Regional Differences following Partial Salivary Gland Resection

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 but also an experimental injury model used to examine mechanisms of regeneration and repair in organs. We performed a partial resection, or partial sialoadenectomy, in the female 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 d and found that the gland increased slightly in size. We used microarray analysis and immunohistochemistry (IHC) to examine messenger RNA and protein changes in glands over time. Microarray analysis identified dynamic changes in the transcriptome 3 d after injury that were largely resolved by day 14. At the 3-d time point, we detected gene signatures for cell cycle regulation, inflammatory/repair response, and extracellular matrix (ECM) remodeling in the partially resected glands. Using quantitative IHC, we identified a transient proliferative response throughout the gland. 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, sustained Ki67 levels in stromal cells, and a persistent M2 macrophage response through day 56. 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 affect regenerative therapies for patients.

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Regional Differences Following Partial Salivary Gland Resection

10.1101/713230 ◽

2019 ◽

Author(s):

Kevin J. O’Keefe ◽

Kara A. DeSantis ◽

Amber L. Altrieth ◽

Deirdre A. Nelson ◽

Ed Zandro M. Taroc ◽

...

Keyword(s):

Wound Healing ◽

Salivary Gland ◽

Microarray Analysis ◽

Stromal Cells ◽

Regional Differences ◽

Submandibular Salivary Gland ◽

Clinical Approach ◽

Matrix Remodeling ◽

Fibrotic Response ◽

Healing Response

AbstractRegenerative 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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PDFGRα+ Stromal Cells Promote Salivary Gland Proacinar Differentiation Through FGF2-dependent BMP7 Signaling.

10.1101/2021.11.19.469144 ◽

2021 ◽

Author(s):

Nicholas Moskwa ◽

Ayma Mahmood ◽

Deirdre Nelson ◽

Amber Altrieth ◽

Paolo E Forni ◽

...

Keyword(s):

Salivary Gland ◽

Stromal Cells ◽

Stromal Cell ◽

Gene Expression Analysis ◽

Submandibular Salivary Gland ◽

Myofibroblast Differentiation ◽

Autocrine Signaling ◽

Regenerative Therapies ◽

Gland Development ◽

Differentiation Gene

Stromal cells can direct epithelial differentiation during organ development; however, these pathways remain poorly defined. FGF signaling is essential for submandibular salivary gland development, and FGF2 can regulate proacinar cell differentiation in organoids through autocrine signaling in stromal cells. We performed scRNA Seq and identified stromal cell subsets expressing Fgf2 and Fgf10 that also express Pdgfrα. When combined with epithelial cells in organoids, MACS-sorted PDGFRα+ cells sufficiently promoted proacinar differentiation. Gene expression analysis revealed FGF2 activates the gene Bmp7 in the stroma. BMP7 could replace stromal signaling and stimulate epithelial acinar differentiation but not branching. However, in the absence of FGF2, pathway analysis revealed that the stromal cells differentiated into myofibroblasts. Myofibroblast differentiation was induced when we treated organoids with TGFβ1, which also prevented proacinar differentiation. Conversely, FGF2 reversed TGFβ's effects. Dissecting pathways driving acinar differentiation will facilitate development of regenerative therapies.

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Healing gone wrong: convergence of hemostatic pathways and liver fibrosis?

Clinical Science ◽

10.1042/cs20191102 ◽

2020 ◽

Vol 134 (16) ◽

pp. 2189-2201

Author(s):

Jessica P.E. Davis ◽

Stephen H. Caldwell

Keyword(s):

Wound Healing ◽

Liver Disease ◽

Hepatic Fibrosis ◽

Cell Activation ◽

Stellate Cell ◽

Factor Xa ◽

Clinical Trial Data ◽

Chronic Liver ◽

Healing Response ◽

Wound Healing Response

Abstract Fibrosis results from a disordered wound healing response within the liver with activated hepatic stellate cells laying down dense, collagen-rich extracellular matrix that eventually restricts liver hepatic synthetic function and causes increased sinusoidal resistance. The end result of progressive fibrosis, cirrhosis, is associated with significant morbidity and mortality as well as tremendous economic burden. Fibrosis can be conceptualized as an aberrant wound healing response analogous to a chronic ankle sprain that is driven by chronic liver injury commonly over decades. Two unique aspects of hepatic fibrosis – the chronic nature of insult required and the liver’s unique ability to regenerate – give an opportunity for pharmacologic intervention to stop or slow the pace of fibrosis in patients early in the course of their liver disease. Two potential biologic mechanisms link together hemostasis and fibrosis: focal parenchymal extinction and direct stellate cell activation by thrombin and Factor Xa. Available translational research further supports the role of thrombosis in fibrosis. In this review, we will summarize what is known about the convergence of hemostatic changes and hepatic fibrosis in chronic liver disease and present current preclinical and clinical data exploring the relationship between the two. We will also present clinical trial data that underscores the potential use of anticoagulant therapy as an antifibrotic factor in liver disease.

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Modulation Of Wound Healing Response In Chronic Irradiated Tissues

Clinics in Plastic Surgery ◽

10.1016/s0094-1298(20)31189-5 ◽

1993 ◽

Vol 20 (3) ◽

pp. 465-472 ◽

Cited By ~ 8

Author(s):

Thomas A. Mustoe ◽

Beatriz H. Porras-Reyes

Keyword(s):

Wound Healing ◽

Healing Response ◽

Wound Healing Response

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Small lymphocytic lymphoma as a random finding in lymph nodes with metastasis from an undifferentiated carcinoma of the submandibular salivary gland

10.26226/morressier.596dfd59d462b80292387cc3 ◽

2017 ◽

Author(s):

Maria Kilmpasani

Keyword(s):

Salivary Gland ◽

Lymph Nodes ◽

Undifferentiated Carcinoma ◽

Submandibular Salivary Gland ◽

Small Lymphocytic Lymphoma

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PHENOTYPIC HETEROGENEITY OF CARDIAC MACROPHAGES DURING WOUND HEALING FOLLOWING MYOCARDIAL INFARCTION: PERSPECTIVES IN CLINICAL RESEARCH

Siberian Medical Journal ◽

10.29001/2073-8552-2018-33-2-70-76 ◽

2018 ◽

Vol 33 (2) ◽

pp. 70-76 ◽

Cited By ~ 1

Author(s):

A. E. Gombozhapova ◽

Yu. V. Rogovskaya ◽

M. S. Rebenkova ◽

J. G. Kzhyshkowska ◽

V. V. Ryabov

Keyword(s):

Myocardial Infarction ◽

Wound Healing ◽

Cardiac Remodeling ◽

Phenotypic Heterogeneity ◽

Macrophage Infiltration ◽

Myocardial Regeneration ◽

Control Group ◽

M2 Macrophage ◽

Inflammatory Phase ◽

Regenerative Phase

Purpose. Myocardial regeneration is one of the most ambitious goals in prevention of adverse cardiac remodeling. Macrophages play a key role in transition from inflammatory to regenerative phase during wound healing following myocardial infarction (MI). We have accumulated data on macrophage properties ex vivo and in cell culture. However, there is no clear information about phenotypic heterogeneity of cardiac macrophages in patients with MI. The purpose of the project was to assess cardiac macrophage infiltration during wound healing following myocardial infarction in clinical settings taking into consideration experimental knowledge.Material and Methods. The study included 41 patients with fatal MI type 1. In addition to routine analysis, macrophages infiltration was assessed by immunohistochemistry. We used CD68 as a marker for the cells of the macrophage lineage, while CD163, CD206, and stabilin-1 were considered as M2 macrophage biomarkers. Nine patients who died from noncardiovascular causes comprised the control group.Results. The intensity of cardiac macrophage infiltration was higher during the regenerative phase than during the inflammatory phase. Results of immunohistochemical analysis demonstrated the presence of phenotypic heterogeneity of cardiac macrophages in patients with MI. We noticed that numbers of CD68+, CD163+, CD206+, and stabilin-1+ macrophages depended on MI phase.Conclusion. Our study supports prospects for implementation of macrophage phenotyping in clinic practice. Improved understanding of phenotypic heterogeneity might become the basis of a method to predict adverse cardiac remodeling and the first step in developing myocardial regeneration target therapy.

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