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conjunctival epithelium into the lacrimal gland epithelium bud (Grindley et al.
1995 ; Hill et al. 1992 ). The temporal periorbital mesenchyme around the Pax6-
expressing epithelium expresses fibroblast growth factor 10 (Fgf10), which plays an
essential role in the induction of the lacrimal glands and the harderian glands
(Makarenkova et al. 2000 ; De Moerlooze et al. 2000 ; Finch et al. 1989 ; Lu et al.
1999 ; Govindarajan et al. 2000 ; Ahrens and Schlosser 2005 ). The signaling of Fgf10
involves the regulation of branching morphogenesis, including the formation of aci-
nar lobes, by activation of Sox9-Sox10 pathways through Fgfr2 (Chen et al. 2014 ).
Heparan sulfate, a sulfated glycosaminoglycan on cell surface, interacts with Fgf10-
Fgfr2 signaling pathway to regulate the development of the lacrimal gland branch-
ing (Qu et al. 2011 ; Patel et al. 2007 , 2008 ; Izvolsky et al. 2003 ). Fgfs also control
Six1 expression, which involves the induction of the ocular placode and the devel-
opment of the lacrimal glands (El-Hashash et al. 2011 ; Ahrens and Schlosser 2005 ).
Barx2, which expresses in epithelium of the lacrimal gland germ, regulates the
expression of metalloproteinases for epithelial elongation and outgrowth (Tsau
et al. 2011 ). Bone morphogenetic protein (Bmp) family such as Bmp7 promotes
mesenchymal proliferation and condensation during branching morphogenesis
(Dean et al. 2004 ). The exchange of signals between epithelium and mesenchyme
modulates the progress and maturation of the lacrimal gland development.
8.4 Dry Eye Disease and Current Clinical Trials to Restore
Lacrimal Gland Functions
DED is caused by a tear shortage due to lacrimal gland dysfunction, and it leads to
ocular surface epithelial damage with ocular pain, impaired visual acuity, and reduc-
tion of the quality of life (Tsubota et al. 1996 ; Stern et al. 1998 ; Stern et al. 2004 ;
The definition and classification of dry eye disease: report of the Definition and
Classification Subcommittee of the International Dry Eye WorkShop ( 2007 ).
Complete lack of tears, which is caused by chemical or heat burn and immunologi-
cal disorders such as Stevens-Johnson syndrome and Sjogren syndrome, leads to
corneal and conjunctival keratinization and then formed a skin-like surface (Gregory
2008 ; Ciralsky et al. 2013 ; Hyon et al. 2007 ; Ramos-Casals et al. 2010 ; Wagoner
1997 ; Fish and Davidson 2010 ). The only means of surgical intervention to prevent
loss of vision is corneal transplantation, including artificial device-supported cornea
such as keratoprosthesis devices using polymers or autologous dental tissue
(Srikumaran et al. 2014 ; Tan et al. 2012 ; Liu et al. 2008 ). Usage of artificial tear
solutions contributes to increase temporary tear volume on the ocular surface and
tear stability (Barabino et al. 2014 ; Kaya et al. 2015 ; Schmidl et al. 2015 ). To supply
tear proteins and biological subjects from the lacrimal gland, albumin containing
tear solution and autologous serum are frequently used as a substitute (Shimmura
et al. 2003 ; Higuchi et al. 2007 ; Kojima et al. 2008 ; Kojima et al. 2005 ). An ectopic
transplantation of autologous labial salivary glands to the ocular conjunctiva has
M. Hirayama et al.