Table 1.

Main growth factors involved in corneal epithelial healing.

Growth factors	Utilized pathway	Cellular target	Cellular effects	Corneal effects	Tear level	Serum level	References
EGF	EGFR/erbB1/HER1, erbB2/HER2/neu, erbB3/HER3, erbB4/HER4	Corneal epithelial cells (limbal region)	It increases epithelial migration and proliferation, inhibits corneal epithelial terminal differentiation, and upregulates activations of B4 integrins.	It stimulates epithelial wound closure accelerating the healing time.	2053 ± 312.4 pg/mL	199.74/±64.74 pg/mL	[16]
TGF-α	EGFR/erbB1/HER1, erbB2/HER2/neu, erbB3/HER3, erbB4/HER4	Corneal epithelial cells	It increases epithelial migration and proliferation and inhibits the expression of keratin K3.	It leads edge extension in epithelial sheet migration during eyelid closure.	84 ± 19 pg/mL	120 to 207 pg/mL	[16, 20, 21]
KGF	Ras-MAPK, PI3K/p70S6	Corneal epithelial cells	It increases epithelial cell proliferation protecting them from hypoxia.	It stimulates epithelial wound closure accelerating the healing time in the limbus zone.	Not provided	10.63 ± 4.98 pg/mL	[56]
HGF	c-Met, Ras-MAPK, PI3K/AKT, p70S6K, EGFR	Corneal epithelial cells, fibroblasts	It increases epithelial cell migration and motility and proliferation and inhibits apoptosis.	It stimulates epithelial wound closure.	200 pgmL−1	573.9 ± 142.8 pgmL−1	[18, 57]
IGF-1	PI3K/AKT	Corneal epithelial cells, fibroblasts	It increases epithelial cell proliferation, inhibits apoptosis, increases chemotaxis, and increases the expression of connexin 43 in corneal fibroblasts.	It stimulates epithelial wound closure improving gap-junctions.	Not provided	173.5 ng/mL	[6]
TGF β1/β2	TGF β-RI TGF β-RII	Corneal epithelial cells, fibroblasts (limbal and central region)	It inhibits epithelial cells proliferation, increases keratocyte proliferation, and promotes myofibroblast differentiation.	It promotes scar formations, delays reepithelialization, and inhibits angiogenesis.	10 ng/mL	50 ng/mL	[24]
PDGF	PDGF-R	Endothelial cell, fibroblasts, epithelial cells	It increases endothelial cell proliferation, enhances fibroblast migration, and increases chemotaxis of epithelial cells.	It stimulates epithelial wound closure.	95–1330 ng/L	1.70 ng/mL	[22]
FGF-2	FGF-R, heparan sulfate proteoglycans, RTKs	Corneal epithelial cells, fibroblasts (Bowman's and Descemet's membrane)	It increases epithelial, endothelial, and stromal cell proliferation.	It stimulates epithelial wound closure and improves gap-junctions.	Not provided	8.3 ± 1.75 pg/mL	[13]
NGF	TRKA-R	Corneal epithelial cells, endothelial cells, fibroblasts	It increases epithelial cell proliferation and differentiation.	It stimulates epithelial wound closure, improves nerve regrowth, and induces inflammation and vascularization.	8.3 +/− 4.7 ng/ml	18.5 +/− 6.1 ng/mL	[19, 62, 63]

EGF: epidermal growth factor; TGF-α: transforming growth factor α; KGF: keratinocyte growth factor; HGF: hepatocyte growth factor; IGF-1: insulin growth factor 1; TGFβ1/β2: transforming growth factor β1/β2; PDGF: platelet derived growth factor; FGF-2: fibroblastic growth factor 2; NGF: nerve growth factor.