Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Weng, Pei‐Lun; Aure, Marit H.; Maruyama, Takamitsu; Ovitt, Catherine E.

doi:10.1016/j.celrep.2018.07.016

Cited by 99 publications

(140 citation statements)

References 33 publications

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“…While most current treatments for salivary gland dysfunction target expansion of residual salivary acinar cells to repair damaged tissue, regenerative therapy with stem cells is a novel and promising therapeutic approach to replace damaged salivary glands (Carpenter and Cotroneo, 2010;Lombaert et al, 2017;Ogawa and Tsuji, 2017). Several studies have identified and characterized subsets of endogenous salivary progenitor cells that can be exploited to promote tissue regeneration (Lombaert et al, 2008;Chibly et al, 2014Chibly et al, , 2018Pringle et al, 2016;Emmerson et al, 2018;Weng et al, 2018). The use of modified fibrin hydrogels (Nam et al, 2019a), layered sheets of isolated salivary gland cells released from thermoresponsive culture dishes (Nam et al, 2019b) and salivary organoid cultures generated from embryonic pluripotent stem cells (Tanaka et al, 2018) have been explored as regenerative therapies for damaged salivary glands.…”

Section: P2 Receptors In Salivary Gland Regenerationmentioning

confidence: 99%

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

et al. 2020

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Although often overlooked in our daily lives, saliva performs a host of necessary physiological functions, including lubricating and protecting the oral cavity, facilitating taste sensation and digestion and maintaining tooth enamel. Therefore, salivary gland dysfunction and hyposalivation, often resulting from pathogenesis of the autoimmune disease Sjögren's syndrome or from radiotherapy of the head and neck region during cancer treatment, severely reduce the quality of life of afflicted patients and can lead to dental caries, periodontitis, digestive disorders, loss of taste and difficulty speaking. Since their initial discovery in the 1970s, P2 purinergic receptors for extracellular nucleotides, including ATP-gated ion channel P2X and G protein-coupled P2Y receptors, have been shown to mediate physiological processes in numerous tissues, including the salivary glands where P2 receptors represent a link between canonical and non-canonical saliva secretion. Additionally, extracellular nucleotides released during periods of cellular stress and inflammation act as a tissue alarmin to coordinate immunological and tissue repair responses through P2 receptor activation. Accordingly, P2 receptors have gained widespread clinical interest with agonists and antagonists either currently undergoing clinical trials or already approved for human use. Here, we review the contributions of P2 receptors to salivary gland function and describe their role in salivary gland dysfunction. We further consider their potential as therapeutic targets to promote physiological saliva flow, prevent salivary gland inflammation and enhance tissue regeneration.

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Section: P2 Receptors In Salivary Gland Regenerationmentioning

confidence: 99%

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

et al. 2020

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“…Regeneration following irradiation can also occur but is typically partial and depends upon the degree of injury (Weng et al 2018). Multiple mechanisms can limit regenerative ability.…”

Section: Discussionmentioning

confidence: 99%

Regional Differences Following Partial Salivary Gland Resection

O’Keefe

DeSantis

Altrieth

et al. 2019

Preprint

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Regenerative medicine aims to repair, replace, or restore function to tissues damaged by aging, disease, or injury. Partial organ resection is not only a common clinical approach in cancer therapy, it is also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialodenectomy, in the murine submandibular salivary gland (SMG) to establish a model for investigation of repair mechanisms in salivary glands (SGs). After partial sialoadenectomy we performed whole gland measurements over a period of 56 days and found that the gland reached its maximum size 14 days after injury. We used microarray analysis and immunohistochemistry to examine mRNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome three days after injury that were largely resolved by day 14. At the 3 day time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix remodeling in the partially resected glands.Using quantitative immunohistochemistry, we identified a transient proliferative response throughout the gland, in which both secretory epithelial and stromal cells expressed Ki67 that was detectable at day 3 and largely resolved by day 14. IHC also revealed that while most of the gland underwent a wound healing response that resolved by day 14, a small region of the gland showed an aberrant sustained fibrotic response characterized by increased levels of ECM deposition and sustained Ki67 levels in stromal cells. The partial submandibular salivary gland resection model provides an opportunity to examine a normal healing response and an aberrant fibrotic response within the same gland to uncover mechanisms that prevent wound healing and regeneration in mammals. Understanding regional differences in the wound healing responses may ultimately impact regenerative therapies for patients.

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“…KRT5 and AXIN2 mark distinct subpopulations of duct cells which give rise to additional duct cells but do not develop into acinar cells. However, following irradiation causing extensive damage, both acinar and duct cells contribute to regeneration by producing cells of both lineages (Weng, Aure, Maruyama, & Ovitt, 2018).…”

Section: Cellular Plasticity Contributes To Tissue Regenerationmentioning

confidence: 99%

Cellular mechanisms of epithelial stem cell self‐renewal and differentiation during homeostasis and repair

Das

Fletcher

Ngai

2019

WIREs Developmental Biology

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Epithelia in adult mammals exhibit remarkable regenerative capacities owing to the presence of adult stem cells, which self‐renew and differentiate to replace cells lost to normal turnover or injury. The mechanisms supporting tissue homeostasis and injury‐induced repair often differ from each other as well as from those used in embryonic development. Recent studies have also highlighted the phenomenon of cellular plasticity in adult tissues, in which differentiated cells can change fate and even give rise to new stem cell populations to complement the canonical stem cells in promoting repair following injury. Signaling pathways such as WNT, bone morphogenetic protein, and Sonic Hedgehog play critical roles in stem cell maintenance and cell fate decisions across diverse epithelia and conditions, suggesting that conserved mechanisms underlie the regenerative capacity of adult epithelial structures. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Adult Stem Cells, Tissue Renewal, and Regeneration > Tissue Stem Cells and Niches Adult Stem Cells, Tissue Renewal, and Regeneration > Stem Cell Differentiation and Reversion Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration

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Limited Regeneration of Adult Salivary Glands after Severe Injury Involves Cellular Plasticity

Cited by 99 publications

References 33 publications

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction

Regional Differences Following Partial Salivary Gland Resection

Cellular mechanisms of epithelial stem cell self‐renewal and differentiation during homeostasis and repair

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