These mediators promote wound resolution by acting upon the immune and endothelial cells and help to control the duration and nature of the immune and phagocytic cell infiltration at the injury site (Serhan, 2014). Another broad group of lipid carriers that are recognized for their role in activating stem cells are extracellular vesicles (EVs), which are released locally at the site of injury or from a distant site and through their lipid and other cargoes regulate regeneration of injured tissues by way of stem cell activation (Riazifar, Pone, Ltvall, & Zhao, 2017). This relies upon the coordinated action of the machinery that polarizes the repair response to the site of injury, resulting in resealing of the damaged membrane and subsequent remodeling to return the injured plasma membrane to its pre-injury state. and transmitted securely. Sheng R, Chen Y, Gee HY, Stec E, Melowic HR, Blatner NR, Fujiwara TK (2012). PTRF presumably contributes to the translocation of MG53 to the injury-site, where MG53 is also able to bind PS and become activated in an oxidation-dependent manner (Cai et al., 2009). Alteration in this response inhibits the subsequent stages, tissue regeneration and remodeling, leading to increased tissue scarring. However, these repair activities can also be observed at the single-cell level. Marmots maintain strong bones during hibernation by building up without breakingdown. Intriguingly, PA preferentially binds the Rho family member Rac1, resulting in nanocluster formation (Maxwell et al., 2018). Campelo F, Fabrikant G, McMahon HT, & Kozlov MM (2010). The plasma membrane is semi-permeable, allowing the cell to communicate with and utilize resources from its surrounding environment. Development of cell therapy and regenerative medicine using stem cells is expanding the medical industry and businesses as well as increasing the understanding of the nature of the cell itself. Cell damage (also known as cell injury) is a variety of changes of stress that a cell suffers due to external as well as internal environmental changes. In addition to their structural role in shaping the physical properties of the plasma membrane, lipids also play an important signaling role in maintaining plasma membrane integrity. Instead, distinct inter- and intra-leaflet heterogeneity exists. Sarcolemmal repair is a slow process and includes EHD2, Effect of oxidative stress on membrane structure: small-angle X-ray diffraction analysis. Sci Rep. 2023 Mar 23;13(1):4763. doi: 10.1038/s41598-023-31973-2. Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Eukaryotic cells have been shown to utilize calcium-activated exocytosis to reduce membrane tension and promote repair via lipid-disorder driven attractions. (2011). Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, Scheffer L. (2013). Before This is achieved in part through the activity of lipid modifying enzymes, such as phospholipases, which are activated by the changing biochemical environment after injury. Palmitate-mediated disruption of the endoplasmic reticulum decreases intracellular vesicle motility. Shear stress on the plasma membrane also results in the dissociation of the negative regulator RhoGDI and its binding partner Rho (Shao et al., 2018). Regulation of the actin cytoskeleton-plasma membrane interplay by phosphoinositides. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. Furthermore, individual lipids may be modified by proteins, which generate new lipid species that can change membrane structural properties (red, Cer) or be used for signaling (purple, DAG). We will highlight how lipids respond to injury and facilitate repair both at the level of individual molecules and at the bulk level by collectively altering the plasma membrane form and function. This phase represents restoration of the barrier function of the plasma membrane; however, cells must still undergo a membrane remodeling phase due to the presence of cytoskeletal as well as other repair proteins and lipids that accumulate during the repair process. Similar to the changes in tension described above, the fluidity of the plasma membrane is also dynamic after injury. Please enable it to take advantage of the complete set of features! Furthermore, exposure of the plasma membrane hydrophobic core as a result of reduced lipid packing provides the opportunity for injury-triggered lipid signaling through the binding of cholesterol (see Section 4). While this mechanism outlines how ESCRT proteins assemble, the lipid signaling that determines the appropriate spatial localization relative to the membrane injury in order to limit wound expansion has not been elucidated. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. 8600 Rockville Pike Cell before mitosis showing the location of the centrioles, microtubules, nuclear membrane, nucleolus, and DNA (Let's Talk Science using an image by Aldona via iStockphoto). Being the most abundant component of the plasma membrane, lipids are also essential player in the process of plasma membrane repair; however, much of the research committed to identifying the mechanisms of plasma membrane repair has focused on the proteins associated with plasma membrane repair (Cooper & McNeil, 2015). Calcium-regulated exocytosis is required for cell membrane resealing. It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. ESCRT assembly for membrane shedding is activated by the calcium-dependent ALG-2 protein, which then recruits its interacting partner ALIX leading to subsequent recruitment of the remaining complex members (Scheffer et al., 2014). This allows local and functional diversity between the two leaflets as well as various parts of the single contiguous plasma membrane (Figure 2B). The plasma membrane separates the extracellular environment from the cell interior, where biochemical reactions necessary for life occur. However, uninjured muscle cells from Limb Girdle Muscular Dystrophy 2B (LGMD2B) patients show increased membrane fluidity, which is associated with their poor membrane repair ability (Sreetama et al., 2018). This is notable because it is hypothesized that a beneficial role of decreasing membrane fluidity is preventing the spread of harmful lipid hydroperoxides, which likely form in the oxidative environment near the site of injury (Braughler & Hall, 1992; Hall, Wang, Miller, Cebak, & Hill, 2018). Why does our body heal itself? In contrast, Annexin 1, one of the earliest responders to plasma membrane injury (Leikina et al., 2015; McNeil, Rescher, Gerke, & McNeil, 2006), does not appear to be essential for plasma membrane repair (Leikina et al., 2015; McNeil et al., 2006). Gazzerro E, Sotgia F, Bruno C, Lisanti MP, & Minetti C (2010). PA is itself generated primarily from glycerol-3-phosphate, which is a product of glycolysis. While small injuries to the plasma membrane (on the nanometer scale) can be spontaneously resealed due to the line tension imposed by plasma membrane lipids alone (McNeil & Terasaki, 2001), larger membrane injuries (on the micron scale) require a series of coordinated mechanisms to undergo repair. A single cell is often a complete organism in itself, such as a bacterium or yeast. In addition to allowing for the lateral translocation of membrane lipids, injury-triggered increase in membrane fluidity also results in reduced lipid packing. While often considered to be a passive resident of the plasma membrane, there is ample evidence to support a more active role of lipids in the process of plasma membrane repair as well as tissue repair. In this review, we have discussed how lipids working at the individual as well as at the population level facilitate the proper orchestration of the repair response. Elife. (A) Plasma membrane phospholipids are generated from biosynthetic pathways, which rely on formation of the molecule diacylglycerol (DAG) or cytidine diphosphate diacylglycerol (CDP-DAG) from phosphatidic acid (PA). official website and that any information you provide is encrypted PTRF Anchors MG53 to Cell Injury Site for Initiation of Membrane Repair. Arun SN, Xie D, Howard AC, Zhong Q, Zhong X, McNeil PL, & Bollag WB (2013). While the structural importance of plasma membrane cholesterol is well appreciated, it can also play a role in signaling. Given their integral role in forming the structural backbone of the membrane, lipids are ideally placed to act as damage sensors, initiating early signaling that sets the stage for subsequent repair machinery. National Library of Medicine For example, PIP2 interacts with actin-associated proteins, resulting in a local strengthening of the plasma membrane-cytoskeleton interface. Abrams ST, Wang L, Yong J, Yu Q, Du M, Alhamdi Y, Cheng Z, Dart C, Lane S, Yu W, Toh CH, Wang G. Biomedicines. 2013 Dec 19;(82):e50848. Live tracking of inter-organ communication by endogenous exosomes in vivo. Limiting the spread of lipid hydroperoxides may also explain the beneficial effect of vitamin E treatment on plasma membrane repair (Howard, McNeil, & McNeil, 2011; Labazi et al., 2015). The site is secure. Along with the annexins, which act quickly to physically manipulate the membrane itself, reassembly of the cytoskeleton plays a crucial role in restoring membrane tension in the later stages of repair. 2012 Sep-Oct;52(3-4):191-5. doi: 10.1016/j.ceca.2012.06.003. Microfluidic guillotine reveals multiple timescales and mechanical modes of wound response in Stentor coeruleus. In this review, we will focus on the role of lipids during plasma membrane repair by discussing their functions as both structural and signaling molecules. Skalman LN, Holst MR, Larsson E, & Lundmark R (2018). After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. For example, when inserted into a region abundant in phospholipids, cholesterol has a rigidifying effect; however, the opposite can be true with sphingolipids. Gradients of Rac1 nanoclusters support spatial patterns of Rac1 signaling. Epub 2008 Mar 3. Would you like email updates of new search results? This helps to remodel the newly repaired plasma membrane (Middel et al., 2016), but may also serve to potentiate tissue inflammation. Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. Lateral movement, rotation, and flipping of lipids between the leaflets of the plasma membrane are the physical changes that work together to allow the fluid membrane to adapt to the changes in membrane tension (Nicolson, 2014) (Figure 2C). This site needs JavaScript to work properly. Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). Nojima H, Freeman CM, Gulbins E, & Lentsch AB (2015). Phospholipids and sphingolipids are connected by the head group choline, found on both PC and sphingomyelin (SM). Int J Mol Sci. Togo T, Krasieva TB, & Steinhardt RA (2000). Further, PE and PC head groups can be cleaved and replaced with serine to produce PS (Oropeza, 2017). Cholesterol modulates cell signaling and protein networking by specifically interacting with PDZ domain-containing scaffold proteins. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Different cell-intrinsic PM repair mechanisms have been reported, including membrane fusion and replacement strategies (via exocytosis-mediated repair), removal of damaged membranes (by. Multiplexed molecular descriptors of pressure ulcers defined by imaging mass spectrometry, Targeting and localized signalling by small GTPases. 2022 Dec 14;10(12):3256. doi: 10.3390/biomedicines10123256. For example, caveolae are the site for assembling membrane repair proteins such as EHD2 and MG53 (Cai et al., 2009; Daumke et al., 2007; Marg et al., 2012). Not only is the composition and organization of the plasma membrane in constant flux, the membrane itself also must interact with forces being applied to it from all directions. The plasma membrane has a unique lipid composition that helps distinguish its structural and functional properties from the other internal membrane-bound compartments. Regulation of actin binding proteins by PIP2 occurs in part through electrostatic interactions (Senju et al., 2017), suggesting that clusters of PIP2 molecules may be necessary to achieve build-up of F-actin itself. 2008 Dec 31. Verweij FJ, Revenu C, Arras G, Dingli F, Loew D, Pegtel DM, Zimmermann P (2019). Architectural and mechanistic insights into an EHD ATPase involved in membrane remodelling. Labazi M, McNeil AK, Kurtz T, Lee TC, Pegg RB, Angeli JPF, McNeil PL (2015). HHS Vulnerability Disclosure, Help Middel V, Zhou L, Takamiya M, Beil T, Shahid M, Roostalu U, Nienhaus GU (2016). "Self-repair: Our bodies are packages within packages. FOIA This structural arrangement is important for the organization of cholesterol in biological membranes as it results in the hydroxyl group associating with the neighboring lipid head groups and water, while the majority of the cholesterol molecule resides within the hydrophobic core of the membrane. Two-way traffic on the road to plasma membrane repair. One dead cell is not a big problem. HHS Vulnerability Disclosure, Help As muscle fibers have strong interfiber connections, muscle injuries may manifest both as shearing of the membrane from increased membrane tension and strain, as well as ripping of plasma membrane regions from fiber retraction or hypercontraction. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. Inclusion in an NLM database does not imply endorsement of, or agreement with, S100A11 is required for efficient plasma membrane repair and survival of invasive cancer cells, S100 and annexin proteins identify cell membrane damage as the Achilles heel of metastatic cancer cells. Cell death occurs mainly by two methods: necrosis and apoptosis. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998). Annexin A4 and A6 induce membrane curvature and constriction during cell membrane repair, Involvement of lipid peroxidation in CNS injury, Focal adhesions, stress fibers and mechanical tension. The site is secure. Van Meer G, Voelker DR, & Feigenson GW (2008).