The skeletal muscle is an immunologically unique tissue. Leukocytes, virtually absent in physiological conditions, are quickly recruited into the tissue upon injury and persist during regeneration. Apoptosis, necrosis and autophagy coexist in the injured/regenerating muscles, including those of patients with neuromuscular disorders, such as inflammatory myopathies, dystrophies, metabolic and mitochondrial myopathies and drug-induced myopathies. Macrophages are able to alter their function in response to microenvironment conditions and as a consequence coordinate changes within the tissue from the early injury throughout regeneration and eventual healing, and regulate the activation and the function of stem cells. Early after injury, classically activated macrophages (‘M1’) dominate the picture. Alternatively activated M2 macrophages predominate during resolution phases and regulate the termination of the inflammatory responses. The dynamic M1/M2 transition is increasingly felt to be the key to the homeostasis of the muscle. Recognition and clearance of debris originating from damaged myofibers and from dying stem/progenitor cells, stromal cells and leukocytes are fundamental actions of macrophages. Clearance of apoptotic cells and M1/M2 transition are causally connected and represent limiting steps for muscle healing. The accumulation of apoptotic cells, which reflects their defective clearance, has been demonstrated in various tissues to prompt autoimmunity against intracellular autoantigens. In the muscle, in the presence of type I interferon, apoptotic myoblasts indeed cause the production of autoantibodies, lymphocyte infiltration and continuous cycles of muscle injury and regeneration, mimicking human inflammatory myopathies. The clearance of apoptotic cells thus modulates the homeostatic response of the skeletal muscle to injury. Conversely, defects in the process may have deleterious local effects, guiding maladaptive tissue remodeling with collagen and fat accumulation and promoting autoimmunity itself. There is strong promise for novel treatments based on new knowledge of cell death, clearance and immunity in the muscle.
M1/M2 timely transition triggered by the recognition of apoptotic cells in the skeletal muscle is a key to tissue homeostasis.
Regulatory T lymphocytes accumulate in the injured skeletal muscle and are instrumental for healing, whereas conventional CD4+ or CD8+ T lymphocytes are found in persistently inflamed muscles.
Defective clearance of dead cells prompts maladaptive muscle remodeling with deposition of collagen and fat.
The generation of apoptotic cell-derived autoantigens induces autoimmunity and self-maintaining immune-mediated tissue damage in the presence of type 1 interferon.
Which are the phagocytic receptors and bridging molecules involved in the recognition of apoptotic cells in the muscle and how do they influence the outcome of the clearance?
Do regulatory T cells control immune cell function in muscle and physiologically restrict autoimmunity in the tissue?
Would it be possible to revert the noxious effects of maladaptive tissue remodeling and of autoimmunity by prompting debris disposal?
Unique Immune Privileges of the Skeletal Muscle
Immune privilege is an evolutionary conserved adaptation that protects vulnerable tissues from the noxious effects of inflammation. Allogeneic transplanted tissues are not rejected when transplanted in privileged sites, or immunological ‘sanctuaries’, that are often crucial for the survival either of the individual (the eye and the brain) or of the species (gonads, the pregnant uterus).1, 2 The immune privilege could provide an evolutionary advantage, making immune responses less likely to cause irreversible damage in sites in which cells cannot be easily replaced.3 The immune privilege involves systemic and local regulatory events. They include the physical separation from the immune system by anatomical or functional barriers, such as the blood–brain or the blood–retina barriers,4 a limited constitutive expression of major histocompatibility complex (MHC) molecules, the absence of resident professional antigen-presenting cells (APCs) and a scant lymphatic drainage. When barriers are disrupted, immune-privileged sites initiate regulatory processes that: (1) limit the extent of immune activation and (2) select the potentially less damaging immune response. This has been well characterized in particular for the ocular immune privilege5 but plays a role in the homeostasis of other immunologic sanctuaries, including the brain.6
The skeletal muscle is the largest cellular compartment of the body, characterized in physiological conditions by a relatively slow turnover. It is an immunologically unique tissue or a ‘nonclassical’ immunological privileged site. It is not endowed with anatomical barriers and the lymphatic vasculature is well represented. However, immune cells, including APCs, are in physiological conditions virtually absent and the tissue expression of MHC class I or class II molecules is limited (Figure 1). Moreover, the outcome of sterile inflammation in the skeletal muscle appears to be the recruitment of alternatively activated macrophages and of regulatory T cells that play non-redundant roles in muscle regeneration and possibly contribute to limit autoimmunity7, 8 (see below). Thus, muscle inflammation comprises signals that possibly contribute to initiate tissue regeneration and to terminate it in a timely manner once the tissue has healed and its homeostatic function is no longer required. Data in recent years indicate that the recognition and the clearance of cells dying in the skeletal muscle are critical for muscle homeostasis and maintenance of tolerance. This paradigm, even if exquisitely unique of muscle immunobiology, could be important to understand the link between inflammation and tissue repair at other anatomical sites.
The Prey: Cell Death in the Skeletal Muscle
DNA fragmentation, caspase activation and mitochondria apoptosis-associated protein release have all been described in the muscle as a consequence of trauma, hindlimb unloading, disuse, genetic defect including dystrophy or age-associated sarcopenia.9, 10, 11, 12 The stereotyped sequence of events that characterize apoptosis of single cells can hardly account for the complexity of the programmed death of multinucleated myofibers. Programmed death causes the selective removal of individual targeted myonuclei and of ‘myonuclear domains’, the limited areas of cytoplasm that individual myonuclei support.13, 14 Muscle fiber segment with TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling)-positive nuclei alongside intact nuclei has been described.15 Myonuclear apoptosis might contribute to skeletal muscle atrophy (however, see Bruusgaard et al.16). Apoptosis in response to acute muscle injury appears more straightforward and is modulated by metabolic pathways involving ganglioside biosynthesis.17
Myofibers also dispose of damaged organelles by autophagy that is activated during muscle atrophy and variably contributes to the loss of muscle mass.18, 19 The apoptotic process in the skeletal muscle might be preferentially activated to face defective autophagy,20 suggesting that the two processes are intermingled. Both apoptosis and autophagy possibly contribute to age-related sarcopenia that is associated with loss in the overall mass and with a reduced number of myofibers.14, 21, 22, 23, 24, 25
Disorganization of myofibrils with Z line loss, mitochondrial swelling and sarcolemmal disruption are hallmarks of the skeletal muscle necrosis. Intracellular moieties including myoglobin, creatine phosphokinase (CK) and other sarcoplasm proteins are released into the bloodstream.26 During intense exercise, on-going cell death and DNA fragmentation together with undamaged sarcolemma and preserved contractile proteins are detectable in the muscle.27, 28 Necrosis-released enzymes are found in human blood after eccentric muscular contractions as those performed during marathon, weight-bearing exercises and downhill running.29, 30 Serum CK might not only reflect fiber disruption. In highly energy-demanding conditions, fibers might prevent the bioenergetic collapse by the expulsion of ATP-consuming enzymes. CK would be redistributed to membrane blebs whereas bleb extrusion would allow expulsion of the enzyme.31
Acute sterile injury of the skeletal muscle results in the early mitochondrial generation of reactive oxygen species (ROS). These organelles undergo rapid disruption at later time points and non-mitochondrial sources of ROS generation emerge. In parallel, an antioxidant response is activated in both regenerating fibers and leukocytes that express high levels of free thiols and antioxidant enzymes.32 Intracellular damage-associated molecular patterns (DAMPs) are also released after injury, and their inflammatory action in the extracellular environment might contribute to recruit inflammatory phagocytes, to activate them and to prompt the immunogenicity of dying cells.33 The prototypical DAMP, high-mobility group box 1 (HMGB1), is a redox-sensitive moiety that in a predominantly reduced environment preferentially promotes leukocyte recruitment, upon formation of heterocomplexes with the chemokine (C–X–C motif) ligand 12 chemokine. The partially oxidized isoform in contrast preferentially activates the Toll-like receptor-4 (TLR4) with downstream chemokine and cytokine release.34, 35, 36 The terminally oxidized sulfonate isoform appears even less able to attract leukocytes or to elicit cytokines, even if it maintains the ability to modulate neutrophil integrin transactivation and degranulation.37
HMGB1 is weakly expressed in healthy muscles.32 The expression increases during regeneration in parallel with the antioxidant response in both fibers and leukocytes. A reduced environment may be important to maintain HMGB1 bioactivity. Indeed, oxidation abrogates both muscle stem cell migration in response to HMGB1 and their ability to differentiate into myofibers in vitro.25, 32, 38, 39 The early antioxidant response in regenerating muscle might limit HMGB1 oxidation, thus allowing the timely recruitment of leukocytes, the activation of muscle stem cells, the reconstitution of the vasculature and the eventual successful muscle regeneration.25, 39 Of importance, HMGB1 expression is modulated upon persistent immune-mediated damage of the muscle during inflammatory myopathies, suggesting that its generation might contribute to the natural history of these conditions.40, 41
Apoptosis, necrosis and autophagy represent extremes of the response of the muscle to injury and often coexist (Figure 2). They have been extensively studied in animals exploiting various experimental models of damage. Most models recapitulate the sequence of injury/inflammation/regeneration, even if they are characterized by different patterns of tissue remodeling, kinetics of repair and leukocytes preferentially involved. Table 1 summarizes the most widely used injury models.
Cell death has also been extensively studied in patient specimens and in experimental models of neuromuscular disorders, including inflammatory myopathies, metabolic and mitochondrial myopathies, dystrophinopathies and drug-induced myopathies.42, 43 Muscle dystrophies are paradigmatic examples of muscle fiber loss by necrosis,44 even if segmental apoptosis occurs with areas of caspase expression and TUNEL positivity adjacent to necrotic zones.45 Apoptosis has been described in inflammatory myopathies,46, 47 at least in some cases as a result of the cytotoxic action of T lymphocytes. Finally, the generation of neutrophil extracellular traps (NETs), an event strictly associated with the activation of autophagy pathway in inflammatory leukocytes48 and modulated by the recognition of apoptotic cells,49 has been described in the muscle upon ischemia–reperfusion injury.50 Further studies will evaluate the relevance of NET contribution to muscle remodeling during autoimmune diseases and in homeostatic conditions.
Besides myonuclear apoptosis and myofiber necrosis, other cells die in the midst of the inflamed skeletal muscle (Figure 2). This is specifically the case of muscle stem cells and of stromal cells including fibroadipogenic progenitors (FAPs). Skeletal muscle injury is known to be associated with the early proliferation of the best-characterized muscle stem cells, the satellite cells. A fraction of proliferating satellite cells die, as assessed by positivity of the TUNEL assay and by the cleavage of poly ADP ribose polymerase, via a pathway involving the Foxo3 transcription factor.51 Specific pathways have apparently been generated to modulate the ability of satellite cells to survive in response to various environmental stimuli including those related to the angiopoietin 1/Tie2 system,52 to the member of the Melanoma-associated antigen D1 family of proteins, necdin,53 and to the thyroid hormone.51 FAPs comprise multipotent mesenchymal progenitor cells54 that are a source of matrix-secreting activated myofibroblasts in the skeletal muscle.55 Their fate appears to be finely regulated by the extent and by the characteristics of the inflammatory response (see below) and their regulated death and clearance is possibly critical to prevent tissue fibrosis. Defective FAP clearance reflects and contributes to the maladaptive remodeling of the skeletal muscle.56
Inflammatory leukocytes represent another source of dying cells in the damaged/regenerating skeletal muscle. Their fate has not been characterized in detail. The kinetics of their accumulation in the tissue and the insight derived from the studies of apoptosis in other inflamed tissues strongly imply that regulated death and phagocytic clearance of infiltrated leukocytes are a prerequisite for appropriate resolution of the inflammatory response and possibly for repair of the injured tissue.57
The Regeneration of Injured Muscles Depends on Inflammation
Skeletal muscle has a remarkable capability to regenerate. Main players are the satellite cells, localized between the basal lamina and the fiber membrane.58 Satellite cells leave the quiescent state, characterized by expression of the paired-box protein Pax7,59 and proliferate, eventually yielding myoblasts that express the MyoD regulatory factor.60 After multiple cell divisions, myoblasts terminally differentiate and fuse, forming small centronucleated fibers that gradually grow in size providing complete muscle regeneration.60, 61, 62, 63
Leukocytes are quickly drawn into the damaged muscle. An epimysial/perimysial connective tissue-resident macrophage population possibly endowed with antigen-presenting capacity and with the ability to migrate into the draining lymph would be in charge of the early attraction and local activation of inflammatory cells.64 Other sentinels of tissue injury, including platelets and mast cells,65 are likely to contribute. Leukocytes are constantly detectable in the injured muscle while the regeneration process occurs. They disappear once the tissue is completely healed.66 Polymorphonuclear cells, including neutrophils and eosinophils, are the first leukocytes to be recruited in the damaged tissue. Shortly after, macrophages accumulate and subsequently become the dominant leukocyte population.67, 68 Macrophages are responsible for the removal of cellular debris, most likely including those derived from dying eosinophils and neutrophils (see above). Their ability to perceive the characteristics of the tissues that dramatically change from the early injury throughout regeneration and eventual healing and to coordinate the activation and the function of stem cells is critical for muscle homeostasis69, 70, 71 (see below). Lymphocytes also accumulate in the injured skeletal muscle. In normal conditions they mostly comprise regulatory T cells and are instrumental for healing. This action is mediated by the productive interaction with muscle stem cells.7, 8 In contrast, the accumulation of conventional CD4+ or CD8+ T lymphocytes reflects persistent inflammatory and immune-mediated injury, such as that taking place as a consequence of muscular dystrophy or inflammatory myopathies.72, 73 Figure 3 depicts some cellular players of muscle regeneration.
Muscle stem cells fail to activate their regenerative potential in the absence of the inflammatory response.66, 70, 74 The release of DAMPs/alarmins as a consequence of cell death and of immune cell activation might be important in the reciprocal activation/regulation of immune and of muscle stem/progenitor cells. The availability of novel elegant genetic inducible cell-fate mapping models will be valuable for the better understanding of the overall scenario. In skeletal muscle, immune responses depend almost completely on recruited inflammatory cells that decode the need of the tissue for healing and broadcast the news to resident stem/progenitor cells. Thus, the characteristics of immune cell activation are critical.
The Predators: Macrophages Scavenge Muscle Debris
Despite the significant amount of cell death that occurs in inflamed muscle, under physiological conditions cell remnants are extremely rare, indicating that the debris disposal mechanisms are effective. Macrophages are essential. Their depletion results in the persistence of cell remnants, deriving either from necrotic fibers, dying progenitor cells or inflammatory leukocytes. Moreover, upon depletion of macrophages muscle regeneration is severely compromised (reviewed in Bosurgi et al.70 and Tidballand and Villalta71). Macrophages and muscle regeneration are therefore closely associated. The dissection of the macrophage plasticity in the tissue has allowed in the past years to define more precisely the hierarchy of events in the maintenance of muscle homeostasis.
Macrophages that infiltrate the tissue at early time points after injury are classically activated inflammatory macrophages, also referred to as ‘M1’ cells. They generate inflammatory cytokines and sustain the activation and the proliferation of muscle stem cells.75 ‘Alternatively activated’ or ‘M2’ macrophages predominate during the resolution phases of the damage when they regulate the termination of the inflammatory responses.69, 76 Monocyte-derived macrophages undergo dynamic transitions between M1 and M2 and this timely transition is increasingly felt to be the key to muscle homeostasis.77, 78
MAP kinase phosphatase-1 (MKP-1) regulates cell remnant disposal, macrophage transition and muscle healing.79, 80 Gene expression analyses on sorted MKP-1−/− muscle macrophages suggest that MKP-1 regulates the inflammatory response as well as the macrophage polarization via p38 MAPK downregulation. Another enzyme, the AMP-activated protein kinase (AMPK)-α1, which ‘senses’ the cellular energy levels, also regulates the inflammatory status of macrophages. AMPK-α1-deficient macrophages fail to undergo an alternative M2 activation upon the recognition of apoptotic cells,81 suggesting a relationship between macrophage polarization and debris disposal. Studies on the cAMP response element-binding protein (CREB), a transcription factor involved in the upregulation of M2-associated genes, further strengthen the existence of a cause–effect relationship between recognition of apoptotic cells and acquisition of the macrophage ability to guide muscle stem cell regenerative potential. Deletion of CREB-binding sites from the C/EBPβ gene promoter indeed blocks the downstream induction of regulatory genes. Debris are effectively cleared but muscle fiber regeneration is severely jeopardized.76 In contrast, other crucial pathways, such as those coordinated by myeloid hypoxia-inducible factors, are apparently dispensable for M1/M2 shift and muscle healing after sterile injury.82 Of importance, other cells, including eosinophils and FAPs, are apparently involved in the clearance of necrotic muscle debris in experimental models56, 83 (Figure 2). Even myoblasts in vitro appear to be endowed with the ability to internalize apoptotic myoblasts.84 The actual contribution of these unconventional phagocytes in physiological conditions and their impact on the skeletal muscle immunobiology will require further study.
The expression of phagocytic tags by dying cells is fundamental for their recognition and clearance.85, 86, 87, 88 Relatively little is known on the role of phagocytic tags in the skeletal muscle. Exposure of anionic phospholipids, such as phosphatidylserine (PS), is among the best-characterized events involving in apoptotic cell recognition.89 Induction of fusion appears to cause death of a fraction of myoblasts.90 Intriguingly, PS recognition is important for the formation of myotubes.84, 91, 92 In vivo, expression of the well-characterized PS receptor BAI1 is required for muscle regeneration, further strengthening the link between cell death in the tissue, exposure and recognition of PS and successful tissue healing.84
Phagocytes uphold muscle stem cell differentiation and function. Conversely, muscle stem cells influence macrophages. This is the case for vessel-associated muscle stem cells (also referred to as mesoangioblasts), myogenic precursors that express pericyte markers and cross vessel walls;69, 93, 94 they sustain the ability of macrophages to clear apoptotic cells and promote the expression of genes associated with their alternative activation.95
Outcomes of Defective Apoptotic Cell Clearance: Maladaptive Muscle Remodeling with Ectopic Tissue Deposition
The skeletal muscle homeostasis is in most cases maintained upon injury. However, in some cases the original damaging noxa cannot be removed, such as in muscular dystrophies96 or in immune-mediated inflammatory myopathies (IIM).97 As a consequence, inflammation persists and repeated cycles of necrosis and regeneration ensue, eventually causing the substitution of myofibers with noncontractile elements such as fat, fibrotic tissue or bone.98
Acellular lipid droplets and adipocytes, defined based on triglycerides and cholesterol ester content and by the expression of peroxisome proliferator-activated receptor γ2, perilipin, leptin, adiponectin and fatty acid-binding protein 4, account for the muscle fat.99 Intra- and intermuscular fat is a histopathological hallmark of persistently damaged and inflamed muscles. Cells of mesenchymal origin yield adipocytes in vitro and in vivo, including satellite cells, fibroblasts, myoendothelial cells, pericytes, mesoangioblasts, PW1-expressing cells and FAPs.99
FAPs sustain satellite cell-driven myogenesis or directly differentiate into myoblasts in physiological conditions.54 When regeneration fails because of satellite cell defect55, 100 and/or inadequate inflammatory response,83 they generate adipocytes or differentiate into myofibroblasts. Myofibroblasts physiologically proliferate and synthesize extracellular matrix as scaffold to new fibers in reparative myogenesis. Upon injury resolution they induce matrix remodeling and degradation before undergoing apoptosis.101 The counterpart of this event, that is, a self-perpetuating matrix deposition, eventually causing fibrosis, is characteristic of the persistently inflamed skeletal muscle.56, 102, 103, 104
Heterotopic ossification may occur after severe traumatic skeletal muscle damage or neurological injury105 and seems to result from inappropriate differentiation of mesenchymal progenitors. Persisting inflammation, inadequate phagocytosis and bone morphogenetic proteins activation are all thought to contribute.106, 107 A rare genetic disorder, fibrodysplasia ossificans progessiva, associated with the activating mutation in the bone morphogenetic protein type I receptor ALK2 clearly highlights the link.108
Outcomes of Defective Apoptotic Cell Clearance: Autoimmunity
IIM leads to disability, decreased quality of life and increased mortality.109 Persistent inflammation with recruitment of autoreactive T cells characterizes the skeletal muscle.110, 111 Available evidence strongly supports the autoimmune underpinnings of IIM and commonly targeted autoantigens include proteins involved in DNA transcription or protein synthesis, such as the histidyl-tRNA synthase (HisRS).73, 112, 113, 114 Regenerating fibers appear a preferential source of autoantigens, suggesting that regeneration plays an important role in initiating and/or perpetuating the disease process.114 However, the signals that confer immunogenicity to a rather limited set of ubiquitously expressed intracellular antigens have only partially been characterized. Modifications of the autoantigens, including enhanced expression, altered distribution and/or access to phagocytes/APCs for processing, might be mechanistically important. Adjuvant signals selectively generated during various forms of inflammation might further influence the antigen presentation in given tissues. In turn, this might contribute to the onset and the maintenance of autoimmune responses targeting ubiquitously expressed antigens while selectively damaging particular tissues, such as the skeletal muscle in IIM.115
We have recently observed that despite its abundant expression in myogenic precursors within inflamed muscles, HisRS is not by itself fully immunogenic. Lack of immunogenicity could depend on: (1) the lack of access of an intracellular moiety to APCs that must process and cross-present epitopes to autoreactive T cells; and/or (2) a still noncharacterized action in the maintenance of tolerance of Treg populations that are physiologically recruited during regeneration of the tissue.7, 8
Apoptotic HisRS-expressing myogenic precursors might represent a preferential substrate for phagocytic uptake and processing by APCs. In fact, several observations support the relevance of the link between apoptosis and autoimmunity that has been extensively studied in other contexts. For example, the programmed death of keratinocytes influences the structure and the pattern of expression of intracellular antigens that are selectively redistributed to apoptotic bleb structures.116, 117 In turn, apoptotic cells represent immunogenic substrate for uptake and presentation to autoreactive lymphocytes.
Protective immunity targeting viral and neoplastic intracellular antigens and the establishment of self-sustaining systemic autoimmune diseases are among the in vivo consequences of the T-cell activation.118, 119, 120, 121, 122, 123, 124 Indeed, treatment with cancer cells killed with lethal doses of doxorubicin vaccinates mice against a subsequent challenge with living neoplastic cells of the same type and leads to the identification of the ‘immunogenic cell death’.125, 126 Various signals and processes influence the immunogenic outcome of the cell death including the action of DAMPs, like cell surface-exposed calreticulin, extracellular ATP and HMGB1, and the processes that make the DAMP available in the extracellular environment, such as endoplasmic reticulum (ER) stress, autophagy and plasma membrane permeabilization disruption upon necrosis. Implications of these concepts are being actively studied in particular in the oncology field and consensus guidelines for the detection of immunogenic cell death have been recently published.127
Of interest, virtually all the processes involved in facilitating DAMP release and biological action are well characterized in the inflamed skeletal muscle: HMGB1 is a critical signal not only in the physiological remodeling of the injured tissue (see above), but also plays well-characterized role in IIM.41, 128 Autophagy is critically involved in the physiologic response of the muscle to stressful conditions (see above). Impaired autophagosome maturation with consequent accumulation of multiprotein aggregates is a key factor in the myofiber degeneration characteristic of inclusion body myopathy, while evidence of sustained autophagic flux is detectable in IIM muscles.129 Upregulation of the expression of MHC class I molecules in skeletal muscle fibers is an early feature of IIM and ectopic expression of the molecule induced ER stress response and resulted in a disease that shares several features with human IIM.130, 131
Considering that muscle injury and the associated inflammatory response represent rather common event in vivo,109 the relative rarity of IIM indicates that a number of events must simultaneously occur to set the stage for self-sustaining autoimmunity. We have recently observed that apoptotic myoblasts are immunogenic only if appropriate adjuvants are provided in the injured/regenerating muscle.132 Specifically, apoptotic myoblasts in the presence of stimuli activating TLR7-dependent inflammatory pathways and the generation of type I interferon, a key cytokine expressed in IIM patients and physiologically produced by myogenic precursors,133 induce the production of anti-HisRS antibodies, linked to persistent leukocyte infiltration of the tissue, reproducing several features that occur in the tissue of patients with IIM132 (Figure 4).
Major histocompatibility complex
antigen presenting cells
reactive oxygen species
damage Associated Molecular Patterns
high-mobility group box 1
terminal deoxynucleotidyl transferase dUTP nick end labelling
neutrophil extracellular traps
MAP kinase phosphatase-1
AMP-activated protein kinase
cAMP response element-binding protein
histidyl t-RNA synthase
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The authors declare no conflict of interest.
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Sciorati, C., Rigamonti, E., Manfredi, A. et al. Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ 23, 927–937 (2016). https://doi.org/10.1038/cdd.2015.171
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