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«J. Funct. Biomater. 2015, 6, 634-649; doi:10.3390/jfb6030634 OPEN ACCESS Journal of Functional Biomaterials ISSN 2079-4983 ...»

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J. Funct. Biomater. 2015, 6, 634-649; doi:10.3390/jfb6030634


Journal of



ISSN 2079-4983



Bioengineered Lacrimal Gland Organ Regeneration in Vivo

Masatoshi Hirayama 1, Kazuo Tsubota 1 and Takashi Tsuji 2,3,


Department of Ophthalmology, Keio University School of Medicine, Shinjuku-ku,

Tokyo 160-8582, Japan; E-Mails: mar_hirayama@z2.keio.jp (M.H.); tsubota@z3.keio.jp (K.T.)

Laboratory of Organ Regeneration, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan Organ Technologies Inc., Chiyoda-ku, Tokyo 101-0048, Japan * Author to whom correspondence should be addressed; E-Mail: t-tsuji@cdb.riken.jp;

Tel.: +81-4-7122-9711; Fax: +81-4-7122-1499.

Academic Editor: Dimitrios Karamichos Received: 27 June 2015 / Accepted: 23 July 2015 / Published: 30 July 2015 Abstract: The lacrimal gland plays an important role in maintaining a homeostatic environment for healthy ocular surfaces via tear secretion. Dry eye disease, which is caused by lacrimal gland dysfunction, is one of the most prevalent eye disorders and causes ocular discomfort, significant visual disturbances, and a reduced quality of life. Current therapies for dry eye disease, including artificial tear eye drops, are transient and palliative. The lacrimal gland, which consists of acini, ducts, and myoepithelial cells, develops from its organ germ via reciprocal epithelial-mesenchymal interactions during embryogenesis.

Lacrimal tissue stem cells have been identified for use in regenerative therapeutic approaches aimed at restoring lacrimal gland functions. Fully functional organ replacement, such as for tooth and hair follicles, has also been developed via a novel three-dimensional stem cell manipulation, designated the Organ Germ Method, as a next-generation regenerative medicine. Recently, we successfully developed fully functional bioengineered lacrimal gland replacements after transplanting a bioengineered organ germ using this method. This study represented a significant advance in potential lacrimal gland organ replacement as a novel regenerative therapy for dry eye disease. In this review, we will summarize recent progress in lacrimal regeneration research and the development of

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Keywords: lacrimal glands; regenerative medicine; 3D cell manipulation; organ regeneration;

dry eye disease

1. Introduction Advances in regenerative medicine, influenced by our understanding of developmental biology, stem cell biology, and tissue engineering, are expected to underlie next-generation medical therapies [1–3].

Regenerative medicine for various organs, such as stem cell transplants of enriched or purified tissue-derived stem cells and cytokine therapies that activate tissue stem cell differentiation, have been clinically developed and applied [4,5]. These therapies represent attractive concepts with the potential to partially restore lost organ functionality in damaged tissues, malignant diseases, myocardial infarction, neurological diseases, and hepatic dysfunction [6–9]. Current tissue engineering technologies have established two-dimensional tissue regeneration approaches, including the cell sheet transplant technique [10]. The concept of regenerative medicine in ophthalmology includes corneal limbal stem cell transplants, which are based on the understanding of stem cell biology, and regenerative cell sheets, such as cultivated corneal epithelial cell sheets and cultivated oral mucosal epithelial cell sheets, and this has contributed to effective ocular surface reconstruction in clinics for severe ocular surface disorders [11–13]. Regenerative therapies in ophthalmology have steadily advanced to overcome vision-threatening eye diseases, including those of the cornea and retina [14].

Clinically transplanting donor organs is an important therapeutic approach for severe organ dysfunctions; however, there are related medical issues, including allogenic immunological rejection and critical donor shortage [15]. The use of fully functional substitute organs, including artificial organs made from mechanical devices and bio-artificial organs, which consist of living cells and artificial polymers, has been demonstrated to reproduce physiological functions for various organs [16–19].

Organ replacement regenerative therapy for tissue repair, via reconstruction of a fully functional, bioengineered organ from stem cells using in vitro three-dimensional cell manipulation, is one of the ultimate goals for regenerative medicine: the replacement of dysfunctional organs arising from disease, injury, or aging [20]. Developing cell manipulation techniques in vitro, through the precise arrangement of several different cell species and organ culture methods, is required to realize the next generation of three-dimensional, functional, bioengineered organ replacement regenerative therapy [21].

This review details the physiological functions, diseases, and development of the lacrimal gland obtained from published stem cell research. We illustrate that there is potential for novel, fully functional lacrimal gland regeneration as a next-generation regenerative medicine [22,23].

2. Physiological Function of the Lacrimal Glands

The lacrimal glands are essential for maintaining the physiological function and homeostasis of the ocular surface microenvironment via tear secretion [24,25]. The lacrimal gland consists of the main lacrimal gland, which primarily secretes aqueous tears, and small accessory lacrimal glands [25]. Mature lacrimal glands are organized into a tubuloalveolar system, which includes the acini, the ducts that carry fluid from the acini to a mucosal surface, and the myoepithelial cells that envelop the acini and early J. Funct. Biomater. 2015, 6 636 duct elements [25]. For physiological tear secretion, establishing the secretagogue stimulus-secretion coupling mechanisms and innervation is required. A tear film consisting of lipid, aqueous, and mucin layers contributes to the microenvironment homeostasis and optical properties of the ocular surface [26–30].

The aqueous layer of the tear film is secreted by the lacrimal glands and contains water and various tear proteins, such as lactoferrin, with biological functions including moisturizing capacity and antimicrobial activity [31–36]. The lacrimal gland and tear functions are indispensable in protecting the epithelial surface and visual function.

3. Dry Eye Disease

Dry-eye disease (DED) is caused by a tear shortage due to lacrimal gland dysfunction that results from systemic diseases and environmental exposures, such as Sjogren’s syndrome and ocular cicatricial pemphigoid, or other causes, including aging, long-term work with visual displays, the use of contact lenses, low-humidity environments, and refractive surgery [37–49]. DED is one of the most common eye diseases, and it causes ocular surface epithelial damage, which leads to ocular discomfort, significant loss of vision, and a reduced quality of life [12,50,51]. Current therapies for DED, such as artificial tear solutions, are palliative and do not completely substitute normal tear complexes that contain water, salts, hydrocarbons, proteins, and lipids [52–54]. A therapeutic approach using regenerative medicine is expected to restore lacrimal gland function as a cure for DED [55].

4. Organogenesis of the Lacrimal Glands

Organs, including the lacrimal glands, are functional units composed of various cells with the appropriate three-dimensiona histological architecture, which is achieved through developmental processes in the embryo, to work efficiently. Almost all ectodermal organs, such as teeth, hair follicles, and lacrimal glands, exhibit similar embryonic development from their organ germs that involves reciprocal epithelial and mesenchymal interactions [56]. Branching morphogenesis, which is a fundamental process for developing lacrimal glands, leads to the specification of the ocular surface epithelium and the induction of the lacrimal gland germ (Figure 1a,b) [57,58]. The development of the murine lacrimal gland occurs on embryonic day (ED) 13.5 via a tubular invagination of the conjunctival epithelium at the temporal region of the eye [59]. After the epithelium invaginates and elongates, the lacrimal gland germ invades the mesenchymal sac on ED 16.5 and begins to rapidly proliferate and branch to form a lobular structure [59–62]. The development of lacrimal gland structures is essentially completed by ED 19. By the time the eyes open, seven days after birth, secretory tear components including proteins and lipids are produced [63,64]. Mouse harderian glands, which secrete lipids, also play an important role in protecting the ocular surface [65]. The harderian glands originate from the nasal region of the conjunctival epithelium at ED 16 via a developmental branching process similar to that of the lacrimal glands, and they are located behind the eye [65,66]. The harderian glands are either degenerated or do not exist in primates, including humans [65]. This comprehensive developmental mechanism, involving branching morphogenesis, modulates lacrimal gland maturation.

J. Funct. Biomater. 2015, 6 637

Figure 1. Lacrimal gland organogenesis via epithelial-mesenchymal interactions:

(a) Schematic representation of the lacrimal gland development during embryogenesis;

(b) Phase-contrast images of the in vitro lacrimal gland germ organ culture development.

Scale bars, 100 µm. Modified and reprinted from Hirayama et al. [23].

5. Tissue Stem Cells in the Lacrimal Gland

To restore lacrimal gland function, several therapeutic approaches have been reported, such as ectopic salivary gland transplantation in vivo [67,68] and regenerative medicine [69]. Secretory glands, including salivary glands, the pancreas [70,71], and mammary glands [72], can self-renew after tissue injury, and this process is mediated by tissue stem cells. Many studies aimed at restoring secretory gland function have attempted to use various stem cells derived from adult tissues [73,74]. For salivary glands, long-term abnormal ligation of the salivary excretory duct leads to inflammation and cell death, which results in gland atrophy; however, some repair processes, including the proliferation of the tubuloalveolar structure, do occur when the ligation is released [75–81]. The salivary gland can potentially regenerate using various stem cells, such as intercalated duct cells from the salivary gland [76], c-kit-positive duct cells in human salivary glands [75], salivary gland-derived progenitor cells isolated from duct-ligated animals, and bone marrow-derived Sca-1- and c-kit-positive cells [73]. For stem cell therapy of the lacrimal glands, the potential existence of stem cells or progenitor cells has been previously described [69,82]. Tissue stem/progenitor cells, which express nestin and Ki67, and mesenchymal cells both contribute to tissue repair after interleukin-1-induced inflammation in murine-lacrimal glands [83–86]. Stem cell candidates expressing stem cell markers such as c-kit, ABCG2, and ALDH1 have been identified in human lacrimal gland cells [87,88]. Tissue regeneration using transplanted stem cells in adult tissues to restore lacrimal gland function is an area of intense research because of its potential clinical benefits [89,90].

J. Funct. Biomater. 2015, 6 638

6. A Novel Three-Dimensional Cell Manipulation Method Termed the Organ Germ Method

To further these biological technologies, the development of methods for the manipulation of multiple cells is required to realize three-dimensional organ regeneration for functional bioengineered organ replacement therapy [20]. A novel strategy for developing bioengineered organs by reproducing the developmental process during organogenesis has been proposed for the functional replacement and complete restoration of lost organs [21]. This bioengineered organ germ method, which manipulates epithelial and mesenchymal cells via cell compartmentalization at a high cell density in a type I collagen gel matrix, was developed to reconstruct bioengineered organ germs in vitro as an organ engineering technology (Figure 2a,b) [91,92]. This method successfully developed bioengineered ectodermal organs, such as teeth and hair follicle germs, through multicellular assembly and epithelial and mesenchymal interactions similar to those in natural organ germs (Figure 2c,d) [91–95]. Importantly, the bioengineered tooth and hair follicle germ transplants could restore physiological functions via cooperation with peripheral tissues at the lost tooth or hair follicle [93–96]. Developing this method was a substantial advance towards potentially regenerating other ectodermal secretory organs, including the salivary glands [97,98] and lacrimal glands [23].

J. Funct. Biomater. 2015, 6 639

Figure 2. Strategy for bioengineered organ regeneration using the organ germ method:

(a) Functional organs, such as teeth, hair follicles, salivary glands, and lacrimal glands, can now be regenerated in vivo by transplanting bioengineered organ germs reconstituted from epithelial and mesenchymal cells via the organ germ method; (b) Representative image of our developed three-dimensional cell processing system, the organ germ method. A high density of dissociated mesenchymal cells is injected into the center of a collagen drop (left panel). Dissociated epithelial cells are subsequently injected into the drop adjacent to the mesenchymal cell aggregate (center-left panel). The bioengineered tooth regenerated via the organ germ method could develop into an appropriate tooth germ via organ culturing (center-right and right panels); (c) Photograph showing the green fluorescence protein (GFP)-labeled bioengineered tooth engrafted in an adult mouse (green); (d) Photograph of the developed bioengineered hair follicles, which were successfully engrafted into a nude mouse. Modified and reprinted from Nakao et al. [21].

7. Fully Functional Lacrimal Gland Organ Regeneration

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