The context-dependent role of the Na+/Ca2+-exchanger (NCX) in pancreatic stellate cell migration

Loeck, Thorsten; Rugi, Micol; Todesca, Luca Matteo; Soret, Benjamin; Neumann, Ilka; Schimmelpfennig, Sandra; Najder, Karolina; Pethő, Zoltán; Farfariello, Valério; Prevarskaya, Natalia; Schwab, Albrecht

doi:10.1007/s00424-023-02847-3

Cited by 5 publications

(2 citation statements)

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“…However, in pancreatic stellate cells (PSCs) exposed to pH e 6.6 overnight, [Ca 2+ ] i is significantly lower, [Na + ] i significantly higher, and the membrane potential strongly hyperpolarized compared to cells kept at pH e 7.4 which impels the Na + /Ca 2+ exchanger NCX1 that usually removes Ca 2+ from the cytosol to function in reverse mode. According to this, NCX1 inhibition stimulates PSC migration at pH e 7.4 because Ca 2+ ions are retained in the cytosol, whereas it abates migration at pH e 6.6 due to a blocked Ca 2+ entry [ 85 ].…”

Section: Acid Primingmentioning

confidence: 99%

pH-regulated single cell migration

Stock

2024

Pflugers Arch - Eur J Physiol

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Over the last two decades, extra- and intracellular pH have emerged as fundamental regulators of cell motility. Fundamental physiological and pathological processes relying on appropriate cell migration, such as embryonic development, wound healing, and a proper immune defense on the one hand, and autoimmune diseases, metastatic cancer, and the progression of certain parasitic diseases on the other, depend on surrounding pH. In addition, migrating single cells create their own localized pH nanodomains at their surface and in the cytosol. By this means, the migrating cells locally modulate their adhesion to, and the re-arrangement and digestion of, the extracellular matrix. At the same time, the cytosolic nanodomains tune cytoskeletal dynamics along the direction of movement resulting in concerted lamellipodia protrusion and rear end retraction. Extracellular pH gradients as found in wounds, inflamed tissues, or the periphery of tumors stimulate directed cell migration, and long-term exposure to acidic conditions can engender a more migratory and invasive phenotype persisting for hours up to several generations of cells after they have left the acidic milieu. In the present review, the different variants of pH-dependent single cell migration are described. The underlying pH-dependent molecular mechanisms such as conformational changes of adhesion molecules, matrix protease activity, actin (de-)polymerization, and signaling events are explained, and molecular pH sensors stimulated by H+ signaling are presented.

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Section: Acid Primingmentioning

confidence: 99%

pH-regulated single cell migration

Stock

2024

Pflugers Arch - Eur J Physiol

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“…The sodium-calcium exchanger (NCX) plays a pivotal role in maintaining cellular Na + and Ca 2+ homeostasis. Studies have substantiated that NCX1 significantly contributes to the migratory behaviors of PSCs, with its impact intricately shaped by the specific cellular context in which it operates [69].…”

Section: Pressure-induced Activation Of Pscsmentioning

confidence: 99%

Activation and Regulation of Pancreatic Stellate Cells in Chronic Pancreatic Fibrosis: A Potential Therapeutic Approach for Chronic Pancreatitis

Kong,

Pan,

2024

Biomedicines

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In the complex progression of fibrosis in chronic pancreatitis, pancreatic stellate cells (PSCs) emerge as central figures. These cells, initially in a dormant state characterized by the storage of vitamin A lipid droplets within the chronic pancreatitis microenvironment, undergo a profound transformation into an activated state, typified by the secretion of an abundant extracellular matrix, including α-smooth muscle actin (α-SMA). This review delves into the myriad factors that trigger PSC activation within the context of chronic pancreatitis. These factors encompass alcohol, cigarette smoke, hyperglycemia, mechanical stress, acinar cell injury, and inflammatory cells, with a focus on elucidating their underlying mechanisms. Additionally, we explore the regulatory factors that play significant roles during PSC activation, such as TGF-β, CTGF, IL-10, PDGF, among others. The investigation into these regulatory factors and pathways involved in PSC activation holds promise in identifying potential therapeutic targets for ameliorating fibrosis in chronic pancreatitis. We provide a summary of recent research findings pertaining to the modulation of PSC activation, covering essential genes and innovative regulatory mediators designed to counteract PSC activation. We anticipate that this research will stimulate further insights into PSC activation and the mechanisms of pancreatic fibrosis, ultimately leading to the discovery of groundbreaking therapies targeting cellular and molecular responses within these processes.

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