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. 2023 Nov-Dec;13(6):693-703.
doi: 10.1016/j.jobcr.2023.08.009. Epub 2023 Sep 12.

Extracellular matrix turnover in salivary gland disorders and regenerative therapies: Obstacles and opportunities

Milos Marinkovic  1   2 , Olivia N Tran  1 , Hanzhou Wang  1 , Parveez Abdul-Azees  1   2 , David D Dean  1   3 , Xiao-Dong Chen  1   2   3 , Chih-Ko Yeh  1   4
Affiliations

Extracellular matrix turnover in salivary gland disorders and regenerative therapies: Obstacles and opportunities

Milos Marinkovic et al. J Oral Biol Craniofac Res. 2023 Nov-Dec.

Abstract

Salivary gland (SG) extracellular matrix (ECM) has a major influence on tissue development, homeostasis, and tissue regeneration after injury. During aging, disease, and physical insult, normal remodeling of the SG microenvironment (i.e. ECM) becomes dysregulated, leading to alterations in matrix composition which disrupt tissue architecture/structure, alter cell activity, and negatively impact gland function. Matrix metalloproteinases (MMPs) are a large and diverse family of metalloendopeptidases which play a major role in matrix degradation and are intimately involved in regulating development and cell function; dysregulation of these enzymes leads to the production of a fibrotic matrix. In the SG this altered fibrotic ECM (or cell microenvironment) negatively impacts normal cell function and the effectiveness of gene and stem cell therapies which serve as a foundation for many SG regenerative therapies. For this reason, prospective regenerative strategies should prioritize the maintenance and/or restoration of a healthy SG ECM. Mesenchymal stem cells (MSCs) have great potential for mitigating damage to the SG microenvironment by ameliorating inflammation, reducing fibrosis, and repairing the damaged milieu of extracellular regulatory cues, including the matrix. This review addresses our current understanding of the impact of aging and disease on the SG microenvironment and suggests critical deficiencies and opportunities in ECM-targeted therapeutic interventions.

Keywords: Aging; Extracellular matrix; Fibrosis; Matrix metalloproteinases; Salivary gland; Tissue remodeling.

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Conflict of interest statement

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Chen is a Board member and shareholder in StemBioSys, Inc. (San Antonio, TX). Dr. Marinkovic is a shareholder and member of the Scientific Advisory Board of StemBioSys, Inc. (San Antonio, TX). All other authors have no financial or competing interests to declare.

Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
SG pathologies are characterized by unique changes in the local microenvironment. Different mechanisms of SG damage perturb the expression of MMPs in addition to up/down regulation of specific ECM components. Created using BioRender.com.
Fig. 2
Fig. 2
Fibrosis is the final common pathway of SG damage. Aging-related degeneration, IR-induced damage, and Sjögren's Syndrome are distinguished by different pathways (e.g. expression and activity of MMPs/TIMPs) which degrade the SG microenvironment and contribute to reduced salivary functionality. Irrespective of the pathway involved, fibrotic remodeling emerges in all three types of SG damage as a consequence of improper repair of the damaged ECM. The impact of fibrosis is a permanently compromised SG structure and loss of function. Created using BioRender.com.
Fig. 3
Fig. 3
Damaged extracellular cues in SG disease. The damaged SG microenvironment produces aberrant cues which contribute to dysregulated of SG organization, cell behavior and function. If unaddressed, these degenerative cues interfere with SG regeneration. Created using BioRender.com.
See this image and copyright information in PMC

References

    1. Marinkovic M., Dean D.D., Chen X.D. In: A Roadmap to Non-hematopoietic Stem Cell-Based Therapeutics. Chen X.-D., editor. Academic Press; 2019. Maintenance and culture of MSCs; pp. 39–61. Published online 2019. - DOI
    1. Karamanos N.K., Theocharis A.D., Piperigkou Z., et al. A guide to the composition and functions of the extracellular matrix. FEBS J. 2021;288(24):6850–6912. doi: 10.1111/febs.15776. - DOI - PubMed
    1. Muncie J.M., Weaver V.M. The physical and biochemical properties of the extracellular matrix regulate cell fate. Curr Top Dev Biol. 2018;130:1–37. doi: 10.1016/bs.ctdb.2018.02.002. - DOI - PMC - PubMed
    1. Jasmer K.J., Gilman K.E., Forti K.M., Weisman G.A., Limesand K.H. Radiation-induced salivary gland dysfunction: mechanisms, therapeutics and future directions. J Clin Medicine. 2020;9(12):4095. doi: 10.3390/jcm9124095. - DOI - PMC - PubMed
    1. Sequeira S.J., Larsen M., DeVine T. Extracellular matrix and growth factors in salivary gland development. Front Oral Biol. 2010;14:48–77. doi: 10.1159/000313707. - DOI - PubMed