc epidermal explant CM |
S100A9 | S100A9 | Increase of CCN2, S100A9, HGF in SSc epidermis compared to dermis and HD epidermis; S100A9 enhances HDF and SScF proliferation, migration, and CTGF production |
| Li et al. (25) | HaCaT, HDF HaCaT-CM |
Fibronectin | HaCaT–CM enhances HDF migration | |
| Varkey et al. (26) | NEK; HDF EE DD (superficial (S)/or deep(D) HDF embedded in a GAG matrix) Skin equivalent |
In organotypic cultures, the levels of col-I and fibronectin were lower and levels of TGFα, PDGF, IL-1 higher compared to embedded HDF only D-HDF produced higher levels of col-I higher levels of TGF-β activity and IL-6 compared to S-HDF S-HDF produced higher MMP-1 levels |
||
| Sun et al. (27) | HaCaT, fibroblast cell line CCD966SK 2D-culture |
KGF, IL-19 | IL-19 induces KGF expression in CCD966SK fibroblasts KGF enhances the production of IL-19 in HaCaT and promotes higher proliferation and migration |
|
| Canady et al. (28) | NEK, HDF, SScF, keloid fibroblasts, HD skin skin explant |
KGF, OSM | KGF is increased in keloid and SSc fibroblasts and sera KGF induces keratinocytes to release OSM leading to fibroblast activation KGF increases the production of OSM, (fibroblast activator protein) FAP, col-I in cultured skin explants |
|
| Kolar et al. (29) | HaCaT, NEK, HDF EE; DE (collagen embedded HDF) Skin equivalent |
IL-6, IL-8, CXCL-1 | NEK-organotypic cultures enhance the expression of FGF-7, FGF-5, FGF-2, CXCL-1, IL-6, IL-8 in HDF | |
| Rock et al. (30) | Female NEK and HDF K-CM |
E2; E2 and UVB | E2 and E2 + UVB increase the production of EGF in NEK Conditioned medium from E2 and E2 + UVB-exposed KCM enhances hyaluronan synthase 3 and versican V2 and proliferation of HDF |
|
| Simon et al. (31) | K-from hypertrophic scars, NEK, HDF, hypertrophic scar F EE or EE-CM DE (F in a dermal matrix) Skin equivalent |
TIMP-1 | Compared to NEK, K from hypertrophic scars increase dermal matrix thickness, by enhanced production of TIMP-1 | |
| Do et al. (32) | Keloids-K, Keloid-F, NEK, HD Transwell coculture |
IL-18 | K form keloids more than NEK produce IL-18, fibroblasts from keloids and HDF enhance IL-18 production by keratinocytes IL-18 enhances col-I, IL-6, IL-8 production by HDF |
|
| Lai et al. (33) | NEK, HDF K-CM |
Stratifin | Conditioned medium from NEK enhances the production by HDF of MMP-1, MMP-3, MMP-12, versican, TN-C, ITGA1, CTNNA1, FN NEK induce the upregulation of aminopeptidase N/CD13 in HDF as consequence of stratifin production |
|
| Tandara and Mustoe (34) | NEK; HDF Transwell coculture K-CM |
K-CM enhance the production of MMP-1, MMP-8, MMP-13, MMP-2, MMP-10, TIMP-1, and TIMP-2 by HDF. NEK-hydration further increases the upregulation of MMPs and decreases TIMP-2 |
||
| Koskela et al. (35) | NEK, HDF, EE DE (HDF embedded in collagen) Skin equivalent |
TGF-β | Compared to HDF alone, organotypic cocultures increase MMP-1, MMP-3, uPA and decrease CTGF, col I, col III, FN, TIMP-2, αSMA, PAI, in the presence or absence of TGF-β | |
| Aden et al. (36) | SSc and HD skin biopsies, HDF, SScF, SSc or HD epidermis explant DE (HDF embedded on collagen) Skin equivalent |
IL-1, TGF-β, ET-1 | Altered keratinocyte differentiation in SSc biopsies Compared to HD, SSc epidermal explants produce more IL-α resulting in enhanced gel contraction SSc and HD explants have similar levels of ET-1 or TGFβ. ET-1 and TGFβ have a role in CTGF production by HDF |
|
| Lim et al. (37) | Keloids-K, keloids-F, NEK, HDF. Monolayer, Transwell coculture |
IL-6, IL-8, MCP1, TIMP-1, TIMP-2 detected in monocultures Angiogenin, OSM, VEGF, IGF-binding protein-1, OPG, and TGF-β2 detected in keloids-K-keloids-F, but absent in NEK–HDF cocultures |
||
| Chavez-Munoz et al. (38) | Differentiated and undifferentiated foreskin K, HDF K-Exosomes |
14-3-3 (stratifin) | Exososomes generated from differentiated more than undifferentiated foreskin K enhance MMP-1 production by HDF. This effect is mediated by stratifin | |
| Ghaffari et al. (39) | NEK, HDF Transwell coculture |
keratinocyte-derived collagen-inhibitory factor of 30–50 kD (KD-CIF) | Keratinocyte-released factors reduce col-I production by HDF by KD-CIF Keratinocyte differentiation do not alter synthesis, release, or activity of KD-CIF |
|
| Wall et al. (40) | NEK, HDF DE (HDF) embedded in collagen gel Skin equivalent |
In comparison to HDF cultured in monolayers, the production of MMP2, MMP9, uPA, uPAR is increased in organotypic cocultures, with no significant changes in contractile responses | ||
| Tandara et al. (41) | NEK, HDF Transwell coculture |
Compared to HDF cultured in monolayers, col-I production is decreased, and KGF production increased in Transwell cultures, more so in hydrated cultures. Compared to NEK cultured in monolayers, TNF production is increased and IL-1 is decreased in Transwell cultures |
||
| Amjad et al. (42) | NEK, HDF, K-CM DE (HDF collagen embedded) Skin equivalent |
NEK decrease TGFβ1 the production by HDF | ||
| Harrison et al. (43) | NEK, HDF Coculture |
NEK conditioned medium and NEK coculture inhibit spontaneously, and IGF, bFGF-stimulated col-I production by HDF, TNF reduce this inhibition |
||
| Ghaffari et al. (44) | NEK, HDF Transwell coculture |
Stratifin | Stratifin is produced only by NEK Stratifin and NEK-conditioned medium enhance MMPs, adhesion molecules, PAI1. PAI2, THSP1, FN (and other detected by microarray) by HDF |
|
| Harrison et al. (45) | NEK, HDF HD epidermal explants Coculture K-CM |
Both NEK-conditioned medium and HD epidermal explants decrease HDF proliferation HD epidermal explants but not NEK-conditioned medium enhance FN production by HDF |
||
| Chinnathambi and Bickenbach (46) | NEK and HDF EE; DE (HDF collagen embedded) skin equivalent |
Compared to HDF cultured in monolayers, the production of MMP1 is increased and MMP-2 is decreased in organotypic cocultures | ||
| Ghahary et al. (47) | NEK, HDF Transwell coculture |
Stratifin | Compared to HDF cultured in monolayer, MMP1 is increased Stratifin induces MMP-1 Stratifin expression is higher in differentiated NEK |
|
| Sawicki et al. (48) | K-foreskin, HDF Transwell coculture |
Compared to NEK cultured alone, HDF enhance the production of MMP-9 and MMP-2 by K. HDF cocultured with K produce MMP-9 TIMP-1, TIMP-2, and TIMP-3, but not, TIMP-4 levels are enhanced both in K and HDF when in coculture |
||
| Shephard et al. (49) |
HaCaT, irradiated HDF Coculture |
Compared to HDF cultured in monolayer, the contractile activity and αSMA expression is increased in coculture ET-1 enhances contraction and TGF-β enhances αSMA expression in cocultures |
||
| Shephard et al. (50) | HaCaT, NEK, irradiated and not irradiated HDF Coculture |
Compared to HDF cultured alone, HDF in cocultures with HaCaT and NEK expresses more—ENA-78, and MCP-1, IL-6, LIF, G-CSF, M-CSF, COX2, PAI, and less Cathepsin K, Cathepsin L, Cathepsin L2
More col-I, col-IV, col-V, col-VI, hyaluran synthtease, lysine hydroxylase, transglutaminase 2, TN-C, decorin, syndecan 2, but less testican, tenascin XA, fibulin, thrombospondin a SMA expression requires close proximity to keratinocytes |
||
| Ghahary et al. (51) | NEK, HDF, DE (HDF collagen embedded) Transwell coculture |
Stratifin | Compared to HDF cultured alone, HDF in cocultures produce more MMP1 and enhance col-I digestion | |
| Satish et al. (52) |
K-foreskin, Hs68 Transwell coculture |
CXCL11 | CXCL11 (IP9) is induced by mechanical wounding in K CXCL11 reduces EGF-induced fibroblast motility and enhance EGF-induced keratinocytes motility |
|
| Funayama et al. (53) | NEK, keloid-K, HDF, keloid-F; Transwell coculture | Compared to NEK, keloid-K enhanced keloid-F proliferation, resistance to apoptosis (upregulation of Bcl-2) and TGF-β1 expression | ||
| Phan et al. (54) | Keloids-K, keloids-F, NEK, HDF. Transwell coculture |
IGFBP-3 | Compared to monocultures, HDF and keloid-F showed higher proliferation when cocultured with keloid-K. IGFBP-3 inhibition reduced keloid-F proliferation | |
| Gron et al. (55) | NEK, HDF Coculture where NEK were grown on polycarbonate membrane coated with col-IV and added to HDF monolayers |
Compared to HDF cultured alone, HDF in cocultures produce more HGF and KGF No difference in HDF proliferation |
||
| Lim et al. (56) | Keloids-K, keloids-F, NEK, HDF. Transwell coculture |
HDF cocultured with keloid-K increased soluble col-I and col-III. Keloid-F cocultured with keloid-K increased both soluble and insoluble collagen |
||
| Lim et al. (57) |
Keloids-K, keloids-F, HDF. Transwell coculture |
Keloid-k induce proliferation HDF more than NEK | ||
| Niessen et al. (58) | Biopsies of normal and hypertrophic scars after breast surgery | High IL-1α expression at month 3 predicts normal scar, no relationship between IL-1β and TNF expression. High levels of PDGF and bFGF at 12 months correlate with hypertrophic scar | ||
| Maas-Szabowski et al. (59) | NEK, irradiated HDF, DE Coculture |
Compared to HDF cultured alone, HDF in coculture expresses more KGF, IL-1α, IL-1β but less IL-8, TGF-β Compared to NEK cultured alone, NEK in col culture express more IL-1α, IL-8, bFGF, GM-CSF |
||
| Zhang et al. (60) | Skin explant culture Coculture (NEK seeded onto stratified HDF embedded on sterile nylon membrane) |
Compared to HDF cultured alone, HDF have enhanced expression of epimorphin particularly beneath the keratinocyte layer | ||
| Garner (61) | NEK, HDF, Coculture |
Compared to HDF cultured alone, col-I is decreased in cocultures | ||
| Ralston et al. (62) | NEK, DE Coculture |
Coculture enhances matrix contraction and FN | ||
| Sato et al. (63) | NEK, HDF, DE Coculture |
IL-1α | Compared to HDF cultured alone, PGE2 production is increased in cocultures via enhanced expression of COX-2 induced by IL-1α | |
| Boxman et al. (64) | NEK, HDF K-CM |
Compared to HDF cultured alone, IL-6, IL-8, production is higher and IL-1 lower in HDF exposed to NEK-conditioned medium | ||
| Chang et al. (65) | NEK, HDF, Transwell coculture |
Compared to HDF cultured alone, col-I and GAG production is reduced in cocultures more so if NEK is hydrated | ||
| Lacroix et al. (66) | NEK, HDF, DE Coculture |
Compared to HDF cultured alone, col-I and FN production is increased in coculture | ||
| Boxman et al. (67) | K-foreskin, HDF Coculture CM |
IL-1α | Compared to HDF cultured alone, IL-1α production is increased in cocultures and K-foreskin conditioned medium | |
| Waelti et al. (68) | NEK, irradiated HDF Coculture |
IL-1β | Compared to HDF cultured alone, IL-6 production is increased in cocultures and NEK conditioned medium, effect mediated by IL-1β |
The references are reported in inverse chronological order. αSMA, alpha-smooth muscle actin; bFGF, basic fibroblast growth factor; CCD966SK, fibroblast cell line; CCL, chemokine (C-C containing) motif; CCR, receptor; for CCL chemokines; CM, conditioned medium; Col, collagen; COX2, Cyclooxygenase 2; CTGF, connective tissue growth factor; CTNNA1, Catenin Alpha 1; CXCL, chemokine (C-X-C containing)motif ligand; DE, dermis equivalent; Differentiated-K, Differentiated keratinocytes; E2, estrogen; EE, epidermal equivalent; EGF, epidermal growth factor; ENaC, Epithelial sodium channel; ENA-78, Epithelial neutrophil-activating protein 78; ET-1, endothelin-1; FAP, fibroblast activation protein; FGF, fibroblast growth factor; FN, fibronectin; Foreskin K, newborn foreskin keratinocytes; G-CSF, granulocyte colony stimulating factor; GM-CSF, granulocyte-monocyte colony stimulating factor; HaCaT, human keratinocytes immortalized cell line; HD, healthy donor; HDF, healthy donor fibroblasts; HMGB1, high mobility group box-1; Hs68, foreskin fibroblasts cell line; IGF, insulin-like growth factor; IGFBP, insulin-like growth factor binding protein; IL, interleukin; ITGA1, alpha 1 subunit of integrin receptors; K-CM, keratinocytes conditioned medium; Keloids-F, keloids fibroblasts; Keloids-K, keloids keratinocytes; KGF, keratinocyte growth factor; K-MV, Keratinocyte-derived microvesicles; LIF, leukemia inhibitory factor; MCP-1, monocyte chemotactic protein-1; M-CSF, monocyte colony stimulating factor; MMP, metalloproteinase; NEK, healthy donor keratinocytes; OPG, osteoprotegerin; OSM, oncostatin M; PAI, plasminogen activator inhibitor; PDGF, platelet-derived growth factor; PGE2, Prostaglandin E2; S100A7, psoriasin; S100A8/A9, calprotectin; S100A15, koebnerisin; SSc, Systemic sclerosis; SSc-F, SSc fibroblasts; SSc-K, SSc keratinocytes; TGF, Transforming growth factor; THBS1, Thrombospondin 1; TN-C, tenascin C; TNFα, Tumor necrosis factor α; uPA, urokinase-type plasminogen activator; UVB, ultraviolet B radiation.