REVIEW
Self-repairing cells: How single cellsheal membrane ruptures and restorelost structuresSindy K. Y. Tang1* and Wallace F. Marshall2*
Many organisms and tissues display the ability to heal and regenerate as needed for normalphysiologyandas a result of pathogenesis. However, these repair activities can also beobservedat the single-cell level.The physical and molecular mechanisms by which a cell can healmembrane ruptures and rebuild damaged or missing cellular structures remain poorlyunderstood.This Review presents current understanding in wound healing and regeneration astwo distinct aspects of cellular self-repair by examining a few model organisms that havedisplayed robust repair capacity, including Xenopus oocytes, Chlamydomonas, and Stentorcoeruleus. Although many open questions remain, elucidating how cells repair themselves isimportant for our mechanistic understanding of cell biology. It also holds the potential for newapplications and therapeutic approaches for treating human disease.
Cells are generally soft and easily damaged.However, many can repair themselves afterbeing punctured, torn, or even ripped inhalf when damaged during the ordinarywear and tear of normal physiology or
as a result of injury or pathology. A cell is like aspacecraft: When it is punctured, cytoplasm spillsout like oxygen escaping from a damaged spacemodule. Like Apollo 13, a damaged cell cannotrely on anyone to fix it. It must repair itself,first by stopping the loss of cytoplasm, and thenregenerate by rebuilding structures that weredamaged or lost. Knowledge of how single cellsrepair and regenerate themselves underpins ourmechanistic understanding of cell biology andcould guide treatments for conditions involvingcellular damage.A standard question that students are asked is
to define what it means to be alive. This is sur-prisingly hard to answer in a precise way, butsurely one of the remarkable features of livingsystems that distinguishes them from human-made machines is their ability to heal and repairthemselves. At the multicellular level, repair andregeneration are effected by generating new cellsto replace the ones that were lost. This type ofrepair thus ends up being a direct consequenceof another basic feature of living systems—theability of a cell to reproduce itself. No additionalprocesses need to be invoked beyond cell division.At the single-cell level, it ismuch less obvious howself-repair is accomplished.In this Review, we will distinguish wound heal-
ing from regeneration as two aspects of self-repairthat serve distinct purposes and discuss each as-pect separately.Wound healing is the process that
stops further loss of material, in much the sameway as a blood clot stops further loss of blood. Re-generation, by contrast, is the process by whichthe cell specifically rebuilds and replaces themiss-ing components (organelles, plasma membrane,cytoplasm, etc.) after the wound has been sta-bilized. Some cells can heal wounds but cannotregenerate. For example, if the giant unicellularciliateBursaria is cut in half, the halves heal theirsurfaces and live, but they lose all their corticalstructures, become spherical, encyst, and then re-develop an entirely new cortical pattern (1). We
contrast such cases from cells that are able to de-tect missing structures and specifically regener-ate the pieces that were missing or damaged.
Examples of self-repairing cells
Many cell types can heal wounds and regeneratemissing structures (Fig. 1). Neurons are sometimesable to repair and regenerate damaged axons (2, 3),which is important because neurons do not pro-liferate. Cardiacmyocytes routinely suffermechan-ical wounding as the heart beats and are able tosurvive and heal membrane ruptures (4, 5).Wound healing has been extensively studied
in Xenopus oocytes (6, 7). The Xenopus oocyte, al-though produced by a multicellular animal, is alarge, single cell easily obtained andmanipulated.Whenpuncturedwith either a glass needle or laserablation, the oocyte rapidly restores an intact plas-ma membrane.Some unicellular model systems illustrate cel-
lular regeneration. There is an advantage of study-ing free-living single-celled organisms in that theirnormal behavior can be examined without influ-ence from any neighboring cells, as would be thecase for cells within a tissue. This is importantbecause if a cell regenerates in a tissue context,one cannot be sure whether the necessary spatialinformation comes from the cell itself or frominformation supplied by neighboring cells.Chlamydomonas is a unicellular green alga sur-
rounded by a thick cell wall. Two motile flagella,~10 mm long, protrude fromholes in the cell wall,allowing the cell to swim.When the cell is stressed(for example, by pHshock), it severs its own flagella.This process, known as flagellar autotomy (8), pre-sumablyhelps the cell survive ahostile environment
REPAIR AND REGENERATION
Tang et al., Science 356, 1022–1025 (2017) 9 June 2017 1 of 4
1Department of Mechanical Engineering, Stanford University,Stanford, CA, USA. 2Department of Biochemistry andBiophysics, University of California–San Francisco, SanFrancisco, CA, USA.*Corresponding author. Email: [email protected] (S.K.Y.T.);[email protected] (W.F.M.)
Xenopus oocyte
Puncture
Flagellum
Loss ofcytoplasm
StresspH shock
Damagedneuron
Restoredplasmamembrane
Neurons Chlamydomonas
Fig. 1. Examples of self-repairing cells. Healing of a punctured Xenopus oocyte, where the darkand light halves represent the animal and vegetal poles, respectively. Regrowth of damaged axons inneurons. Regeneration of flagella in Chlamydomonas. In each case, regenerated components areindicated in red. The dots represent the loss of cell content from damaged sites.G
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by eliminating the only point of vulnerability notsurrounded by a cell wall. Once the stress is re-moved, flagella grow backwithin 90min. Flagellarregeneration inChlamydomonasprovides a simpleand highly reproducible paradigm for studying or-ganelle regeneration.Another classical system for studying regener-
ation in single cells is Stentor coeruleus (Fig. 2).Stentor is a giant, blue-colored ciliate that canreach sizes of more than amillimeter. A Stentorcell is cone shaped, with a circular oral apparatus(OA) consisting of thousands of cilia at the ante-rior end of the cell, specialized for sucking in foodparticles. Stentor cells show an amazing ability toself-repair afterwounding.Whenpieces of aStentorcell such as theOAare removedwith aglass needle,or when cells are cut in half, they can self-repairwithout losing cytoplasm (9). Instead, the cell con-tinues to live and can regenerate themissing com-ponents within hours (10). In bisected cells, bothhalves can regenerate because Stentor contains ahighly polyploidmacronucleus such that even smallcell fragmentswill contain enough genomic copiesto survive. Regeneration of the OA in Stentor hasbeen amajor paradigm for studying cellular regen-eration (Fig. 2). Although the OA is located at theanterior end of the cell, it does not at first re-generate in its original location. Instead, the cellsynthesizes all of the basal bodies necessary to as-semble the OA at a site on the surface of the cellroughly halfway down the length of the cell body,where narrow and wide pigment stripes meeteach other. These basal bodies organize into thecomplete structure of the OA, at which point it isknown as an oral primordium. The primordiumthen migrates to the anterior end of the cell andtwists into the correct orientation. This entire
process sometimes occurs spontaneously in thepresence of an existing OA, which is then re-sorbed and replaced by the new one. This re-placement process is termed “reorganization,”which is hypothesized to help ensure proper scal-ing of OA size with cell size as the cell grows.These examples illustrate the ability of cells to
heal wounds and regenerate missing structures.
Themechanisms used for self-repair in these casesremain unclear and pose an interesting challengefor cell biology. Several questions apply to bothwound healing and regeneration. First, does re-pair reflect a constitutive behavior or does it needan active pathway to be triggered? For example,given that the StentorOA is spontaneously replacedduring reorganization, can the regeneration of theOA simply be considered as an accelerated formof this same turnover process by which an OA isoccasionally replaced by a new one? Or is there adistinct signaling program that needs to be trig-gered to drive regeneration?Many self-organizingsystems can restore patterning after perturbation.It is important to determinewhether woundheal-
ing and/or regeneration represents a “response”where pathways need to be turned on, or whetherit simply reflects constitutive cellular activities. Ifrepair turns out to be triggered, what is the stim-ulus? How does the cell detect that something iswrong? Finally, once a repair response is triggered,how is it actually carried out at themolecular level?
Wound healing
Before discussing how wounds are repaired, wefirst consider the size and time scales that char-acterize thewound-healing problem. Openings incell membranes occur rather regularly, but not allopenings are recognized by the cell as a wound totrigger a healing response. For example, smallmembrane pores form spontaneously from lipidmotion. Studies on planar lipid-bilayer mem-branes found that when the pore is small (tensof nanometers or less), the restoring force arisingfrom membrane tension will reseal these pores(11, 12). Under physiological conditions, themem-brane can also be permeated in processes such asconjugation in bacteria, which use pili—tubelikeconduits (~10 nm)—to transfer DNA from onecell to another (13). In vitro, cellmembranes havebeen permeated during processes such as elec-troporation, microinjection, and more recently,“nanostraws,”which are hollowmetal-oxide nano-tubes (~100 nm) for intracellular delivery of ionsand molecules (14, 15). These processes do nottypically damage the cell, nor do they trigger awound response. So then, when is an openingrecognized as a wound?One perspective is to consider the function of
the membrane, which is to separate the intracel-lular environment from the external and to main-tain physiological concentrations of ions, proteins,and other macromolecules. A sudden change inthe intracellular environment could thus serve asa proxy to alert the cell to a membrane rupture.Specifically, influx of calcium ions is often a keytrigger for wound response (6, 16, 17). Physiolog-ically, this makes sense, given that Ca2+ is an im-portant intracellular messenger and underliesmany important signaling pathways. Excessiveintracellular Ca2+ levels are toxic and can lead tocell death (18, 19). Although nowork, to our knowl-edge, has explicitly described the minimum sizeof a membrane rupture that will trigger a woundresponse, one can expect that the opening shouldbe big enough and last long enough to allow theinflux of ions like Ca2+ to perturb the intracellularenvironment for the rupture to be recognized asa wound.Once a hole is recognized, how long does the
cell have to fix it before irreversible damage isdone? As with oxygen leaking from a spacecraft,loss can be tolerated, but only up to some limit.In the case of a cell, the woundmust be sealed intime to prevent the excessive loss of cell mass, aswell as the influx and accumulation of unwantedcomponents from the external environment. In theabsence of a wound response, one can apply theequation for the flow through a circular apertureto estimate the leakage rateQ of cell mass from apunctured cell (20). Assuming the cytoplasm is asimple fluid leaking out of a membrane wound,
Tang et al., Science 356, 1022–1025 (2017) 9 June 2017 2 of 4
OA is removed
from anterior
end of Stentorcoeruleus
Holdfast
Pigment
stripes
Assembly of an
oral primordium,
which migrates to
the anterior end
Existing OA is
absorbed, and
oral primordium
migrates to
anterior end
Primordium
reorganizes
into a new OA
Primordium
regenerates
into new OA
Regeneration Reorganization
Oral
primordium
Oral
primordium
Fig. 2. The regeneration and reorganization of the oral apparatus (OA) of Stentor coeruleus.Graylines indicate surface pigment stripes, and the red region indicates the oral primordium. At theopposite end from the OA, Stentor possesses a posterior holdfast,which the cell uses to attach itself toa solid substrate.
“Knowledge of how singlecells repair and regeneratethemselves underpins ourmechanistic understanding ofcell biology and could guidetreatments for conditionsinvolving cellular damage.”
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Q = r3DP/(3mi), where r is the radius of thewound, DP is the pressure difference across themembrane, and mi is the viscosity of the inner fluid.Assuming DP ~ 10 Pa and mi ~ 1 to 100mPa·s (1 to100 times that of water), the leakage rate wouldbe ~80 to 0.8% of cell volume per second for awound size that is 10% of cell size. This simpleapproximation ignores the complexity of manyaspects of the cell (e.g., viscoelastic properties ofthe cytoplasm).Nevertheless, purely fromthephys-ics and mass transport perspective, the approx-imation suggests that healing should take placeon the order of seconds to tens of seconds, in-stead of days, to prevent the excessive loss of cellmass. If we consider the influx of unwanted com-ponents (e.g., Ca2+) by simple diffusion, we get asimilar time scale t ~ x2/D ~ 1 to 10 s, for adistance x ~ 10 mmand a diffusivityD ~ 10−10 to10−11 m2/s (21). Indeed, in studies across quite awide range of cell types, including sea urchineggs (22), fibroblasts (23), and alveolar epithe-lial cells (24), the time scales of wound sealingwere around seconds to tens of seconds.However, some cells have been reported to take
minutes to even hours to seal the wound. It ispossible to rationalize such differences by consid-ering theparameters in themass-transport approx-imations above. For example, a low extracellularCa2+ level would slow down the diffusive influxand subsequent accumulation of Ca2+ to a levelnecessary to trigger wound response (17). Simi-larly, a high cellular viscosity would decrease theleakage rate of cell mass. In both cases, the cellwould not need to heal as quickly. Relevant to thefirst case, it was found that in the absence of Ca2+,sea urchin eggs did not seal their wounds (22).Relevant to the second case, earthworm giantaxons take minutes to heal. Coincidentally, theseaxons also have densely packed cytoskeleton,whichcan slow down diffusion (25).How do cells heal wounds on the necessary
time scale? Themechanism of wound healing hasbeen relatively well studied in a few model sys-tems such as sea urchin eggs andXenopus oocytesand has been reviewed elsewhere (6, 17, 26, 27).Herewewill briefly describe knownmechanisms.It is generally recognized that Ca2+ is necessaryto trigger a wound response. As early as 1930,Heilbrunn reported that Ca2+ is needed for woundhealing (28), a requirement seen in many celltypes (22, 29). The use of Ca2+ as the trigger forwound response makes sense not just because ofthe physiological importance of Ca2+ but also froman engineering perspective. For many cell types,unbound Ca2+ has the steepest concentration gra-dient across the cell membrane (~104-fold differ-ence for Ca2+; <102-fold difference for other ionssuch as Na+, K+, and Mg2+) (30, 31). Using an ionspecies with a steep gradient as a trigger increasesthe sensitivity of the cell to wounding events. Butwhat does calcium actually do to heal a wound?In general, Ca2+ has been shown to trigger two
complementarymechanisms on the basis of priorstudies in a few model organisms (Fig. 3): (i) Themembrane hole is patched asmembrane fusion isinduced through a range of processes, includingexocytosis, endocytosis, and the more recently de-
scribed “explodosis,”which involves the fusion ofintracellular compartments that then rupture out-ward from the cell to the external environment(17, 32). Extra membranes can be derived fromintracellular vesicles and organelles. (ii) An acto-myosin purse string that contracts around thewound is formed. This contraction brings intactmembrane and underlying cortical cytoskeletonto close the wound (6, 17).Ca2+ may not be the only signal that triggers
woundhealing. Recently, an oxidative species fromthe extracellular environment was found to playa role that is independent of the Ca2+-triggeredwound response. Upon the wounding of striatedmuscles, oxidationwasproposed to cause the oligo-merization of MG53, a muscle-specific tripartitemotif–family protein, and could recruit MG53-containing vesicles to the wound site (33). The en-try of Ca2+ then leads to the fusion of vesicles with
the membrane to patch the wound. In a separatestudy on the transection of neurons, it was foundthatmelatonin, an antioxidant, decreases healingrate, supporting oxidation as an additional triggerfor wound response (2).
Regeneration
Once a wound has healed, the cell faces the prob-lem of rebuilding damaged or lost structures. Apopulation of dividing cells might not need an ac-tive regenerationmechanism, because as the cellsproliferate, they will be building new structuresin the course of normal growth. In the absence ofan active regeneration pathway, cellular structureswould continue to grow in size and number andthen be partitioned between the daughter cellswhen the cell divides. For organelles that grow atconstant rate and then partition between daugh-ters, it has been shown that these two processesare sufficient to restore organelle size following aperturbation (34), but the restoration of size cantakemany cell generations. Other cells can rebuildlost or damaged structureswithin a single cell cycle.We will discuss two model systems—flagellar re-generation in Chlamydomonas and oral appara-tus regeneration in Stentor.Both flagellar regeneration in Chlamydomonas
(35) and oral regeneration in Stentor (36) are ac-companied by transcriptional activation and trans-lation of proteins related to the structure beingregenerated. Transcription is obligatory forStentorOA regeneration, but not for Chlamydomonas fla-gellar regeneration. If flagella are removed in thepresence of translational inhibitors, flagella stillregenerate but only to half the normal length (37),suggesting that new protein synthesis is triggeredduring regeneration to provide enough materialto reach the correct final length. How does a cell“know” that the flagellum or OA has been re-moved in order to trigger the transcriptional pro-grams? In principle, a cell could know a structureis missing by sensing (i) a loss of function of thestructure, (ii) removal of the structure leading tocellular stresses that occur when part of the cellis ripped out, or (iii) the absence of a signal mol-ecule produced by the structurewhen it is present.For flagella, whose function is to generate fluid
flow, paralysis does not induce regeneration butsevering does, suggesting that the stimulus is nota loss of function. If only one flagellum is severed,it will regenerate with similar kinetics to whenboth flagella are severed. While this happens, theother flagellum shortens until both flagella reachthe same length (38), presumably because of com-petition for precursor proteins (39). The two flagellathen regrow to thenormal length. If this experimentis repeated with translation inhibitors, the twoflagella reach a shorter length (38), implying thatgene expression can be triggered even by removalof just one flagellum. This result argues against amodel in which the presence of flagella producesan inhibitory signal that keeps the genes turned off.What is the trigger for regeneration in Stentor?
If an OA is grafted onto a cell that is in the pro-cess of regenerating, regeneration immediatelystops and the oral primordium is resorbed (40),suggesting that the presence of an OA generates
Tang et al., Science 356, 1022–1025 (2017) 9 June 2017 3 of 4
Vesicles
Plasma membrane
Ca2+ Oxidative species
Wound
Cortical
cytoskeleton
Fusion of membranes
derived from
intracellular vesicles
and organelles
Membrane
hole patched
Contraction of
actomyosin purse
string around wound
Fig. 3. Wound healing in model cells. Studiesin Xenopus oocytes and muscle cells found thatthe wound-healing process is triggered by theinflux of Ca2+ and oxidative species.G
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an inhibitory signal that prevents the formationof a new oral primordium. If a Stentor cell isscrambledwith glass needles, it will typically formoneor several oral primordia, but this is completelyprevented if a new OA is grafted onto the mincedcell (41). Conversely, if two cells are grafted to-gether, followed by the surgical removal of oneOA, two oral primordia form, even though oneintact OA remains (Fig. 4) (42). This experimentsuggests that the stimulus triggering regenerationis not the complete loss of all OAs but rather thelack of anOA corresponding to a primordiumsite.Nevertheless, it has been reported that regen-eration can be inhibited by insertion of an isolatedOA randomly into the cytoplasmof a regeneratingcell (43). The positional requirements for inhibitionthus remain unclear.
Opportunities and applications
Althoughmany studies on single-cell repair havebeen performed in lower organisms, the mecha-nisms identified have potential for new strategiesfor treating human disease. For example, metas-tasis can subject cancer cells to damagingmechan-ical forces. The ability of tumor cells to repair theirnuclear envelope, which often ruptures duringmetastasis when they penetrate tissues, is neces-sary for cell survival (44). Inhibition of nuclearrepair in such cells might reduce metastatic po-tential. In another example, cells can be punc-tured during attack by bacterial pathogens. Forexample, streptolysinO produced by Streptococcuspyogenes formsmembrane pores with diametersup to 38 nm (45). If it were possible to make cellsin a patient transiently more vulnerable to dam-age, this might induce a “scorched-earth defense,”whereby infected cells would die, limiting fur-ther spread of infection. Conversely, understand-ing how cells repair and regenerate holds thepotential for strategies in regenerativemedicine inwhich damaged cells can be induced to regeneratein situ, rather than replacing themwith new cells.Pursuing these opportunities requires the devel-
opment of tools and assays similar to those usedin tissue-level wounding studies. A reproducible,physiologically relevant, andhigh-throughput assaywould permit identification of gene expression andmolecular pathways involved. Wounding experi-ments in Stentor, for example, are still primarilybased onmanual surgery with glass needles (46).This method has not changed for over 100 yearsand is slow and not easily reproducible. Recently,laser ablation is increasingly used for wounding.Laser wounding allows precise control of boththe position and the size of the wound. The effectof a laser on cells is still an active area of research,however (47, 48). The speed at which cells arewounded may also be insufficient to generateenough cells in the same stage of their repairprocess for molecular studies such as RNA se-quencing. In addition to the wounding method,techniques areneeded to quantify healing.Wound-size measurement based on imaging is limitedby optical resolution and the availability ofmem-brane dyes. The alternative method—measuringrates of external dye uptake—can be misleading,as uptake depends on not only the wound size
but also the viscoelasticity of the cytoskeleton,which can change dynamically during the heal-ing process.Single-cell repair is increasingly recognized
to be a conserved phenomenon across a widerange of biological systems. Clearly, there arestill many open questions, in particular aboutthe molecular mechanisms of wound healingand regeneration. These phenomena also raiselarger questions. For example, the question ofwhat is the smallest cell fragment from whichcells can heal also leads one to think about theminimum set of components necessary for heal-ing and subsequent survival. Such a minimumset can perhaps be another approach to define a“minimum cell.” Understanding how cells repairthemselves is thus important not only for ourmechanistic understanding of cell biology but also,ultimately, for understanding what it means tobe alive.
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ACKNOWLEDGMENTS
The authors thank members of their respective labs for manyinteresting conversations. Work in the authors’ labs on wound healingand regeneration is supported by NSF award no. 1517089 (S.K.Y.T.and W.F.M.) and NIH grant GM113602 (W.F.M.), respectively. Bothauthors acknowledge support from NSF award no. 1548297.
10.1126/science.aam6496
Tang et al., Science 356, 1022–1025 (2017) 9 June 2017 4 of 4
OA
Two Stentor cells
are grafted together
to form a doublet
cell, which has
two OAs
One OA is
surgically
removed
Both of the fused
cells form oral
primordia (red)
Half of the doublet
regenerates and the
other reorganizes
Fig. 4. Evidence of oral regeneration inStentor.Oneof the strengths ofStentoras amodelsystem is the ability to graft cells and cell fragmentstogether to study regeneration and reorganization.G
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Self-repairing cells: How single cells heal membrane ruptures and restore lost structuresSindy K. Y. Tang and Wallace F. Marshall
DOI: 10.1126/science.aam6496 (6342), 1022-1025.356Science
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