136
8.1 Introduction
Regenerative medicine to restore organ function has been developed as realizable
therapy due to perpetual advance of our understanding of developmental biology,
stem cell biology, and tissue engineering (Brockes and Kumar 2005 ; Atala 2005 ). In
various organs, the concept of regenerative medicine, including stem cell transplan-
tation of enriched tissue-derived stem cells and activation therapy of tissue stem cell
using cytokine, has been clinically applied to treat damaged tissues (Copelan 2006 ;
Segers and Lee 2008 ; Wang et al. 2003 ; Takahashi et al. 1998 ). Advances in tissue
engineering technologies enable to make 2D tissue regeneration such as a cultivated
cell sheet transplant procedure (Ge et al. 2015 ; Ito et al. 2014 ; Sawa and Miyagawa
2013 ; Takagi et al. 2014 ). Current ophthalmology, including corneal limbal stem
cell transplantation surgery and cultivated cell sheets of corneal epithelial cell or
oral mucosal epithelial cell, has accomplished clinical evidence to reconstruct the
ocular surface for severe ocular surface disorders by integrating the concept of
regenerative medicine (Tsubota et al. 1999 ; Shimazaki et al. 2002 ; Nishida et al.
2004 ; Hirayama et al. 2012 ). This methodology has expanded as pluripotent stem
cell-derived retinal pigment epithelium cell sheet transplant to overcome age-related
macular degeneration, the vision-threatening retinal disease (Kamao et al. 2014 ;
Westenskow et al. 2014 ). Regenerative medicine has been expected to be an indis-
pensable therapy for future ophthalmology.
Functional restoration of the lacrimal glands, which protect a healthy microenvi-
ronment of the ocular surface via secretion of tears, has attracted ophthalmologists
as an effective way to be realized for improvement of visual functions (Mathers
2000 ; Hirayama et al. 2013b). Tear fluids contain water, electrolytes, and various
tear proteins, and they promise the smoothness of the ocular surface and lid lubrica-
tion with cooperation of lipid secretion from periocular glands (Schechter et al.
2010 ; Mishima 1965 ; Seal et al. 1986 ). Acini of the lacrimal glands produce tear
water and tear proteins, which are critical for physiological tear functions such as
tear stability and anti-microbiotic effect. Produced fluids reach to the ocular surface
all over through the lacrimal gland excretory duct. A stable ocular surface with
homeostatic tear environment is fundamental to maintain visual functions.
Dysfunction of the lacrimal glands leads to dry eye disease (DED), which has
become one of the big public health problems because it is a multifactorial disease,
including aging, and environmentally induced such as use of visual display, immu-
nological reaction, and trauma (Uchino et al. 2011 ; Uchino et al. 2008a, b; Lin et al.
2003 ; Paulsen et al. 2014 ). Severe DED decreases the quality of life due to signifi-
cant visual disturbance from epithelial cell damage of the cornea, which can cause
loss of vision (Tsubota et al. 1996 ; Dogru et al. 2008 ; Kaido et al. 2011 ). The first
step to restore tear function for DED is replenishment therapy using artificial tear
solution, which is mainly constituted of water, whereas it has conservative effect
(Matsumoto et al. 2012 ; Johnson 1989 ; Ubels et al. 2004 ; Rangarajan et al. 2015 ).
Therefore, an establishment of curable therapeutic approach to restore functions of
M. Hirayama et al.