Plasma Membrane Repair: A Central Process for Maintaining Cellular Homeostasis.

Plasma membrane repair is a conserved cellular response mediating active resealing of membrane disruptions to maintain homeostasis and prevent cell death and progression of multiple diseases. Cell membrane repair repurposes mechanisms from various cellular functions, including vesicle trafficking, exocytosis, and endocytosis, to mend the broken membrane. Recent studies increased our understanding of membrane repair by establishing the molecular machinery contributing to membrane resealing. Here, we review some of the key proteins linked to cell membrane repair.

Attitudes of Dilated Cardiomyopathy Patients and Investigators Toward Genomic Study Enrollment, Consent Process, and Return of Genetic Results.

Precision medicine genetics study design requires large, diverse cohorts and thoughtful use of electronic technologies. Involving patients in research design may increase enrollment and engagement, thereby enabling a means to relevant patient outcomes in clinical practice. Few data, however, illustrate attitudes of patients with dilated cardiomyopathy (DCM) and their family members toward genetic study design. This study assessed attitudes of 16 enrolled patients and their family members (P/FM), and 18 investigators or researchers (I/R) of the ongoing DCM Precision Medicine Study during a conjoint patient and investigator meeting using structured, self-administered surveys examining direct-to-participant enrollment and web-based consent, return of genetic results, and other aspects of genetic study design. Survey respondents were half women and largely identified as white. Web-based consent was supported by 93% of P/FM and 88% of I/R. Most respondents believed that return of genetic results would motivate study enrollment, but also indicated a desire to opt out. Ideal study design preferences included a 1-hour visit per year, along with the ability to complete study aspects by telephone or web and possibility of prophylactic medication. This study supports partnership of patients and clinical researchers to inform research priorities and study design to attain the promise of precision medicine for DCM.

Therapeutic Development of Mesenchymal Stem Cells or Their Extracellular Vesicles to Inhibit Autoimmune-Mediated Inflammatory Processes in Systemic Lupus Erythematosus.

Since being discovered over half a century ago, mesenchymal stem cells (MSCs) have been investigated extensively to characterize their cellular and physiological influences. MSCs have been shown to possess immunosuppressive capacity through inhibiting lymphocyte activation/proliferation and proinflammatory cytokine secretion while simultaneously demonstrating limited allogenic reactivity, which subsequently led to the evaluation of therapeutic feasibility to treat inflammatory diseases. Although regulatory constraints have restricted MSC development pharmacologically, limited clinical studies have shown encouraging results using MSC infusions to treat systemic lupus erythematosus (SLE); but, more trials will have to be performed to conclusively determine the clinical efficacy of MSCs to treat SLE. Moreover, there are some data to suggest that MSCs possess tumorigenic potential and that the immunosuppressive influence can be dramatically affected by both donor variability and ex vivo expansion. Given that recent studies have found that the immunosuppressive effects of MSCs are a result, at least in part, to extracellular vesicle (EV) secretion, the use of MSC-derived EVs has been suggested as a cell-free therapeutic alternative. Despite the positive data observed using EVs isolated from human MSCs to suppress inflammatory responses in vitro and in inhibiting autoimmune disease pathogenesis in preclinical work, there are no studies to date examining EVs from MSCs to treat SLE in humans or animal models. Considering that EVs are not subject to the strict regulatory constraints of stem cell-based pharmacological development and are more readily standardized with regard to industrial-scale production and storage, this review outlines the anti-inflammatory biology of MSCs and the scientific evidence supporting the potential use of EVs derived from human MSCs to treat patients with SLE.

Delocalization of Endogenous A-kinase Antagonizes Rap1-Rho-α2C-Adrenoceptor Signaling in Human Microvascular Smooth Muscle Cells.

The second messenger cyclic AMP (cAMP) plays a vital role in the physiology of the cardiovascular system, including vasodilation of large blood vessels. This study focused on cAMP signaling in peripheral blood vessels, specifically in human vascular smooth muscle (microVSM) cells explanted from skin punch biopsy arterioles (also known as resistance vessels) of healthy volunteers. Using these human microVSM we recently demonstrated cAMP activation of exchange protein activated by cAMP (Epac), the Ras-related small GTPase Rap1A, and RhoA-ROCK-F-actin signaling in human microVSM to increase expression and cell surface translocation of functional α2C-adrenoceptors (α2C-ARs) that mediate vasoconstriction. Protein-protein association with the actin-binding protein filamin-2 and phosphorylation of filamin-2 Ser2113 by cAMP-Rap1A-Rho-ROCK signaling were necessary for receptor translocation in these cells. Although cAMP activated A-kinase in these cells, these effects were independent of A-kinase, and suggested compartmentalized A-kinase local signaling facilitated by A-kinase anchoring proteins (AKAPs). In this study we globally disrupted A-kinase-AKAP interactions by the anchoring inhibitor decoy peptide Ht31 and examined the effect on α2C-AR expression, translocation, and function in quiescent microVSM treated with the adenylyl cyclase activator and cAMP elevating agent forskolin. The results show that Ht31, but not the control peptide Ht31-P, reduced forskolin-stimulated Ser133 phosphorylation of A-kinase substrate CREB, reduced α2C-AR mRNA levels, reduced cell surface translocated receptors, and attenuated agonist-triggered receptor functional responses. Together, the results suggest that compartmentalized cAMP signaling elicits a selective cellular response in microVSM, which may have relevance to arteriole physiological function and responses.

Mechanosignaling in bone health, trauma and inflammation.

SIGNIFICANCE: Mechanosignaling is vital for maintaining the structural integrity of bone under physiologic conditions. These signals activate and suppress multiple signaling cascades regulating bone formation and resorption. Understanding these pathways is of prime importance to exploit their therapeutic potential in disorders associated with bone loss due to disuse, trauma, or disruption of homeostatic mechanisms. RECENT ADVANCES: In the case of cells of the bone, an impressive amount of data has been generated that provides evidence of a complex mechanism by which mechanical signals can maintain or disrupt cellular homeostasis by driving transcriptional regulation of growth factors, matrix proteins and inflammatory mediators in health and inflammation. Mechanical signals act on cells in a magnitude dependent manner to induce bone deposition or resorption. During health, physiological levels of these signals are essential for maintaining bone strength and architecture, whereas during inflammation, similar signals can curb inflammation by suppressing the nuclear factor kappa B (NF-κB) signaling cascade, while upregulating matrix synthesis via mothers against decapentaplegic homolog and/or Wnt signaling cascades. Contrarily, excessive mechanical forces can induce inflammation via activation of the NF-κB signaling cascade. CRITICAL ISSUES: Given the osteogenic potential of mechanical signals, it is imperative to exploit their therapeutic efficacy for the treatment of bone disorders. Here we review select signaling pathways and mediators stimulated by mechanical signals to modulate the strength and integrity of the bone. FUTURE DIRECTIONS: Understanding the mechanisms of mechanotransduction and its effects on bone lay the groundwork for development of nonpharmacologic mechanostimulatory approaches for osteodegenerative diseases and optimal bone health.