Elsevier

The Ocular Surface

Volume 25, July 2022, Pages 129-141
The Ocular Surface

Lacrimal gland regeneration: The unmet challenges and promise for dry eye therapy

https://doi.org/10.1016/j.jtos.2022.06.005Get rights and content

Abstract

Dry eye disease (DED) is a common multifactorial disease of the tear film and the ocular surface. The problem of DED has gained attention globally, with millions of people affected by the disorder. Although the treatment strategies for DED have significantly evolved over time, most of the existing modalities fall under the category of standard palliative care when viewed from a long-term perspective. To address these limitations, different approaches have been explored by various groups to uncover alternative treatment strategies that can contribute to a full regeneration of the damaged lacrimal gland, which is responsible for producing the major aqueous component of the tear film. For this, multiple groups have investigated the role of lacrimal gland cells in DED based on their regenerating, homing, and differentiating capabilities. In this review, we discuss in detail the therapeutic mechanisms and regenerative strategies that can potentially be applied for lacrimal gland regeneration as well as their therapeutic applications. This review mainly focuses on aqueous deficiency dry eye disease (ADDE) caused by lacrimal gland dysfunction and possible future treatment strategies. The current key findings from cell and tissue-based regenerative therapy modalities that could be utilised to achieve lacrimal gland tissue regeneration are summarized. In addition, this review summarises the available literature from in vitro to in vivo studies, their limitations in relation to lacrimal gland regeneration and the possible clinical applications. Finally, current issues and unmet needs of cell-based therapies in providing complete lacrimal gland tissue regeneration are discussed.

Section snippets

Methodology of review

This review addresses aqueous deficiency dry eye disease (ADDE) caused by lacrimal gland dysfunction and recent advances in regenerative medicine, which might lead to new therapeutic approaches to treat dry eye disease. The review is based on relevant publications (150–170, published until January 2022) retrieved by a selective search on PubMed, Google Scholar, and Scopus and drawing on the authors' own clinical and scientific experience. In addition, the latest advances in lacrimal gland

Lacrimal gland cell cultures

Understanding the normal physiological processes occurring in the lacrimal gland is of utmost importance to study various disease mechanisms. Identifying proper lacrimal gland histology, lacrimal gland cells, progenitors, maintenance, and the characterization of all distinct cell types are primary goals in exploring the disease. Extrapolating the progress made with regards to the exocrine salivary gland cultures and the application to dry mouth models, culturing various types of cells from the

Native and decellularized glands

The human lacrimal gland is a 3D structure with a well-controlled secretory function. Various strategies to mimic this composition have been explored. The use of autologous minor and major salivary glands (represented by the parotid, submandibular, and sublingual glands) have been proposed as a source of lubrication to treat severe cases of DED since 1951 by different authors [148,149]. However, surgical complications and the salivary characteristics of the new tear film have limited the

Challenges and unmet needs

For decades, the existing treatment modalities for DED have remained palliative. Based on the emerging novel tissue regenerative treatments, we hypothesise that regeneration of the damaged lacrimal gland tissue could be possible in future by providing a complete cure based on tissue regeneration. A more detailed evaluation of the primary regulatory genes involved in lacrimal gland development and the discovery of appropriate cell sources would help in the lacrimal gland regeneration [132].

Summary

Emerging therapies will hopefully reduce the dry eye disease burden worldwide by addressing the root cause of the disease. An important step toward this relates to the identification of the biological cues necessary for the regeneration of the impaired lacrimal gland and reducing the inflammation that aggravates the condition. The need for a promising translational therapy using stem cells is of utmost importance, given the increase in the number of dry eye disease patients. The strategies

Disclosure

The authors have no conflict of interests to declare.

Acknowledgement

We acknowledge Prof. Usha Raman (Department of Communication, Hyderabad University, India) for her English and grammar editing support.”

Support in part was provided by Champalimaud Translational Centre for Eye Research, Hyderabad Eye Research Foundation; and Science and Engineering Research Board - Core Research Grant (SERB-CRG) (CRG/2018/003514; Dr. Vivek Singh, CRG/2018/004122; prof Geeta K Vemuganti) and DBT special Institutional Grant (BT/PR32404/MED/30/2136/2019).

References (172)

  • J. Dietrich et al.

    Analysis of lacrimal gland derived mesenchymal stem cell secretome and its impact on epithelial cell survival

    Stem Cell Res

    (2019)
  • L. Basova et al.

    Origin and lineage plasticity of endogenous lacrimal gland epithelial stem/progenitor cells

    iScience

    (2020)
  • R.R. Hodges et al.

    Regulatory pathways in lacrimal gland epithelium

    Int Rev Cytol

    (2003)
  • D. Zoukhri

    Effect of inflammation on lacrimal gland function

    Exp Eye Res

    (2006)
  • D.A. Dartt

    Dysfunctional neural regulation of lacrimal gland secretion and its role in the pathogenesis of dry eye syndromes

    Ocul Surf

    (2004)
  • C.J. Catt et al.

    Ocular manifestations of Stevens-Johnson syndrome and toxic epidermal necrolysis in children

    Am J Ophthalmol

    (2016)
  • B. Parkin et al.

    Lymphocytic infiltration and enlargement of the lacrimal glands: a new subtype of primary Sjogren's syndrome?

    Ophthalmology

    (2005)
  • C.Q. Nguyen et al.

    Unraveling the pathophysiology of Sjogren syndrome-associated dry eye disease

    Ocul Surf

    (2009)
  • R. Desgraz et al.

    beta-cell regeneration: the pancreatic intrinsic faculty

    Trends Endocrinol Metabol

    (2011)
  • D. Zoukhri et al.

    A single injection of interleukin-1 induces reversible aqueous-tear deficiency, lacrimal gland inflammation, and acinar and ductal cell proliferation

    Exp Eye Res

    (2007)
  • M.A. Gonzalez et al.

    Adipose-derived mesenchymal stem cells alleviate experimental colitis by inhibiting inflammatory and autoimmune responses

    Gastroenterology

    (2009)
  • M. Moller-Hansen et al.

    Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease

    Ocul Surf

    (2021)
  • Y. Shi et al.

    How mesenchymal stem cells interact with tissue immune responses

    Trends Immunol

    (2012)
  • A.I. Caplan et al.

    The MSC: an injury drugstore

    Cell Stem Cell

    (2011)
  • E. Pastrana et al.

    Eyes wide open: a critical review of sphere-formation as an assay for stem cells

    Cell Stem Cell

    (2011)
  • Y. Fu et al.

    Oral mucosal graft to correct lid margin pathologic features in cicatricial ocular surface diseases

    Am J Ophthalmol

    (2011)
  • J.J. Nichols et al.

    The TFOS international workshop on contact lens discomfort: executive summary

    Invest Ophthalmol Vis Sci

    (2013)
  • J.D. Nelson et al.

    The international workshop on meibomian gland dysfunction: report of the definition and classification subcommittee

    Invest Ophthalmol Vis Sci

    (2011)
  • H. Obata

    Anatomy and histopathology of the human lacrimal gland

    Cornea

    (2006)
  • G.K. Vemuganti et al.

    Lacrimal gland regeneration: progress and promise

    Regen. Med.- Protoc. Patient.

    (2016)

  • The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye WorkShop (2007)

    Ocul Surf

    (2007)
  • S.I. Brown et al.

    The oils of the meibomian glands. Physical and surface characteristics

    Arch Ophthalmol

    (1969)
  • M.M. Hom et al.

    Prevalence of Meibomian gland dysfunction

    Optom Vis Sci

    (1990)
  • L. Tong et al.

    Association of tear proteins with Meibomian gland disease and dry eye symptoms

    Br J Ophthalmol

    (2011)
  • D.A. Dartt

    Physiology of tear production

    Dry Eye

    (1992)
  • A. Yagci et al.

    The role and treatment of inflammation in dry eye disease

    Int Ophthalmol

    (2014)
  • S.C. Pflugfelder et al.

    The diagnosis and management of dry eye: a twenty-five-year review

    Cornea

    (2000)
  • L. Zhu et al.

    Topical steroid and non-steroidal anti-inflammatory drugs inhibit inflammatory cytokine expression on the ocular surface in the botulinum toxin B-induced murine dry eye model

    Mol Vis

    (2012)
  • S. Rashid et al.

    Topical omega-3 and omega-6 fatty acids for treatment of dry eye

    Arch Ophthalmol

    (2008)
  • T.G. Coursey et al.

    Once-daily cyclosporine-A-MiDROPS for treatment of dry eye disease

    Transl Vis Sci Technol

    (2018)
  • K.K. Nichols et al.

    Reduction of artificial tears and use of adjunctive dry eye therapies after lifitegrast treatment: evidence from clinical and real-World studies

    Clin Ophthalmol

    (2022)
  • E.J. Johnson et al.

    Potential role of dietary n-3 fatty acids in the prevention of dementia and macular degeneration

    Am J Clin Nutr

    (2006)
  • R.M. Sanchez-Avila et al.

    Plasma rich in growth factors for the treatment of dry eye from patients with graft versus host diseases

    Eur J Ophthalmol

    (2020)
  • E. Anitua et al.

    Plasma rich in growth factors for the treatment of ocular surface diseases

    Curr Eye Res

    (2016)
  • E. Anitua et al.

    Plasma rich in growth factors (PRGF-Endoret) stimulates proliferation and migration of primary keratocytes and conjunctival fibroblasts and inhibits and reverts TGF-beta1-Induced myodifferentiation

    Invest Ophthalmol Vis Sci

    (2011)
  • M.A. Lemp

    Management of dry eye disease

    Am J Manag Care

    (2008)
  • Y. Qin et al.

    Labial salivary gland transplantation for severe dry eye in a rhesus monkey model

    Invest Ophthalmol Vis Sci

    (2018)
  • A.J. Villatoro et al.

    Regenerative therapies in dry eye disease: from growth factors to cell therapy

    Int J Mol Sci

    (2017)
  • N. Polisetty et al.

    Mesenchymal cells from limbal stroma of human eye

    Mol Vis

    (2008)
  • N. Pinnamaneni et al.

    Concise review: stem cells in the corneal stroma

    Stem Cell

    (2012)

    • Cited by (0)

    1

    equal contribution.

    View full text
    © 2022 Published by Elsevier Inc.