Decreased serotonin transporter activity in the mitral valve contributes to progression of degenerative mitral regurgitation.

Degenerative mitral valve (MV) regurgitation (MR) is a highly prevalent heart disease that requires surgery in severe cases. Here, we show that a decrease in the activity of the serotonin transporter (SERT) accelerates MV remodeling and progression to MR. Through studies of a population of patients with MR, we show that selective serotonin reuptake inhibitor (SSRI) use and SERT promoter polymorphism 5-HTTLPR LL genotype were associated with MV surgery at younger age. Functional characterization of 122 human MV samples, in conjunction with in vivo studies in SERT-/- mice and wild-type mice treated with the SSRI fluoxetine, showed that diminished SERT activity in MV interstitial cells (MVICs) contributed to the pathophysiology of MR through enhanced serotonin receptor (HTR) signaling. SERT activity was decreased in LL MVICs partially because of diminished membrane localization of SERT. In mice, fluoxetine treatment or SERT knockdown resulted in thickened MV leaflets. Similarly, silencing of SERT in normal human MVICs led to up-regulation of transforming growth factor ß1 (TGFß1) and collagen (COL1A1) in the presence of serotonin. In addition, treatment of MVICs with fluoxetine not only directly inhibited SERT activity but also decreased SERT expression and increased HTR2B expression. Fluoxetine treatment and LL genotype were also associated with increased COL1A1 expression in the presence of serotonin in MVICs, and these effects were attenuated by HTR2B inhibition. These results suggest that assessment of both 5-HTTLPR genotype and SERT-inhibiting treatments may be useful tools to risk-stratify patients with MV disease to estimate the likelihood of rapid disease progression.

Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma.

Senescent cells can drive age-related tissue dysfunction partially via a senescence-associated secretory phenotype (SASP) involving proinflammatory and profibrotic factors. Cellular senescence has been associated with a structural and functional decline during normal lung aging and age-related diseases such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Asthma in the elderly (AIE) represents a major healthcare burden. AIE is associated with bronchial airway hyperresponsiveness and remodeling, which involves increased cell proliferation and higher rates of fibrosis, and resistant to standard therapy. Airway smooth muscle (ASM) cells play a major role in asthma such as remodeling via modulation of inflammation and the extracellular matrix (ECM) environment. Whether senescent ASM cells accumulate in AIE and contribute to airway structural or functional changes is unknown. Lung tissues from elderly persons with asthma showed greater airway fibrosis compared with age-matched elderly persons with nonasthma and young age controls. Lung tissue or isolated ASM cells from elderly persons with asthma showed increased expression of multiple senescent markers including phospho-p53, p21, telomere-associated foci (TAF), as well as multiple SASP components. Senescence and SASP components were also increased with aging per se. These data highlight the presence of cellular senescence in AIE that may contribute to airway remodeling.

Cellular Senescence in Aging Lungs and Diseases.

Cellular senescence represents a state of irreversible cell cycle arrest occurring naturally or in response to exogenous stressors. Following the initial arrest, progressive phenotypic changes define conditions of cellular senescence. Understanding molecular mechanisms that drive senescence can help to recognize the importance of such pathways in lung health and disease. There is increasing interest in the role of cellular senescence in conditions such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) in the context of understanding pathophysiology and identification of novel therapies. Herein, we discuss the current knowledge of molecular mechanisms and mitochondrial dysfunction regulating different aspects of cellular senescence-related to chronic lung diseases to develop rational strategies for modulating the senescent cell phenotype in the lung for therapeutic benefit.

Craniofacial Bone Tissue Engineering: Current Approaches and Potential Therapy.

Craniofacial bone defects can result from various disorders, including congenital malformations, tumor resection, infection, severe trauma, and accidents. Successfully regenerating cranial defects is an integral step to restore craniofacial function. However, challenges managing and controlling new bone tissue formation remain. Current advances in tissue engineering and regenerative medicine use innovative techniques to address these challenges. The use of biomaterials, stromal cells, and growth factors have demonstrated promising outcomes in vitro and in vivo. Natural and synthetic bone grafts combined with Mesenchymal Stromal Cells (MSCs) and growth factors have shown encouraging results in regenerating critical-size cranial defects. One of prevalent growth factors is Bone Morphogenetic Protein-2 (BMP-2). BMP-2 is defined as a gold standard growth factor that enhances new bone formation in vitro and in vivo. Recently, emerging evidence suggested that Megakaryocytes (MKs), induced by Thrombopoietin (TPO), show an increase in osteoblast proliferation in vitro and bone mass in vivo. Furthermore, a co-culture study shows mature MKs enhance MSC survival rate while maintaining their phenotype. Therefore, MKs can provide an insight as a potential therapy offering a safe and effective approach to regenerating critical-size cranial defects.

Photoencapsulated-BMP2 in visible light-cured thiol-acrylate hydrogels for craniofacial bone tissue engineering.

Aim: The study aimed to examine the impact of crosslinking BMP2 in biodegradable visible light-cured thiol-acrylate hydrogels. Materials & methods: BMP2 was photoencapsulated in 10 wt% PEG-diacrylate hydrogels with or without immortalized mouse bone marrow stromal cells (BMSC). Results & conclusion: Photoencapsulated-BMSC with BMP2 (BMBMP2) showed a significantly (p < 0.05) increased level in metabolic activity, by 54.61%, compared with photoencapsulated-BMSC at day 3. Furthermore, BMBMP2 groups showed significantly increased levels in ALP activity compared with BMSC at days, 1, 3, 7 (p < 0.01) and 10 (p < 0.05). This study shows promising results photoencapsulating BMP2 in thiol-acrylate hydrogels for craniofacial bone tissue engineering applications.

Photoencapsulated-mesenchymal stromal cells in biodegradable thiol-acrylate hydrogels enhance regeneration of craniofacial bone tissue defects.

Aim: This study investigated biodegradable thiol-acrylate hydrogels as stem cell carriers to facilitate cranial bone regeneration. Materials & methods: Two formulations of thiol-acrylate hydrogels (5 and 15 wt% Poly[ethylene glycol]-diacrylate [PEGDA] hydrogels) were used as stem cell carriers. Bone marrow mesenchymal stromal cells and dental pulp mesenchymal stromal cells were photoencapsulated and cultured in basal or osteogenic medium 3 days before the surgery. Using New Zealand White Rabbits, four defects (5 mm diameter and 2 mm thickness) were created and hydrogel scaffolds were implanted in each rabbit cranium for 6 weeks. Results & Conclusion: AlamarBlue assay showed increasing metabolic activity levels in 5 wt% PEGDA hydrogels than 15 wt% PEGDA hydrogels. Photoencapsulated-mesenchymal stromal cells in 15 wt% PEGDA hydrogels demonstrated significantly increasing alkaline phosphatase activity levels on day 7 compared with days 1 and 3. Histological diagnosis showed 5 wt% PEGDA hydrogels resulted in lower averaged residual gel areas than 15 wt% PEGDA hydrogel specimens and control groups 6 weeks postimplantation.