As structural components of the plasma membrane, lipids are responsible for contributing to membrane tension, rigidity, and overall shape. The long held dogma in the cardiac biology community was that these cells do not . HHS Vulnerability Disclosure, Help Lee I-H, Kai H, Carlson L-A, Groves JT, & Hurley JH (2015). Survival from bacterial pore-forming toxins utilizes both exocytic and endocytic responses. The vast majority of biochemical assembly and break down processeseven by the most complex organismsoccur within cells. These observations align well with the observed kinetics of membrane resealing, which suggests that plasma membrane wounds can be resealed within 30 seconds; however, restoration of membrane tension shortly afterward is required for successful membrane remodeling and completion of the repair process. How the cell membrane maintains the integrity of the cell? The discussion above illustrates several roles for lipids in changing biophysical properties of the injured plasma membrane during repair. The plasma membrane is a dynamic barrier that separates the cell interior from the extracellular space (Figure 2C). Each of these provides another mechanism for generating specific membrane lipids acutely in parallel to biosynthetic inputs. Disclaimer. Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, Andrews NW (2010). Enzymes that generate lipid signaling after plasma membrane injury (in red) include the phospholipases C and D (PLC and PLD), phosphatidyloinositol kinases (PI5K and PI3K), and sphingomyelinase (SMase). As MG53 interacts with the plasma membrane in a cholesterol-dependent manner ((Zhu et al., 2012); see Section 4), its extracellular role may involve a mode of action similar to poloxamer 188, where it inserts within membranes in a disordered lipid environment. Gurtner GC, Werner S, Barrandon Y, & Longaker MT (2008). In this way, lipids play an important role in polarizing the cellular response to an injury. Mechanistic principles underlying regulation of the actin cytoskeleton by phosphoinositides, Regulation of actin dynamics by PI (4, 5) P2 in cell migration and endocytosis, Pro-resolving lipid mediators are leads for resolution physiology. Int J Mol Sci. Intriguingly, PIP2 is needed for PLD activity suggesting the possibility that a feed-forward loop leads to increasing PIP2 concentrations as repair progresses ultimately facilitating the necessary build-up of F-actin (Figure 1B). Visualizing cytoplasmic flow during single-cell wound healing in Stentor coeruleus. official website and that any information you provide is encrypted It must repair itself, first by stopping the loss of cytoplasm, and then regenerate by rebuilding structures that were damaged or lost. (C) Plasma membrane is dynamic and individual lipids have the capacity to move laterally within a leaflet (shown in pink) and between the leaflets (shown in blue). Compared with cytosolic antioxidants, which can be detrimental to repair (Spaeth et al., 2012), vitamin E is membrane-localized and could therefore allow for the local buildup of oxidized lipids at the site of injury while preventing the global spread of lipid oxidation. Another role identified for lysosomal fusion in membrane repair is the secretion of the lipid modifying enzyme acid sphingomyelinase (ASM) (Defour et al., 2014; Tam et al., 2010). It remains possible that caveolar endocytosis does help partially balance membrane tension, but another possibility is that they serve as mechanosensitive platforms during membrane repair. Healing, Examples of self-repairing cells. Endogenous mechanisms of repair in healthy cells appear to mimic the beneficial effect provided by poloxamer 188 by allowing for transient increases in lipid mobility while restricting fluidity increase to a relatively small spatial or temporal window. MG53 (40) shows diffuse enrichment at injury sites within 2 s of membrane injury in a calcium-independent manner (150). Examples of self-repairing cells. While reassembly of the cortical cytoskeleton in the minutes following injury is known to restore membrane tension (described in Section 3.3), membrane remodeling also contributes to increasing tension. 2018 Apr 23;28(8):R392-R397. Mechanical feedback between membrane tension and dynamics. The physical and molecular mechanisms by which a cell can heal membrane ruptures and rebuild damaged or missing cellular structures remain poorly understood. Spatiotemporal dynamics of actin remodeling and endomembrane trafficking in alveolar epithelial type I cell wound healing. Inclusion in an NLM database does not imply endorsement of, or agreement with, Front Cell Dev Biol. The plasma membrane forms the physical barrier between the cytoplasm and extracellular space, allowing for biochemical reactions necessary for life to occur. Calcium-regulated exocytosis is required for cell membrane resealing. Patients with muscular dystrophy are more susceptible to injury from eccentric stretch (216), with studies in mouse models suggesting susceptibility to injury can escalate with multiple insults (53). 2008 Nov;18(11):552-9. doi: 10.1016/j.tcb.2008.09.001. Muscle fibers are subject to huge variations in membrane tension, due to their contractile activity. Self-repairing cells: How single cells heal membrane ruptures and restore lost structures Many organisms and tissues display the ability to heal and regenerate as needed for normal physiology and as a result of pathogenesis. The structural role of lipids may extend into the signaling role, which can then impact back on the structural characteristics of the repairing membrane by changing the composition or distribution of individual lipids. Membrane injury causes a local influx of calcium and activation of calpains. This study showed that endocytosis occurs after membrane resealing and is mediated by the CLIC/GEEC pathway effector GRAF1, which is implicated in repair of muscle fiber plasma membrane injury (Lenhart et al., 2015). Sphingosine 1-phosphate stimulates proliferation and migration of satellite cells: role of S1P receptors, Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. After an injury, the biophysical properties of the plasma membrane, and the individual lipids themselves, are altered, eliciting changes to membrane rigidity and fluidity. Lipid domaindependent regulation of single-cell wound repair, Rho family GTPases bring a familiar ring to cell wound repair. The chemical structure of the cell membrane makes it remarkably flexible, the ideal boundary for rapidly growing and dividing cells. These observations suggest that lipids are not bystanders during the repair process, but are instead actively involved in organizing the playing field on which repair machinery operates. 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). While it is unclear whether caveolae can provide structural assistance to the damaged membrane in the context of a large membrane injury (as opposed to sub-injury threshold stress, (Sinha et al., 2011)), caveolae may still provide a signaling function during the repair process. Roach AN, Wang Z, Wu P, Zhang F, Chan RB, Yonekubo Y, Du G (2012). An organelle (think of it as a cell's internal organ) is a membrane bound structure found within a cell. There are mechanisms that allow some products to enter or leave the cell either actively or passively. ASM activity at the plasma membrane has been shown to facilitate microvesicle shedding (Bianco et al., 2009). Recombinant MG53 protein modulates therapeutic cell membrane repair in treatment of muscular dystrophy. Treatment with Recombinant Human MG53 Protein Increases Membrane Integrity in a Mouse Model of Limb Girdle Muscular Dystrophy 2B. While being a mostly non-polar molecule, owing to its steroid backbone and hydrocarbon chain, cholesterol does possess a hydroxyl group opposite the hydrocarbon chain. This raises the intriguing possibility that MG53 may affect plasma membrane structural properties. (2013). Plasma membrane lipids are routinely interconverted as a means to maintain lipid homeostasis and for lipid-mediated signaling. government site. 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. PIP2 accumulation was observed as early as 4 seconds in mouse myofibers; however, it continued to accumulate even 1 minute post-injury suggesting a role in the later stages of repair (Demonbreun et al., 2016). increased lipid fluidity described in Section 3) and allows for the membrane associated PLD to diffuse outward from lipid rafts and interact with PIP2 in order to metabolize PC. Accessibility Presence of PS at the free membrane wound edge helps directs the annexin proteins to this site in a calcium-dependent manner, where they perform vital functions required for stabilization and shaping of the repairing membrane (see Section 3.3). Defour A, Van der Meulen JH, Bhat R, Bigot A, Bashir R, Nagaraju K, & Jaiswal JK (2014). 2023 Feb 28;24(5):4647. doi: 10.3390/ijms24054647. . Using these dating methods, it was inferred that fat cells (adipocytes) replace at a rate of 86% per year (BNID 103455). Failure of injured cells to repair results in cell death and activates a tissue repair response. Translocation of existing lipid species to the site of injury provides a mechanism to recruit and activate protein machinery. Therefore, injury-triggered protein-lipid interactions that result in modified lipids generates signaling that allows for changes in activity and localization of plasma membrane repair machinery. What is Mitosis? | Let's Talk Science "Self-repair: Our bodies are packages within packages. This phenomenon may be explained by the kinetic energy imparted on the membrane lipids by mechanical disruption, which can result in lipid mixing without relying on membrane tension (Petersen, Chung, Nayebosadri, & Hansen, 2016). As described above, damage to the plasma membrane transiently increases the mobility of individual lipids. The primary method for PIP2 formation in cells is by the activity of PI(4)P-5 kinase (PI5K) (Kolay, Basu, & Raghu, 2016). Unable to load your collection due to an error, Unable to load your delegates due to an error, Examples of self-repairing cells. 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). Bianco F, Perrotta C, Novellino L, Francolini M, Riganti L, Menna E, Clementi E. (2009). Cell Energy, Cell Functions | Learn Science at Scitable - Nature We use cookies to give you the best browsing experience. Daumke O, Lundmark R, Vallis Y, Martens S, Butler PJG, & McMahon HT (2007). Unauthorized use of these marks is strictly prohibited. Shed microvesicles containing streptolysin-O have been shown to also contain annexins A1 and A6 (219). Before An official website of the United States government. While PA mediates targeting to the membrane, Rac1 activity depends on PIP3, suggesting multiple roles for signaling lipids in GTPase activity after repair. Cells respond to mechanical stress by rapid disassembly of caveolae. However, in addition to this role, restoring membrane tension is another role that has been proposed for endocytosis after the membrane is resealed following a pore forming toxin injury (Skalman, Holst, Larsson, & Lundmark, 2018). Bomal E, Grandgeorge P, Yeo RJ, Candau N, Reis PM, Frauenrath H. Nat Commun. 2008 Dec 31. Shao S, Liao X, Xie F, Deng S, Liu X, Ristaniemi T, & Liu B (2018). MG53 nucleates assembly of cell membrane repair machinery. Similar benefits have been attributed to membrane stabilizing copolymers such as poloxamer 188, that improved repair after physiological mechanical injury (Plataki, Lee, Rasmussen, & Hubmayr, 2011), and injury to dystrophic cells (Houang et al., 2015; Yasuda et al., 2005). Their localization and function in response to injury is controlled by the patterning of anionic lipids such as PS, which is present at the wound edge and is a known binding partner of annexins (Gerke, Creutz, & Moss, 2005). A decrease in membrane tension precedes successful cell-membrane repair. Zhang KS, Blauch LR, Huang W, Marshall WF, Tang SKY. Cambridge (MA): Harvard Stem Cell Institute; 2008. 2017 Jul 11;114(28):7283-7288. doi: 10.1073/pnas.1705059114. The wounded cell can survive if a rapid repair response is mounted that restores boundary integrity. Lipids are a class of biomolecules, which are generally insoluble in water, and may refer to fatty acids, sterols, mono-, di-, and triglycerides, as well as phospholipids, among others. 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). Thus, DAG acts as a scaffold that initiates and coordinates downstream signaling pathways within a tight spatial and temporal window rather than as a marker of membrane injury for fast-acting structural proteins. Interestingly, as a result of caveolae flattening, EHD2 dissociates from the plasma membrane and translocates to the nucleus where it alters gene transcription (Torrino et al., 2018). For example, membrane shedding is a known mechanism of plasma membrane repair, which functions to limit the lateral expansion of the wound area (Andrews, Almeida, & Corrotte, 2014; Horn & Jaiswal, 2018). Stem cell therapy in pain medicine - PMC - National Center for When . 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). Semin Cell Dev Biol. Inherent plasticity and microfracture toughening mechanisms work together to prevent antlers from breaking. Gauthier NC, Masters TA, & Sheetz MP (2012). In this case, cholesterol actually increases the fluidity among these lipids, which prevents them from forming a gel-like phase that is incompatible with the overall fluid nature of the plasma membrane (Krause & Regen, 2014). Ligeti E, Dagher M-C, Hernandez SE, Koleske AJ, & Settleman J (2004). A different model for plasma membrane repair began to emerge when mammalian cells injured mechanically or by SLO pores were found to undergo massive endocytosis, after Ca 2+ -triggered exocytosis of lysosomes ( Figure 1 C). Please enable it to take advantage of the complete set of features! PMC Plasma Membrane Lipid Domains as Platforms for Vesicle Biogenesis and Shedding? Rapid actin-cytoskeletondependent recruitment of plasma membranederived dysferlin at wounds is critical for muscle membrane repair. Analysis of Dysferlin Direct Interactions with Putative Repair Proteins Links Apoptotic Signaling to Ca. They include glycerophosphocholines, glycerophosphoglycerols, glycerophosphoinositols, as well as triacylglycerols (Taverna, Nanney, Pollins, Sindona, & Caprioli, 2011). ESCRT machinery is required for plasma membrane repair. While a common thread in lipid signaling is the modification of a target protein, either directly or indirectly, the numerous mechanisms lipids use to achieve this outcome allows for a great diversity of signaling. These roles of lipids in plasma membrane repair include both a structural role and a signaling role. This signaling function may occur due to the activity of the repair protein EHD2, which accumulates at the site of membrane injury and is thought to play a role in shaping membrane dynamics (Daumke et al., 2007; Demonbreun et al., 2016; Marg et al., 2012). Diz-Muoz A, Fletcher DA, & Weiner OD (2013). The organization of lipids within the membrane also affects the structure of underlying cortical cytoskeleton. However, excessive force applied to the membrane can result in physical damage, such as the shear force applied on the endothelial cells by blood flow, on muscle cells during contraction, on lung alveolar cells during breathing, or by a blunt force trauma to any cell (Cong, Hubmayr, Li, & Zhao, 2017; Demonbreun & McNally, 2016; McNeil & Steinhardt, 2003). Mitochondrial fragmentation and ROS signaling in wound response and repair. Spatial arrangement of lipids is also known to regulate Rho family GTPase activity (see Section 4.3). FOIA Cebecauer M, Amaro M, Jurkiewicz P, Sarmento M. J. o., achl R, Cwiklik L, & Hof M (2018). Spontaneous resealing of plasma membrane, Spontaneous resealing of plasma membrane injuries in the nanometer range is opposed by, Calcium-activated exocytosis reduces membrane tension, Calcium-activated exocytosis reduces membrane tension and promotes spontaneous repair driven by lipid disorder, Very large plasma membrane disruptions (micron diameter) require membrane patching. In response to increased stress on the plasma membrane, caveolae have been proposed to act as mechanosensors, buffering membrane tension in response to mechanical stress (Cheng et al., 2015; Sinha et al., 2011). For example, Annexin 5 accumulates first to form a lattice structure, which provides a force opposing the tension at the wound edge (Bouter et al., 2011). Membrane tension: A challenging but universal physical parameter in cell biology, Paper presented at the Seminars in cell & developmental biology. For example, the cytoskeletal proteins interact with membrane lipids to supply the cortical tension that regulates the global shape of the plasma membrane and produces cell movement (Cebecauer et al., 2018; Sezgin et al., 2017). Sood P, Lin A, Yan C, McGillivary R, Diaz U, Makushok T, Nadkarni AV, Tang SKY, Marshall WF. In general, PIP2 is a positive regulator of F-actin polymerization and the presence of PIP2 increases the stability of the actin cytoskeletonplasma membrane interface. "Think of a . Thus, it is clear that there is a need to acknowledge the role of lipids as an active participant in the processes of both cell and tissue repair. In mammalian cells the majority of cellular cholesterol is found in the plasma membrane, where it can make up to 50% of lipid content (Van Meer, Voelker, & Feigenson, 2008). Water is essential to life. Interphase has three stages: G1, S and G2. Amongst other causes, this can be due to physical, chemical, infectious, biological, nutritional or immunological factors. 2023 Apr 4;122(7):1355-1363. doi: 10.1016/j.bpj.2023.03.001. This remodeling is likely provided by processes described previously: membrane endocytosis (Section 3.1) and membrane shedding (Section 4.1). The wounded cell can survive if a rapid repair respons Membrane Repair: Mechanisms and Pathophysiology While initial depolymerization of the local F-actin network is thought to assist with vesicle fusion and membrane shedding, delayed accumulation of F-actin may facilitate repair either by working in coordination with myosin to pull the wounded membrane edges toward each other or by providing a barrier and stabilizing function for the newly formed membrane. In order to balance any decrease in membrane tension, such as that caused by exocytosis, cells routinely utilize endocytosis, which reduces the membrane area and results in increased tension (Dai & Sheetz, 1995). 3.1 The Cell Membrane - Anatomy & Physiology Lysosome fusion is required for the process of repair (Reddy, Caler, & Andrews, 2001). Plasma membrane integrity in health and disease: significance and If you break a bone, your body immediately begins producing new cells to heal the damage. Disclaimer. The plasma membrane is not a homogenous mixture of the different lipids described above (Figure 2A). Sezgin E, Levental I, Mayor S, & Eggeling C (2017). EVs are known to be generated in response to plasma membrane injury of single cells, and this is required for successful repair (Jimenez et al., 2014; Scheffer et al., 2014). Myofiber injury in zebrafish was found to cause rapid loss of PIP2, followed by restoration to pre-injury levels by 30 seconds post-injury (Middel et al., 2016). Do Heo W, Inoue T, Park WS, Kim ML, Park BO, Wandless TJ, & Meyer T (2006). Regulation of Rac1 translocation and activation by membrane domains and their boundaries, Stressing caveolae new role in cell mechanics, Membrane cytoskeleton: PIP2 pulls the strings, The FluidMosaic Model of Membrane Structure: Still relevant to understanding the structure, function and dynamics of biological membranes after more than 40 years, Biochimica et Biophysica Acta (BBA)-Biomembranes. With larger injuries, the opposing force of membrane tension exceeds the resealing forces of lipid disorder at the edges of the disruption, negating the driving forces of spontaneous membrane resealing. One of the roles of lipid mobility may be to allow for the movement of individual lipids to form microdomains near the site of injury, which has been shown to be important for repair (Vaughan et al., 2014), perhaps by facilitating lipid-mediated signaling. This cell membrane provides a protective barrier around the cell and regulates which materials can pass in or out. 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. 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. (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). In either case, the outward budding of the membrane produced by these ceramide-rich microdomains is thought to assist in microvesicle shedding. "Knowledge of how single cells repair and regenerate themselves underpins our mechanistic understanding of cell biology and could guide treatments for conditions involving cellular damage." These examples illustrate the ability of cells to heal wounds and regenerate missing structures. This allows for the movement and patterning of lipids into signaling domains, changing the spatial arrangement of proteins that selectively interact with a particular lipid species. In a similar manner, PS signaling may be involved in the early recruitment of other membrane repair proteins such as dysferlin (McDade et al., 2014; Middel et al., 2016) and MG53 (Cai et al., 2009). Given their ability to traverse away from the site of synthesis (Verweij et al., 2019), the EVs generated during plasma membrane injury may activate both local and distant tissue regeneration responses needed for repair. Drescher DG, Drescher MJ, Selvakumar D, Annam NP. Copyright 2015 the American Physiological Society. Transient and local lipid peroxidation may affect membrane stabilization as peroxidation of polyunsaturated fatty acids changes head group separation and acyl chain interdigitation, increasing their molecular volume and causing formation of distinct cholesterol domains in the membrane, which increases the membrane rigidity (Jacob & Mason, 2005; Mason, Walter, & Mason, 1997). 2015 Sep;45:2-9. doi: 10.1016/j.semcdb.2015.09.023. Dysferlin-mediated phosphatidylserine sorting engages macrophages in sarcolemma repair. Self-repair: Our bodies are packages within packages. When cells have DNA damage but fail to undergo apoptosis, they may be on the road to cancer. The Biomimicry Institute empowers people to create nature-inspired solutions for a healthy planet. 2021 The Biomimicry Institute. Instead, distinct inter- and intra-leaflet heterogeneity exists. diacylglycerol - DAG) backbone are called glycerophospholipids (referred to as phospholipids hereafter) and make up the majority of the plasma membrane. Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, & McNally EM (2016). Elife. Torrino S, Shen W-W, Blouin CM, Mani SK, de Lesegno CV, Bost P, Chambon V (2018). This may allow these lipids and proteins to interact with new partners that were unavailable due to spatial segregation prior to injury. Self-repairing cells: How single cells heal membrane ruptures and Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy. The https:// ensures that you are connecting to the Accessibility Each month, well bring you a selection of compelling updates to this ever-growing library of biological strategies and innovations. Role of phosphatidylinositol 4, 5-bisphosphate in regulating EHD2 plasma membrane localization. These structural changes to lipids are both necessary for repair and potentially pathogenic if left uncorrected (Sreetama et al., 2018). The fluidity of the membrane is determined in part by its composition, with cholesterol and sphingolipid-rich regions being less fluid than those areas comprised primarily of phospholipids. National Library of Medicine National Library of Medicine The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). In the subsequent sections, we will discuss how this is achieved and utilized by the cell. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Donati MA (1998).