Regional Differences Following Partial Salivary Gland Resection

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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Regional Differences following Partial Salivary Gland Resection

Journal of Dental Research ◽

10.1177/0022034519889026 ◽

2019 ◽

Vol 99 (1) ◽

pp. 79-88 ◽

Cited By ~ 1

Author(s):

K.J. O’Keefe ◽

K.A. DeSantis ◽

A.L. Altrieth ◽

D.A. Nelson ◽

E.Z.M. Taroc ◽

...

Keyword(s):

Wound Healing ◽

Salivary Gland ◽

Microarray Analysis ◽

Stromal Cells ◽

Regional Differences ◽

Submandibular Salivary Gland ◽

M2 Macrophage ◽

Clinical Approach ◽

Fibrotic Response ◽

Healing Response

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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Augmentation of Dermal Wound Healing by Adipose Tissue-Derived Stromal Cells (ASC)

Bioengineering ◽

10.3390/bioengineering5040091 ◽

2018 ◽

Vol 5 (4) ◽

pp. 91 ◽

Cited By ~ 5

Author(s):

Joris van Dongen ◽

Martin Harmsen ◽

Berend van der Lei ◽

Hieronymus Stevens

Keyword(s):

Extracellular Matrix ◽

Wound Healing ◽

Adipose Tissue ◽

Stromal Cells ◽

Randomized Clinical Trials ◽

Cell Types ◽

Matrix Remodeling ◽

Skin Wound Healing ◽

Dermal Wound Healing ◽

Dermal Wound

The skin is the largest organ of the human body and is the first line of defense against physical and biological damage. Thus, the skin is equipped to self-repair and regenerates after trauma. Skin regeneration after damage comprises a tightly spatial-temporally regulated process of wound healing that involves virtually all cell types in the skin. Wound healing features five partially overlapping stages: homeostasis, inflammation, proliferation, re-epithelization, and finally resolution or fibrosis. Dysreguled wound healing may resolve in dermal scarring. Adipose tissue is long known for its suppressive influence on dermal scarring. Cultured adipose tissue-derived stromal cells (ASCs) secrete a plethora of regenerative growth factors and immune mediators that influence processes during wound healing e.g., angiogenesis, modulation of inflammation and extracellular matrix remodeling. In clinical practice, ASCs are usually administered as part of fractionated adipose tissue i.e., as part of enzymatically isolated SVF (cellular SVF), mechanically isolated SVF (tissue SVF), or as lipograft. Enzymatic isolation of SVF obtained adipose tissue results in suspension of adipocyte-free cells (cSVF) that lack intact intercellular adhesions or connections to extracellular matrix (ECM). Mechanical isolation of SVF from adipose tissue destructs the parenchyma (adipocytes), which results in a tissue SVF (tSVF) with intact connections between cells, as well as matrix. To date, due to a lack of well-designed prospective randomized clinical trials, neither cSVF, tSVF, whole adipose tissue, or cultured ASCs can be indicated as the preferred preparation procedure prior to therapeutic administration. In this review, we present and discuss current literature regarding the different administration options to apply ASCs (i.e., cultured ASCs, cSVF, tSVF, and lipografting) to augment dermal wound healing, as well as the available indications for clinical efficacy.

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Cancer Response to Therapy-Induced Senescence: A Matter of Dose and Timing

Cancers ◽

10.3390/cancers13030484 ◽

2021 ◽

Vol 13 (3) ◽

pp. 484

Author(s):

Maria Patrizia Mongiardi ◽

Manuela Pellegrini ◽

Roberto Pallini ◽

Andrea Levi ◽

Maria Laura Falchetti

Keyword(s):

Wound Healing ◽

Growth Factors ◽

Cell Division ◽

Stromal Cells ◽

Cell Types ◽

Response To Therapy ◽

Matrix Remodeling ◽

Aggressive Cancer ◽

Secretory Phenotype ◽

Different Cell Types

Cellular senescence participates to fundamental processes like tissue remodeling in embryo development, wound healing and inhibition of preneoplastic cell growth. Most senescent cells display common hallmarks, among which the most characteristic is a permanent (or long lasting) arrest of cell division. However, upon senescence, different cell types acquire distinct phenotypes, which also depend on the specific inducing stimuli. Senescent cells are metabolically active and secrete a collection of growth factors, cytokines, proteases, and matrix-remodeling proteins collectively defined as senescence-associated secretory phenotype, SASP. Through SASP, senescent cells modify their microenvironment and engage in a dynamic dialog with neighbor cells. Senescence of neoplastic cells, at least temporarily, reduces tumor expansion, but SASP of senescent cancer cells as well as SASP of senescent stromal cells in the tumor microenvironment may promote the growth of more aggressive cancer subclones. Here, we will review recent data on the mechanisms and the consequences of cancer-therapy induced senescence, enlightening the potentiality and the risk of senescence inducing treatments.

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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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