promoting tissue regeneration by modulating the immune system

Accepted Manuscript Review article Promoting Tissue Regeneration by Modulating the Immune System Ziad Julier, Anthony J Park, Priscilla S Briquez, Mikaël M Martino PII: DOI: Reference: S1742-7061(17)30066-1 http://dx.doi.org/10.1016/j.actbio.2017.01.056 ACTBIO 4691 To appear in: Acta Biomaterialia Received Date: Revised Date: Accepted Date: 31 October 2016 January 2017 20 January 2017 Please cite this article as: Julier, Z., Park, A.J., Briquez, P.S., Martino, M.M., Promoting Tissue Regeneration by Modulating the Immune System, Acta Biomaterialia (2017), doi: http://dx.doi.org/10.1016/j.actbio.2017.01.056 This is a PDF file of an unedited manuscript that has been accepted for publication As a service to our customers we are providing this early version of the manuscript The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain Promoting Tissue Regeneration by Modulating the Immune System a,1 a,1 b Ziad Julier , Anthony J Park ,Priscilla S Briquez , Mikaël M Martino a a,* European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Victoria 3800, Australia b Institute for Molecular Engineering, University of Chicago, Chicago IL 60637, USA These authors contributed equally * To whom correspondence should be addressed: mikael.martino@emblaustralia.org Australian Regenerative Medicine Institute 15 Innovation Walk, Building 75, Level Martino lab Victoria 3800 Australia Tel: +61 990 29719 Abstract The immune system plays a central role in tissue repair and regeneration Indeed, the immune response to tissue injury is crucial in determining the speed and the outcome of the healing process, including the extent of scarring and the restoration of organ function Therefore, controlling immune components via biomaterials and drug delivery systems is becoming an attractive approach in regenerative medicine, since therapies based on stem cells and growth factors have not yet proven to be broadly effective in the clinic To integrate the immune system into regenerative strategies, one of the first challenges is to understand the precise functions of the different immune components during the tissue healing process While remarkable progress has been made, the immune mechanisms involved are still elusive, and there is indication for both negative and positive roles depending on the tissue type or organ and life stage It is well recognized that the innate immune response comprising danger signals, neutrophils and macrophages modulates tissue healing In addition, it is becoming evident that the adaptive immune response, in particular T cell subset activities, plays a critical role In this review, we first present an overview of the basic immune mechanisms involved in tissue repair and regeneration Then, we highlight various approaches based on biomaterials and drug delivery systems that aim at modulating these mechanisms to limit fibrosis and promote regeneration We propose that the next generation of regenerative therapies may evolve from typical biomaterial-, stem cell-, or growth factorcentric approaches to an immune-centric approach Keywords: Regenerative medicine; Immune system; Biomaterials; Drug delivery systems; Cytokines; Inflammation; Scarring; Fibrosis; Macrophages; T cells Introduction While remarkable progress has been achieved in understanding the cellular and molecular mechanisms of tissue repair and regeneration, it remains unexplained why mammals have a tendency for imperfect healing and scarring rather than regeneration There is ample evidence in different model organisms indicating that the immune system is crucial to determine the quality of the repair response, including the extent of scarring, and the restoration of organ structure and function A widespread idea derived from findings in diverse species is that the loss of regenerative capacity is linked to the evolution of immune competence (Fig 1) Still, there are many situations where the immune response to tissue injury promotes tissue healing Indeed, the relationship between tissue healing and the immune response is very complex, since there are both negative and positive roles, depending on the tissue, organ and life stage (embryonic, neonatal or adult) [1] The type of immune response, its duration and the cells involved can drastically change the outcome of the tissue healing process from incomplete healing and repair (i.e scarring or fibrosis) to complete restoration (i.e regeneration) In regenerative medicine, strategies based on stem cells and growth factors have not yet proven broadly effective in the clinic Here, we propose that immune-mediated mechanisms of tissue repair and regeneration may support existing regenerative strategies or could be an alternative to using stem cells and growth factors In the first part of this review, we present key immune mechanisms involved in the tissue healing process, in order to highlight potential targets In the second part, we discuss various approaches using biomaterials and drug delivery systems that aim at modulating the components of the immune system to promote tissue repair and regeneration The main actors of the immune response following tissue injury An immune response almost always follows tissue damage and this response is usually resolved within days to weeks after an injury The first phase of the immune response involves components of the innate immune system, which provide instant defense against potential pathogens invading the damaged tissue However, even in the absence of pathogens, the immune response initially triggered by danger signals released from damaged tissues produces a so-called sterile inflammation [2, 3] In many if not all tissues, the innate immune response strongly modulates the healing process For instance, macrophages and their various phenotypes play a predominant role in the restoration of tissue homeostasis by clearing away cellular debris, remodeling the extracellular matrix (ECM), and synthesizing multiple cytokines and growth factors The innate immune response is then followed by the activation of the adaptive immune system Although this was originally thought of as a secondary actor in the tissue healing process, the adaptive immune response to tissue injury most likely plays a critical role during tissue repair and regeneration, in particular the activity of T cells While a large research effort has focused on how transplanted mesenchymal stem cells (MSCs) modulate T cell activities and immune tolerance [4, 5], our understanding of how T cells modulate tissue-resident stem cells and the tissue healing process is just beginning In the next sections, we review the roles and importance of the main actors that shape the immune response following tissue injury 2.1 Danger signals Directly after tissue injury, a local inflammation is induced in response to damageassociated molecular patterns (DAMPs, or alarmins) and pathogen-associated molecular patterns Endogenous danger signals are typically released from necrotic or stressed cells and damaged ECM [2, 3] Well-known DAMPs include heat shock proteins (HSP), monosodium urate, high-mobility group box protein (HMGB1), extracellular ATP, and nucleic acids including mitochondrial DNA Inflammatory cytokines such as interleukin (IL)-1α and IL-33 can also work as DAMPs and are released passively from necrotic cells In addition, fragments from ECM components such as hyaluronic acid, collagen, elastin, fibronectin and laminin all stimulate inflammation [6, 7] Toll-like receptors (TLRs) and other types of pattern recognition receptors recognize danger signals and trigger inflammation via the activation of the transcription factors NF-κ B B or interferon-regulatory factors TLRs activate tissue-resident macrophages and promote the expression of chemoattractants for neutrophils, monocytes and macrophages (Fig 2A,B) They also induce the expression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α )), IL-1β and and IL IL-6 [8, 9] Interestingly, inflammation in response to necrotic cells is mostly mediated by IL-1 receptor (IL-1R), which leads to NF-κ B B activation activation [10] IL-33 also acts as a primary danger signal via the ST2 receptor [11] However, the dominant danger signal varies in the context of the injury, including the location, magnitude, manner of cell death, and time point after the injury [3] TLRs and IL-1R1 have been shown to negatively influence the repair of several tissues [12-22] For instance, the harmful effect of TLR4 signaling is apparent in many organs, as seen by the protection of TLR4-mutant or deficient mice after hepatic, renal, cardiac, and cerebral ischemia-reperfusion [12-16] Similarly, IL-1R1 signaling critically regulates infarct healing [17] and disruption of IL-1 signaling can improve the quality of wound healing [18, 20] In addition, it has been shown that IL-1R1/MyD88 signaling negatively regulates bone regeneration in the mouse by impairing the regenerative capacities of mouse MSCs [23] While TLRs and IL-1R1 seem to be detrimental for many tissues, studies have shown that skin wound healing is impaired in mice deficient for various TLRs [24-26] For example, TLR4 signaling helps wound healing through stimulation of transforming growth factor-β (TGF-β )) and CC chemokine ligands (CCL)-5 expression [24] Another endogenous TLR4 agonist, the extra domain A type III repeat of fibronectin (FNIII EDA) [27], has been reported to be overexpressed at sites of injury [28, 29], and is known to influence skin repair [30] For instance, wound healing in FNIII EDA knockout mice is abnormal [31] Overall, it is clear that danger signals significantly influence the healing process at early stages They are indeed necessary to induce inflammation, mainly via NF-κ B, and they are also involved in neutrophil, monocyte and macrophage mobilization Yet, in the case of ischemia-reperfusion and bone regeneration TLR and IL-R1 signaling seem to be detrimental 2.2 Neutrophils and mast cells Neutrophils are usually the first inflammatory cell recruited at a site of injury, enhancing host defense and wound detection while removing contaminants [32] (Fig 2A,B) The recruitment of neutrophils requires changes on endothelium surface mediated by histamine, cytokines, and chemokines such as C-X-C motif ligand (CXCL) that are released by tissue resident cells upon pattern recognition receptor and TLR activation This will triggers a recruitment cascade involving the capture of free flowing neutrophils, followed by their transmigration from the vasculature to the tissue, facilitated by an increase permeability of the blood vessels at the injured site [32] Neutrophils produce antimicrobial substances and proteases that help kill and degrade potential pathogens [33] In addition, they secrete cytokines and growth factors such as IL-17 and vascular endothelial growth factor (VEGF)-A, which recruit and activate more neutrophils and other inflammatory cells, promote angiogenesis, and stimulate proliferation of cells such as fibroblasts, epithelial cells and keratinocytes (Fig 2B) [33-35] Neutrophils are also able to deploy neutrophil extracellular traps (NETs) [36], made of chromatin, proteins and enzymes, able to catch pathogens and either directly kill them or facilitate their phagocytosis Yet, the formation of NETs (or NETosis) needs to be tightly regulated, since NETosis might impair the healing process For example, there are evidences of delayed reepithelization in the case of diabetes where NETosis is enhanced [37] This is consistent with the observation that neutrophil depletion might accelerate wound closure in diabetic mice [38] Importantly, neutrophils exhibit anti-inflammatory capacities They facilitate the recruitment of monocytes and macrophages, which phagocytize dying neutrophils and other cellular debris Thus, neutrophils promote their own removal and thereby contribute to the resolution of inflammation (Fig 2B) [34] For example, following myocardial infarction, neutrophils help controlling, macrophages, polarization, which is a critical step for proper tissue repair [39] Therefore, tightly controlling neutrophil mobilization and functions could be an interesting strategy to promote tissue repair and regeneration For instance, pro-resolving mediators derived from omega fatty acid have the ability to modulate neutrophil mobilization as well as their ingestion by macrophages [40] Similarly to neutrophils, mast cells participate in the innate immune response by secreting an array of effector molecules to recruit eosinophils and monocytes A large number of mast cells seem to be detrimental for tissue regeneration For example, they enhance acute inflammation and promote scarring in the central nervous system [41] Moreover, they persist at high numbers in chronic wounds [42] Nevertheless, controlling mast cells to promote regeneration rather than repair and scarring should be tempered, since mast cells also produce anti-inflammatory mediators, suggesting alternative and dynamic functions for these cells during repair [41] 2.3 Monocytes and macrophages In addition to their role as scavenger cells that phagocytise cellular debris, invading organisms, neutrophils and other apoptotic cells, macrophages actively regulate the tissue healing process [43] A population of tissue macrophages resides in most tissues, but a large number of macrophages are recruited after tissue injury, and these often greatly exceed the population of tissue-resident macrophages [44] The recruited and resident populations proliferate and undergo marked phenotypic and functional changes, in response to the tissue microenvironment Importantly, macrophages are a source of various proteases, cytokines, growth factors, ECM components and soluble mediators promoting tissue repair, fibrosis, or regeneration [43, 45, 46] Macrophages are differentiated from circulating monocytes which usually arrive at the damaged site to days after neutrophils (Fig 2A) [47] Their accumulation will often peak at to days after the injury, although elevated accumulations can be observed up to 21 days [48] The two main blood monocyte subsets in the mouse are the Ly6ChiCX3CR1midCCR2+ (CD62L+CD43low) and the Ly6ClowCX3CR1hiCCR2− (CD62L−CD43hi) monocytes [49] (human equivalents are the CD14+ and the CD14lowCD16+ monocytes) There low is some evidence to suggest that the primary function of LY6C cells is to survey endothelial hi integrity [50, 51] By contrast, Ly6C monocytes represent “classical monocytes” that are recruited to sites of inflammation [49] The two main chemokines/related receptors involved in the inflammation-dependent recruitment of monocyte subsets from blood, bone marrow and spleen are CCL2/CCR2 and CX3CL1/CX3CR1 (Fig 2B) [52, 53] For instance, fibroblast, epithelial, and endothelial cells surrounding the injured tissue produce CCL2, in response to DAMPs and inflammatory cytokines Interestingly, depending on the tissue, one or both monocyte subsets are recruited For example, only Ly6Chi monocytes are recruited from the circulation in muscle injury models [54, 55] They first acquire an inflammatory function and further mature into low Ly6C macrophages with repair functions However, after myocardial infarction, both monocyte subsets appear to home in the injured tissue at different stages of inflammation via CCR2 and CX3CR1, respectively [56] The Ly6Chi subset first infiltrates the infarcted low heart and exhibits inflammatory functions, while the Ly6C subset is recruited at a later stage and stimulates repair by expressing high amounts of VEGF-A and by promoting deposition of collagen Driving the recruitment of different monocyte populations, both CCR2 and CX3CR1 appear to be essential for proper healing in several tissues For example, Cx3cr1-/- mice display reduced levels of α -smooth muscle actin and collagen, reduced neovascularization as well as delayed healing in skin wounds [57] Similarly, the loss of CX3CR1 leads to delayed skeletal muscle repair [58] Moreover, deficiency in the CCL2–CCR2 axis appears to impair muscle and skin repair [59] For instance, Eming and colleagues have shown that hi + CCR2 is critical for the recruitment of Ly6C CCR2 monocytes to skin wounds, leading to proangiogenic macrophages crucial for vascularization [60] Interestingly, the study showed that macrophages are the main source of VEGF-A in early tissue repair Pro-inflammatory macrophages – the so-called “M1” macrophages – may become polarized towards a variety of alternatively activated anti-inflammatory “M2” macrophages [43] Although pro-inflammatory and anti-inflammatory macrophages are the two most frequently investigated phenotypes in studies of tissue healing, macrophages exhibiting tissue repair, pro-fibrotic, anti-fibrotic, pro-resolving, and tissue regeneration characteristics are also commonly mentioned in the literature [43] Indeed, the M1 and M2 nomenclature originate from in vitro characterization where the M1 phenotype is produced by exposure to IFN-γ and TNF-α , while the M2 phenotype is produced by IL-4 or IL-13 [61] In this review, we adopted the new classification system proposed by Murray et al [62] where nomenclature is linked to the activation standards i.e., M(IFN-γ ), M(IL-4), M(IL-10), and so forth Generally, M(IL-4) macrophages are considered as tissue repair macrophages, since they express several wound healing factors such as arginase, ECM components and growth factors such as VEGF-A, platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF) [43, 57, 61] (Fig 2B) Yet, the mechanisms that drive macrophages to adopt various tissue repair phenotypes in vivo are still under intense debate [43, 61] Indeed, macrophage phenotype associated markers may be expressed simultaneously, making in vivo characterization even more challenging [64] In addition to cytokines, microRNAs (miRNA), which control messenger RNA translation and degradation (e.g messenger RNAs of cytokines and transcription factors), are most likely critical regulators of macrophage polarization [63, 64] More specifically, miR-9, miR-127, miR-155, and miR-125b have been shown to promote M(IFN-γ )) polarization while miR-21, miR-124, miR-223, miR-34a, let-7c, miR-132, miR-146a, and miR-125a-5p support M(IL-4) polarization in macrophages by targeting various transcription factors and adaptor proteins [63, 64] While inflammatory macrophages can exacerbate tissue injury and impair tissue healing, persistent activation or sustained mobilization of M(IL-4) macrophages has been hypothesized to contribute to the development of pathological fibrosis [43] (Fig 2C) For example, the pro-fibrotic function of M(IL-4) macrophages has been attributed to their production and activation of TGF-β 1 in in models models of of pulmona pulmonary fibrosis [65] In addition to producing pro-fibrotic mediators, M(IL-4) macrophages have been shown to directly enhance the survival and activation of myofibroblasts, which are key cells producing ECM in all organs [66] Pro-fibrotic M(IL-4) macrophages also produce significant amount of matrix metalloproteinases (MMPs), and some of which serve as essential drivers of fibrosis [67] Macrophages may also be anti-inflammatory/anti-fibrotic and they are thought to be critical for the resolution of most tissue injury inflammation responses IL-10 – an immunoregulatory cytokine produced by a variety of cell types, including T helper cells (Th2), regulatory T (Treg) cells and macrophages – is known to function as a critical antiinflammatory mediator [68] In addition, anti-inflammatory macrophages regulate the development and maintenance of IL-10- and TGF-β 1-producing Tregs, which contribute to the resolution of inflammatory responses in multiple tissues (Fig 2D) [69] Nevertheless, beside the expansion of IL-10–induced anti-inflammatory macrophages, other mechanisms have also been shown to trigger anti-inflammatory macrophages [43] For example, IL-6, IL- 10 and IL-21 have all been found to enhance IL-4R expression on macrophages and contribute to the development of anti-inflammatory and anti-fibrotic macrophage function following stimulation with IL-4 or IL-13 [70, 71] Interestingly, it has been recently demonstrated that macrophages are critical for the regeneration (i.e the full restoration of the tissue function) of various tissues [72-74] For example, Godwin and colleagues found that macrophages are essential for limb regeneration in adult salamanders [72] Moreover, mice can regenerate cardiac tissue until seven days post-birth and it has been demonstrated that monocytes and macrophages are required for the cardiac regeneration process Remarkably, profiling of cardiac macrophages from regenerating and non-regenerating hearts indicated that neonatal macrophages have a unique polarization that does not fit into M(IFN-γ )) or M(IL-4) phenotypes [74] Importantly, it remains unclear whether an individual macrophage (recruited or tissue-resident) is capable of adopting all the phenotypes at different time in response to the injured tissue microenvironment, or if distinct subsets of monocytes and macrophages are committed to adopt the various phenotypes [43, 61] For instance, in several tissues such as the central nervous system and the liver, macrophages switch from a pro-inflammatory phenotype to a repair phenotype where IL-4, IL-10 and phagocytosis play critical roles in the conversion [75-77] In the context of skin injury, chemokines (e.g CX3CL1) drives circulating hi hi CX3CR1 monocytes traffic into the damaged site The CX3CR1 monocytes become M(IL4)-like macrophages and secrete factors such as VEGF-A, TGF-β [57], IL-13, IL-10 and several chemokines [78] Overall, monocytes and macrophages can exacerbate inflammation, promote tissue repair and fibrosis, or drive regeneration While the detailed mechanisms regulating macrophage functions during tissue healing are still unclear, their critical role in the repair and regeneration processes marks them as a primary target when designing regenerative strategies 2.4 Pericytes Pericytes are ubiquitous mural cells of blood microvessels, which facilitate the initial extravasation of immune cells from the blood [79] Pericytes are also a source of stem/progenitor cells and they secrete multiple growth factors and cytokines, as well as other soluble mediators [80] (Fig 2D) For example, they contribute to skeletal muscle regeneration by driving immune cells to cross the endothelium [81] and they are most likely a source of myogenic precursors [81] Pericytes also contribute to tissue healing by promoting [59] Arnold L., Perrin H., de Chanville C.B., Saclier M., Hermand P., Poupel L., Guyon E., Licata F., Carpentier W., Vilar J., CX3CR1 deficiency promotes muscle repair and regeneration by enhancing macrophage ApoE production, Nature communications (2015) [60] Willenborg S., Lucas T., van Loo G., Knipper J.A., Krieg T., Haase I., Brachvogel B., Hammerschmidt M., Nagy A., Ferrara N., CCR2 recruits an inflammatory macrophage subpopulation critical for angiogenesis in tissue repair, Blood 120 (2012) 613-25 [61] Novak M.L., Koh T.J., Macrophage phenotypes during tissue repair, Journal of leukocyte biology 93 (2013) 875-81 [62] Murray P.J., Allen J.E., Biswas S.K., Fisher E.A., Gilroy D.W., Goerdt S., Gordon S., Hamilton J.A., Ivashkiv L.B., Lawrence T., Locati M., Mantovani A., Martinez F.O., Mege J.L., Mosser D.M., Natoli G., Saeij J.P., Schultze J.L., Shirey K.A., Sica A., Suttles J., Udalova I., van Ginderachter J.A., Vogel S.N., Wynn T.A., Macrophage activation and polarization: nomenclature and experimental guidelines, Immunity 41 (2014) 14-20 [63] Essandoh K., Li Y., Huo J., Fan G.C., MiRNA-Mediated Macrophage Polarization and its Potential Role in the Regulation of Inflammatory Response, Shock 46 (2016) 122-31 [64] Wu X.Q., Dai Y., Yang Y., Huang C., Meng X.M., Wu B.M., Li J., Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation, Immunology 148 (2016) 237-48 [65] Murray L.A., Chen Q., Kramer M.S., Hesson D.P., Argentieri R.L., Peng X., Gulati M., Homer R.J., Russell T., van Rooijen N., Elias J.A., Hogaboam C.M., Herzog E.L., TGF-beta driven lung fibrosis is macrophage dependent and blocked by Serum amyloid P, The international journal of biochemistry & cell biology 43 (2011) 154-62 [66] Pradere J.P., Kluwe J., De Minicis S., Jiao J.J., Gwak G.Y., Dapito D.H., Jang M.K., Guenther N.D., Mederacke I., Friedman R., Dragomir A.C., Aloman C., Schwabe R.F., Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice, Hepatology 58 (2013) 1461-73 [67] Madala S.K., Pesce J.T., Ramalingam T.R., Wilson M.S., Minnicozzi S., Cheever A.W., Thompson R.W., Mentink-Kane M.M., Wynn T.A., Matrix metalloproteinase 12-deficiency augments extracellular matrix degrading metalloproteinases and attenuates IL-13-dependent fibrosis, Journal of immunology 184 (2010) 3955-63 [68] Saraiva M., O'Garra A., The regulation of IL-10 production by immune cells, Nature reviews Immunology 10 (2010) 170-81 [69] Soroosh P., Doherty T.A., Duan W., Mehta A.K., Choi H., Adams Y.F., Mikulski Z., Khorram N., Rosenthal P., Broide D.H., Croft M., Lung-resident tissue macrophages generate Foxp3+ regulatory T cells and promote airway tolerance, J Exp Med 210 (2013) 775-88 [70] Mauer J., Chaurasia B., Goldau J., Vogt M.C., Ruud J., Nguyen K.D., Theurich S., Hausen A.C., Schmitz J., Bronneke H.S., Estevez E., Allen T.L., Mesaros A., Partridge L., Febbraio M.A., Chawla A., Wunderlich F.T., Bruning J.C., Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin, Nature immunology 15 (2014) 423-30 [71] Pesce J., Kaviratne M., Ramalingam T.R., Thompson R.W., Urban J.F., Jr., Cheever A.W., Young D.A., Collins M., Grusby M.J., Wynn T.A., The IL-21 receptor augments Th2 effector function and alternative macrophage activation, J Clin Invest 116 (2006) 2044-55 [72] Godwin J.W., Pinto A.R., Rosenthal N.A., Macrophages are required for adult salamander limb regeneration, Proc Natl Acad Sci U S A 110 (2013) 9415-20 [73] Petrie T.A., Strand N.S., Tsung-Yang C., Rabinowitz J.S., Moon R.T., Macrophages modulate adult zebrafish tail fin regeneration, Development 141 (2014) 2581-91 [74] Aurora A.B., Porrello E.R., Tan W., Mahmoud A.I., Hill J.A., Bassel-Duby R., Sadek H.A., Olson E.N., Macrophages are required for neonatal heart regeneration, J Clin Invest 124 (2014) 1382-92 [75] Miron V.E., Boyd A., Zhao J.W., Yuen T.J., Ruckh J.M., Shadrach J.L., van Wijngaarden P., Wagers A.J., Williams A., Franklin R.J., ffrench-Constant C., M2 microglia and 32 macrophages drive oligodendrocyte differentiation during CNS remyelination, Nature neuroscience 16 (2013) 1211-8 [76] Dal-Secco D., Wang J., Zeng Z., Kolaczkowska E., Wong C.H., Petri B., Ransohoff R.M., Charo I.F., Jenne C.N., Kubes P., A dynamic spectrum of monocytes arising from the in situ reprogramming of CCR2+ monocytes at a site of sterile injury, J Exp Med 212 (2015) 447-56 [77] Ramachandran P., Pellicoro A., Vernon M.A., Boulter L., Aucott R.L., Ali A., Hartland S.N., Snowdon V.K., Cappon A., Gordon-Walker T.T., Williams M.J., Dunbar D.R., Manning J.R., van Rooijen N., Fallowfield J.A., Forbes S.J., Iredale J.P., Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis, Proc Natl Acad Sci U S A 109 (2012) E3186-95 [78] Stefater J.A., Ren S., Lang R.A., Duffield J.S., Metchnikoff's policemen: macrophages in development, homeostasis and regeneration, Trends in molecular medicine 17 (2011) 74352 [79] Stark K., Eckart A., Haidari S., Tirniceriu A., Lorenz M., von Bruhl M.L., Gartner F., Khandoga A.G., Legate K.R., Pless R., Hepper I., Lauber K., Walzog B., Massberg S., Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs, Nature immunology 14 (2013) 41-51 [80] Armulik A., Genove G., Betsholtz C., Pericytes: developmental, physiological, and pathological perspectives, problems, and promises, Developmental cell 21 (2011) 193-215 [81] Dellavalle A., Maroli G., Covarello D., Azzoni E., Innocenzi A., Perani L., Antonini S., Sambasivan R., Brunelli S., Tajbakhsh S., Cossu G., Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells, Nature communications (2011) 499 [82] Katare R., Riu F., Mitchell K., Gubernator M., Campagnolo P., Cui Y., Fortunato O., Avolio E., Cesselli D., Beltrami A.P., Angelini G., Emanueli C., Madeddu P., Transplantation of human pericyte progenitor cells improves the repair of infarcted heart through activation of an angiogenic program involving micro-RNA-132, Circulation research 109 (2011) 894-906 [83] Forbes S.J., Rosenthal N., Preparing the ground for tissue regeneration: from mechanism to therapy, Nat Med 20 (2014) 857-69 [84] Pellicoro A., Ramachandran P., Iredale J.P., Fallowfield J.A., Liver fibrosis and repair: immune regulation of wound healing in a solid organ, Nature reviews Immunology 14 (2014) 181-94 [85] Vinish M., Cui W., Stafford E., Bae L., Hawkins H., Cox R., Toliver•Kinsky Kinsky T., T., Dendritic Dendritic cells modulate burn wound healing by enhancing early proliferation, Wound Repair and Regeneration (2016) [86] Gao N., Yin J., Yoon G.S., Mi Q.-S., Fu-Shin X.Y., Dendritic Cell–Epithelium Interplay Is a Determinant Factor for Corneal Epithelial Wound Repair, The American journal of pathology 179 (2011) 2243-53 [87] Anzai A., Anzai T., Nagai S., Maekawa Y., Naito K., Kaneko H., Sugano Y., Takahashi T., Abe H., Mochizuki S., Regulatory role of dendritic cells in postinfarction healing and left ventricular remodeling, Circulation 125 (2012) 1234-45 [88] Jameson J., Ugarte K., Chen N., Yachi P., Fuchs E., Boismenu R., Havran W.L., A role for skin γ δ T T cells cells in in wound wound repair, repair, Science Science 296 296 (2002) (2002) 747 747-9 [89] Ono T., Okamoto K., Nakashima T., Nitta T., Hori S., Iwakura Y., Takayanagi H., IL-17producing [gamma][delta] T cells enhance bone regeneration, Nature communications (2016) [90] Ramirez K., Witherden D.A., Havran W.L., All hands on DE (T) C: Epithelial-resident γ δ T T cells respond to tissue injury, Cellular immunology 296 (2015) 57-61 [91] Simonian P.L., Wehrmann F., Roark C.L., Born W.K., O'Brien R.L., Fontenot A.P., γ δ T T cells protect against lung fibrosis via IL-22, The Journal of experimental medicine 207 (2010) 2239-53 33 [92] Reinke S., Geissler S., Taylor W., Schmidt-Bleek K., Juelke K., Schwachmeyer V Terminally differentiated CD8 (+) T cells negatively affect bone regeneration in humans Sci Transl Med 2013; (177): 177ra36 Epub 2013/03/22 5/177/177ra36 [pii] doi: 10.1126/scitranslmed 3004754 PMID: 23515078; 2013 [93] Liu Y., Wang L., Kikuiri T., Akiyama K., Chen C., Xu X., Yang R., Chen W., Wang S., Shi S., Mesenchymal stem cell-based tissue regeneration is governed by recipient T lymphocytes via IFN-[gamma] and TNF-[alpha], Nature medicine 17 (2011) 1594-601 [94] Toben D., Schroeder I., El Khassawna T., Mehta M., Hoffmann J.-E., Frisch J.-T., Schell H., Lienau J., Serra A., Radbruch A., Duda G.N., Fracture healing is accelerated in the absence of the adaptive immune system, Journal of Bone and Mineral Research 26 (2011) 113-24 [95] Nosbaum A., Prevel N., Truong H.-A., Mehta P., Ettinger M., Scharschmidt T.C., Ali N.H., Pauli M.L., Abbas A.K., Rosenblum M.D., Cutting Edge: Regulatory T Cells Facilitate Cutaneous Wound Healing, The Journal of Immunology 196 (2016) 2010-4 [96] Lei H., Schmidt-Bleek K., Dienelt A., Reinke P., Volk H.-D., Regulatory T cell-mediated anti-inflammatory effects promote successful tissue repair in both indirect and direct manners, Frontiers in Pharmacology (2015) 184 [97] Trujillo G., Hartigan A.J., Hogaboam C.M., T regulatory cells and attenuated bleomycininduced fibrosis in lungs of CCR7-/-mice, Fibrogenesis & tissue repair (2010) 18 [98] Aggarwal N.R., D'Alessio F.R., Tsushima K., Sidhaye V.K., Cheadle C., Grigoryev D.N., Barnes K.C., King L.S., Regulatory T cell-mediated resolution of lung injury: identification of potential target genes via expression profiling, Physiological genomics 41 (2010) 109-19 [99] Garibaldi B.T., D’Alessio F.R., Mock J.R., Files D.C., Chau E., Eto Y., Drummond M.B., Aggarwal N.R., Sidhaye V., King L.S., Regulatory T cells reduce acute lung injury fibroproliferation by decreasing fibrocyte recruitment, American journal of respiratory cell and molecular biology 48 (2013) 35-43 [100] Lai L.-W., Yong K.-C., Lien Y.-H.H., Pharmacologic recruitment of regulatory T cells as a novel therapy for ischemic acute kidney injury, Kidney Int 81 (2012) 983-92 [101] Gandolfo M.T., Jang H.R., Bagnasco S.M., Ko G.-J., Agreda P., Soloski M.J., Crow M.T., Rabb H., Mycophenolate mofetil modifies kidney tubular injury and Foxp3+ regulatory T cell trafficking during recovery from experimental ischemia–reperfusion, Transplant Immunology 23 (2010) 45-52 [102] Burzyn D., Kuswanto W., Kolodin D., Shadrach J.L., Cerletti M., Jang Y., Sefik E., Tan T.G., Wagers A.J., Benoist C., A special population of regulatory T cells potentiates muscle repair, Cell 155 (2013) 1282-95 [103] Rigamonti E., Zordan P., Sciorati C., Rovere-Querini P., Brunelli S., Macrophage plasticity in skeletal muscle repair, BioMed research international 2014 (2014) [104] Meng X., Yang J., Dong M., Zhang K., Tu E., Gao Q., Chen W., Zhang C., Zhang Y., Regulatory T cells in cardiovascular diseases, Nature reviews Cardiology 13 (2016) 167-79 [105] Liu G., Ma H., Qiu L., Li L., Cao Y., Ma J., Zhao Y., Phenotypic and functional switch of macrophages induced by regulatory CD4+CD25+ T cells in mice, Immunol Cell Biol 89 (2011) 130-42 [106] Zaiss Dietmar M.W., van Loosdregt J., Gorlani A., Bekker Cornelis P.J., Gröne A., Sibilia M., van Bergen en Henegouwen Paul M.P., Roovers Rob C., Coffer Paul J., Sijts Alice J.A.M., Amphiregulin Enhances Regulatory T Cell-Suppressive Function via the Epidermal Growth Factor Receptor, Immunity 38 (2013) 275-84 [107] Arpaia N., Green J.A., Moltedo B., Arvey A., Hemmers S., Yuan S., Treuting P.M., Rudensky A.Y., A distinct function of regulatory T cells in tissue protection, Cell 162 (2015) 1078-89 [108] Havran W.L., Jameson J.M., Epidermal T cells and wound healing, The Journal of Immunology 184 (2010) 5423-8 [109] Sharp L.L., Jameson J.M., Cauvi G., Havran W.L., Dendritic epidermal T cells regulate skin homeostasis through local production of insulin-like growth factor 1, Nature immunology (2005) 73-9 34 [110] Toulon A., Breton L., Taylor K.R., Tenenhaus M., Bhavsar D., Lanigan C., Rudolph R., Jameson J., Havran W.L., A role for human skin–resident T cells in wound healing, The Journal of Experimental Medicine 206 (2009) 743-50 [111] Kumar P., Rajasekaran K., Palmer J.M., Thakar M.S., Malarkannan S., IL-22: an evolutionary missing-link authenticating the role of the immune system in tissue regeneration, J Cancer (2013) 57-65 [112] Kular J., Tickner J., Chim S.M., Xu J., An overview of the regulation of bone remodelling at the cellular level, Clinical Biochemistry 45 (2012) 863-73 [113] Könnecke I., Serra A., El Khassawna T., Schlundt C., Schell H., Hauser A., Ellinghaus A., Volk H.-D., Radbruch A., Duda G.N., T and B cells participate in bone repair by infiltrating the fracture callus in a two-wave fashion, Bone 64 (2014) 155-65 [114] Sridharan R., Cameron A.R., Kelly D.J., Kearney C.J., O’Brien F.J., Biomaterial based modulation of macrophage polarization: a review and suggested design principles, Materials Today 18 (2015) 313-25 [115] Browne S., Pandit A., Biomaterial-mediated modification of the local inflammatory environment, Front Bioeng Biotechnol (2015) 67 [116] Badylak S.F., Valentin J.E., Ravindra A.K., McCabe G.P., Stewart-Akers A.M., Macrophage phenotype as a determinant of biologic scaffold remodeling, Tissue Engineering Part A 14 (2008) 1835-42 [117] Orenstein S.B., Qiao Y., Klueh U., Kreutzer D.L., Novitsky Y.W., Activation of human mononuclear cells by porcine biologic meshes in vitro, Hernia : the journal of hernias and abdominal wall surgery 14 (2010) 401-7 [118] Jones J.A., Chang D.T., Meyerson H., Colton E., Kwon I.K., Matsuda T., Anderson J.M., Proteomic analysis and quantification of cytokines and chemokines from biomaterial surface•adherent adherent macrophages macrophages and and foreign foreign body body giant giant cells, cells, Journal Journal of of biomedical biomedical materials materials research Part A 83 (2007) 585-96 [119] McWhorter F.Y., Wang T., Nguyen P., Chung T., Liu W.F., Modulation of macrophage phenotype by cell shape, Proc Natl Acad Sci U S A 110 (2013) 17253-8 [120] Nakamura K., Yokohama S., Yoneda M., Okamoto S., Tamaki Y., Ito T., Okada M., Aso K., Makino I., High, but not low, molecular weight hyaluronan prevents T-cell-mediated liver injury by reducing proinflammatory cytokines in mice, Journal of gastroenterology 39 (2004) 346-54 [121] Je J.Y., Kim S.K., Reactive oxygen species scavenging activity of aminoderivatized chitosan with different degree of deacetylation, Bioorganic & medicinal chemistry 14 (2006) 5989-94 [122] Browne S., Pandit A., Biomaterial-mediated modification of the local inflammatory environment, Frontiers in bioengineering and biotechnology (2015) 67- [123] Turner N.J., Badylak S.F., The use of biologic scaffolds in the treatment of chronic nonhealing wounds, Advances in wound care (2015) 490-500 [124] Badylak S.F., Freytes D.O., Gilbert T.W., Extracellular matrix as a biological scaffold material: structure and function, Acta biomaterialia (2009) 1-13 [125] Brown B.N., Ratner B.D., Goodman S.B., Amar S., Badylak S.F., Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine, Biomaterials 33 (2012) 3792-802 [126] Huleihel L., Hussey G.S., Naranjo J.D., Zhang L., Dziki J.L., Turner N.J., Stolz D.B., Badylak S.F., Matrix-bound nanovesicles within ECM bioscaffolds, Science advances (2016) e1600502 [127] Beattie A.J., Gilbert T.W., Guyot J.P., Yates A.J., Badylak S.F., Chemoattraction of progenitor cells by remodeling extracellular matrix scaffolds, Tissue Engineering Part A 15 (2008) 1119-25 [128] Sadtler K., Estrellas K., Allen B.W., Wolf M.T., Fan H., Tam A.J., Patel C.H., Luber B.S., Wang H., Wagner K.R., Powell J.D., Housseau F., Pardoll D.M., Elisseeff J.H., Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper cells, Science 352 (2016) 366-70 35 [129] Dziki J.L., Wang D.S., Pineda C., Sicari B.M., Rausch T., Badylak S.F., Solubilized extracellular matrix bioscaffolds derived from diverse source tissues differentially influence macrophage phenotype, Journal of biomedical materials research Part A 105 (2017) 138-47 [130] Spiller K.L., Nassiri S., Witherel C.E., Anfang R.R., Ng J., Nakazawa K.R., Yu T., Vunjak-Novakovic G., Sequential delivery of immunomodulatory cytokines to facilitate the M1-to-M2 transition of macrophages and enhance vascularization of bone scaffolds, Biomaterials 37 (2015) 194-207 [131] Asea A., Rehli M., Kabingu E., Boch J.A., Baré O., Auron P.E., Stevenson M.A., Calderwood S.K., Novel signal transduction pathway utilized by extracellular HSP70 role of Toll-like receptor (TLR) and TLR4, Journal of Biological Chemistry 277 (2002) 15028-34 [132] Kovalchin J., Wang R., Wagh M., Azoulay J., Sanders M., Chandawarkar R., In vivo delivery of heat shock protein 70 accelerates wound healing by up•regulating regulating macrophage•mediated mediated phagocytosis, phagocytosis, Wound Wound repair repair and regeneration 14 (2006) 129-37 [133] Yamamoto M., Sato T., Beren J., Verthelyi D., Klinman D.M., The acceleration of wound healing in primates by the local administration of immunostimulatory CpG oligonucleotides, Biomaterials 32 (2011) 4238-42 [134] Kucia M., Jankowski K., Reca R., Wysoczynski M., Bandura L., Allendorf D.J., Zhang J., Ratajczak J., Ratajczak M.Z., CXCR4–SDF-1 signalling, locomotion, chemotaxis and adhesion, Journal of molecular histology 35 (2004) 233-45 [135] Lau T.T., Wang D.-A., Stromal cell-derived factor-1 (SDF-1): homing factor for engineered regenerative medicine, Expert opinion on biological therapy 11 (2011) 189-97 [136] Son B.R., Marquez•Curtis Curtis L.A., L.A., Kucia Kucia M., M., Wysoczynski Wysoczynski M., M., Turner Turner A.R., A.R., Ratajczak Ratajczak J., J., Ratajczak M.Z., Janowska•Wieczorek Wieczorek A., A., Migration Migration of of bone bone marrow marrow and and cord cord blood blood mesenchymal stem cells in vitro is regulated by stromal•derived derived factor•1•CXCR4 factor•1•CXCR4 and and hepatocyte growth factor•c•met c•met axes axes and and involves involves matrix matrix metalloproteinases, metalloproteinases, Stem Stem cells cells 24 24 (2006) 1254-64 [137] Kim Y.H., Tabata Y., Recruitment of mesenchymal stem cells and macrophages by dual release of stromal cell•derived derived factor•1 factor•1 and and a a macrophage macrophage recruitment recruitment agent agent enhances enhances wound closure, Journal of Biomedical Materials Research Part A 104 (2016) 942-56 [138] Shen W., Chen X., Chen J., Yin Z., Heng B.C., Chen W., Ouyang H.-W., The effect of incorporation of exogenous stromal cell-derived factor-1 alpha within a knitted silk-collagen sponge scaffold on tendon regeneration, Biomaterials 31 (2010) 7239-49 [139] Kimura Y., Tabata Y., Controlled release of stromal-cell-derived factor-1 from gelatin hydrogels enhances angiogenesis, Journal of Biomaterials Science, Polymer Edition 21 (2010) 37-51 [140] Rabbany S.Y., Pastore J., Yamamoto M., Miller T., Rafii S., Aras R., Penn M., Continuous delivery of stromal cell-derived factor-1 from alginate scaffolds accelerates wound healing, Cell transplantation 19 (2010) 399-408 [141] Zhang G., Nakamura Y., Wang X., Hu Q., Suggs L.J., Zhang J., Controlled release of stromal cell-derived factor-1alpha in situ increases c-kit+ cell homing to the infarcted heart, Tissue engineering 13 (2007) 2063-71 [142] Thevenot P.T., Nair A.M., Shen J., Lotfi P., Ko C.-Y., Tang L., The effect of incorporation of SDF-1α into into PLGA PLGA scaffolds scaffolds on on ste stem cell recruitment and the inflammatory response, Biomaterials 31 (2010) 3997-4008 [143] Projahn D., Simsekyilmaz S., Singh S., Kanzler I., Kramp B.K., Langer M., Burlacu A., Bernhagen J., Klee D., Zernecke A., Controlled intramyocardial release of engineered chemokines by biodegradable hydrogels as a treatment approach of myocardial infarction, Journal of cellular and molecular medicine 18 (2014) 790-800 [144] Ding J., Hori K., Zhang R., Marcoux Y., Honardoust D., Shankowsky H.A., Tredget E.E., Stromal cell-derived factor (SDF-1) and its receptor CXCR4 in the formation of postburn hypertrophic scar (HTS), Wound Repair and Regeneration 19 (2011) 568-78 [145] Noguchi K., Ishikawa I., The roles of cyclooxygenase•2 and and prostaglandin prostaglandin E2 E2 in in periodontal disease, Periodontology 2000 43 (2007) 85-101 36 [146] Shapira L., Soskolne W.A., Sela M., Offenbacher S., Barak V., The secretion of PGE2, IL-1β ,, IL IL-6, and TNFα by by adherent adherent mononuclear mononuclear cells cells from from early early onset onset periodontitis periodontitis patients, patients, Journal of periodontology 65 (1994) 139-46 [147] Paralkar V., Borovecki F., Ke H., Cameron K., Lefker B., Grasser W., Owen T., Li M., DaSilva-Jardine P., Zhou M., An EP2 receptor-selective prostaglandin E2 agonist induces bone healing, Proceedings of the National Academy of Sciences 100 (2003) 6736-40 [148] Namkoong S., Lee S.-J., Kim C.-K., Kim Y.-M., Chung H.-T., Lee H., Han J.-A., Ha K.S., Kwon Y.-G., Kim Y.-M., Prostaglandin E2 stimulates angiogenesis by activating the nitric oxide/cGMP pathway in human umbilical vein endothelial cells, Exp Mol Med 37 (2005) 588600 [149] Kaliń ski ski P., P., Hilkens Hilkens C., C., Snijders Snijders A., A., Snijdewint Snijdewint F., F., Kapsenberg Kapsenberg M.L., M.L., IL IL-12-deficient dendritic cells, generated in the presence of prostaglandin E2, promote type cytokine production in maturing human naive T helper cells, The Journal of Immunology 159 (1997) 28-35 [150] Cui L., Yin S., Liu W., Li N., Zhang W., Cao Y., Expanded adipose-derived stem cells suppress mixed lymphocyte reaction by secretion of prostaglandin E2, Tissue engineering 13 (2007) 1185-95 [151] Katamura K., Shintaku N., Yamauchi Y., Fukui T., Ohshima Y., Mayumi M., Furusho K., Prostaglandin E2 at priming of naive CD4+ T cells inhibits acquisition of ability to produce IFN-gamma and IL-2, but not IL-4 and IL-5, The Journal of Immunology 155 (1995) 4604-12 [152] Kamolratanakul P., Hayata T., Ezura Y., Kawamata A., Hayashi C., Yamamoto Y., Hemmi H., Nagao M., Hanyu R., Notomi T., Nanogel•based based scaffold scaffold delivery delivery of of prostaglandin E2 receptor–specific agonist in combination with a low dose of growth factor heals critical•size size bone bone defects defects in in mice, mice, Arthritis Arthritis & & Rheumatism Rheumatism 63 63 (2011) (2011) 1021-33 1021 [153] Kato N., Hasegawa U., Morimoto N., Saita Y., Nakashima K., Ezura Y., Kurosawa H., Akiyoshi K., Noda M., Nanogel•based based delivery delivery system system enhances enhances PGE2 PGE2 effects effects on bone formation, Journal of cellular biochemistry 101 (2007) 1063-70 [154] Toyoda H., Terai H., Sasaoka R., Oda K., Takaoka K., Augmentation of bone morphogenetic protein-induced bone mass by local delivery of a prostaglandin E EP4 receptor agonist, Bone 37 (2005) 555-62 [155] Sy J.C., Seshadri G., Yang S.C., Brown M., Oh T., Dikalov S., Murthy N., Davis M.E., Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction, Nature materials (2008) 863-8 [156] Serhan C.N., Pro-resolving lipid mediators are leads for resolution physiology, Nature 510 (2014) 92-101 [157] Serhan C.N., Chiang N., Dalli J The resolution code of acute inflammation: Novel proresolving lipid mediators in resolution Seminars in immunology: Elsevier; 2015 p 200-15 [158] Ariel A., Fredman G., Sun Y.-P., Kantarci A., Van Dyke T.E., Luster A.D., Serhan C.N., Apoptotic neutrophils and T cells sequester chemokines during immune response resolution through modulation of CCR5 expression, Nature immunology (2006) 1209-16 [159] Tang Y., Zhang M.J., Hellmann J., Kosuri M., Bhatnagar A., Spite M., Proresolution therapy for the treatment of delayed healing of diabetic wounds, Diabetes 62 (2013) 618-27 [160] Hong S., Tian H., Lu Y., Laborde J.M., Muhale F.A., Wang Q., Alapure B.V., Serhan C.N., Bazan N.G., Neuroprotectin/protectin D1: endogenous biosynthesis and actions on diabetic macrophages in promoting wound healing and innervation impaired by diabetes, American Journal of Physiology-Cell Physiology 307 (2014) C1058-C67 [161] Vasconcelos D.P., Costa M., Amaral I.F., Barbosa M.A., Águas A.P., Barbosa J.N., Modulation of the inflammatory response to chitosan through M2 macrophage polarization using pro-resolution mediators, Biomaterials 37 (2015) 116-23 [162] Vasconcelos D.P., Fonseca A.C., Costa M., Amaral I.F., Barbosa M.A., Águas A.P., Barbosa J.N., Macrophage polarization following chitosan implantation, Biomaterials 34 (2013) 9952-9 [163] de Oliveira C.P., Magolbo N., De Aquino R., Weller C., Oral aspirin for treating venous leg ulcers, The Cochrane database of systematic reviews (2016) CD009432-CD 37 [164] Cantón I., Mckean R., Charnley M., Blackwood K.A., Fiorica C., Ryan A.J., MacNeil S., Development of an Ibuprofen•releasing releasing biodeg biodegradable PLA/PGA electrospun scaffold for tissue regeneration, Biotechnology and bioengineering 105 (2010) 396-408 [165] Varatharajan L., Thapar A., Lane T., Munster A.B., Davies A.H., Pharmacological adjuncts for chronic venous ulcer healing: a systematic review, Phlebology (2015) 0268355515587194 [166] Wang Q., Li H., Xiao Y., Li S., Li B., Zhao X., Ye L., Guo B., Chen X., Ding Y., Locally controlled delivery of TNFα antibody antibody from from a a novel novel glucose glucose-sensitive scaffold enhances alveolar bone healing in diabetic conditions, Journal of Controlled Release 206 (2015) 23242 [167] Friedrich E.E., Sun L.T., Natesan S., Zamora D.O., Christy R.J., Washburn N.R., Effects of hyaluronic acid conjugation on anti-TNF-α inhibition inhibition of of inflammation inflammation in in burns, burns, Journal of Biomedical Materials Research Part A 102 (2014) 1527-36 [168] Kim Y.S., Park H.J., Hong M.H., Kang P.M., Morgan J.P., Jeong M.H., Cho J.G., Park J.C., Ahn Y., TNF-alpha enhances engraftment of mesenchymal stem cells into infarcted myocardium, Front Biosci 14 (2009) 2845-56 [169] Böcker W., Docheva D., Prall W.C., Egea V., Pappou E., Roßmann O., Popov C., Mutschler W., Ries C., Schieker M., IKK-2 is required for TNF-α -induced invasion and proliferation of human mesenchymal stem cells, Journal of Molecular Medicine 86 (2008) 1183-92 [170] Mountziaris P.M., Mikos A.G., Modulation of the inflammatory response for enhanced bone tissue regeneration, Tissue Engineering Part B: Reviews 14 (2008) 179-86 [171] Yan C., Grimm W.A., Garner W.L., Qin L., Travis T., Tan N., Han Y.-P., Epithelial to mesenchymal transition in human skin wound healing is induced by tumor necrosis factor-α through bone morphogenic protein-2, The American journal of pathology 176 (2010) 224758 [172] Ishida Y., Kondo T., Kimura A., Matsushima K., Mukaida N., Absence of IL-1 receptor antagonist impaired wound healing along with aberrant NF-κ B B activation activation and and a a reciprocal reciprocal suppression of TGF-β signal signal pathway, pathway, The The Journal Journal of of Immunology Immunology 176 176 (2006) (2006) 5598 5598-606 [173] Chang J., Wang Z., Tang E., Fan Z., McCauley L., Franceschi R., Guan K., Krebsbach P.H., Wang C.-Y., Inhibition of osteoblastic bone formation by nuclear factor-κ B, B, Nature Nature medicine 15 (2009) 682-9 [174] Chang J., Liu F., Lee M., Wu B., Ting K., Zara J.N., Soo C., Al Hezaimi K., Zou W., Chen X., NF-κ B B inhibits inhibits osteogenic osteogenic differentiation differentiation of of mesenchymal mesenchymal stem stem cells cells by by promoting promoting β catenin degradation, Proceedings of the National Academy of Sciences 110 (2013) 9469-74 [175] Martino M.M., Maruyama K., Kuhn G.A., Satoh T., Takeuchi O., Muller R., Akira S., Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration, Nat Commun (2016) [176] King A., Balaji S., Le L.D., Crombleholme T.M., Keswani S.G., Regenerative wound healing: the role of interleukin-10, Advances in wound care (2014) 315-23 [177] Chen W.C., Lee B.G., Park D.W., Kim K., Chu H., Kim K., Huard J., Wang Y., Controlled dual delivery of fibroblast growth factor-2 and Interleukin-10 by heparin-based coacervate synergistically enhances ischemic heart repair, Biomaterials 72 (2015) 138-51 [178] King A., Balaji S., Le L.D., Crombleholme T.M., Keswani S.G., Regenerative Wound Healing: The Role of Interleukin-10, Adv Wound Care (New Rochelle) (2014) 315-23 [179] Mokarram N., Merchant A., Mukhatyar V., Patel G., Bellamkonda R.V., Effect of modulating macrophage phenotype on peripheral nerve repair, Biomaterials 33 (2012) 8793801 [180] Rao A.J., Nich C., Dhulipala L.S., Gibon E., Valladares R., Zwingenberger S., Smith R.L., Goodman S.B., Local effect of IL•4 delivery delivery on on polyethylene polyethylene particle particle induced induced osteolysis osteolysis in the murine calvarium, Journal of biomedical materials research Part A 101 (2013) 192634 38 [181] Penn J.W., Grobbelaar A.O., Rolfe K.J., The role of the TGF-beta family in wound healing, burns and scarring: a review, International journal of burns and trauma (2012) 1828 [182] Johnston C.J., Smyth D.J., Dresser D.W., Maizels R.M., TGF-beta in tolerance, development and regulation of immunity, Cell Immunol 299 (2016) 14-22 [183] Ferguson M.W., Duncan J., Bond J., Bush J., Durani P., So K., Taylor L., Chantrey J., Mason T., James G., Prophylactic administration of avotermin for improvement of skin scarring: three double-blind, placebo-controlled, phase I/II studies, The Lancet 373 (2009) 1264-74 [184] Mountziaris P.M., Tzouanas S.N., Sing D.C., Kramer P.R., Kasper F.K., Mikos A.G., Intra-articular controlled release of anti-inflammatory siRNA with biodegradable polymer microparticles ameliorates temporomandibular joint inflammation, Acta Biomater (2012) 3552-60 [185] Leuschner F., Dutta P., Gorbatov R., Novobrantseva T.I., Donahoe J.S., Courties G., Lee K.M., Kim J.I., Markmann J.F., Marinelli B., Panizzi P., Lee W.W., Iwamoto Y., Milstein S., Epstein-Barash H., Cantley W., Wong J., Cortez-Retamozo V., Newton A., Love K., Libby P., Pittet M.J., Swirski F.K., Koteliansky V., Langer R., Weissleder R., Anderson D.G., Nahrendorf M., Therapeutic siRNA silencing in inflammatory monocytes in mice, Nature biotechnology 29 (2011) 1005-10 [186] Sager H.B., Dutta P., Dahlman J.E., Hulsmans M., Courties G., Sun Y., Heidt T., Vinegoni C., Borodovsky A., Fitzgerald K., Wojtkiewicz G.R., Iwamoto Y., Tricot B., Khan O.F., Kauffman K.J., Xing Y., Shaw T.E., Libby P., Langer R., Weissleder R., Swirski F.K., Anderson D.G., Nahrendorf M., RNAi targeting multiple cell adhesion molecules reduces immune cell recruitment and vascular inflammation after myocardial infarction, Science translational medicine (2016) 342ra80 [187] Yin H., Kanasty R.L., Eltoukhy A.A., Vegas A.J., Dorkin J.R., Anderson D.G., Non-viral vectors for gene-based therapy, Nature reviews Genetics 15 (2014) 541-55 [188] Mehta A., Baltimore D., MicroRNAs as regulatory elements in immune system logic, Nature reviews Immunology 16 (2016) 279-94 [189] Das A., Sinha M., Datta S., Abas M., Chaffee S., Sen C.K., Roy S., Monocyte and macrophage plasticity in tissue repair and regeneration, The American journal of pathology 185 (2015) 2596-606 [190] O'Connell R.M., Rao D.S., Chaudhuri A.A., Baltimore D., Physiological and pathological roles for microRNAs in the immune system, Nature Reviews Immunology 10 (2010) 111-22 [191] Banerjee J., Chan Y.C., Sen C.K., MicroRNAs in skin and wound healing, Physiological genomics 43 (2011) 543-56 [192] Banerjee J., Sen C.K., MicroRNAs in skin and wound healing, MicroRNA Protocols (2013) 343-56 [193] Li D., Wang A., Liu X., Meisgen F., Grünler J., Botusan I.R., Narayanan S., Erikci E., Li X., Blomqvist L., MicroRNA-132 enhances transition from inflammation to proliferation during wound healing, The Journal of clinical investigation 125 (2015) 3008-26 [194] Singh Y., Garden O.A., Lang F., Cobb B.S., MicroRNA-15b/16 enhances the induction of regulatory T cells by regulating the expression of rictor and mTOR, The Journal of Immunology 195 (2015) 5667-77 [195] Baumjohann D., Ansel K.M., MicroRNA-mediated regulation of T helper cell differentiation and plasticity, Nature Reviews Immunology 13 (2013) 666-78 [196] Li Q.-J., Chau J., Ebert P.J., Sylvester G., Min H., Liu G., Braich R., Manoharan M., Soutschek J., Skare P., miR-181a is an intrinsic modulator of T cell sensitivity and selection, Cell 129 (2007) 147-61 [197] Sethi A., Kulkarni N., Sonar S., Lal G., Role of miRNAs in CD4 T cell plasticity during inflammation and tolerance, Frontiers in genetics (2013) 39 [198] Li Q.J., Chau J., Ebert P.J., Sylvester G., Min H., Liu G., Braich R., Manoharan M., Soutschek J., Skare P., Klein L.O., Davis M.M., Chen C.Z., miR-181a is an intrinsic modulator of T cell sensitivity and selection, Cell 129 (2007) 147-61 [199] Frith J.E., Porrello E.R., Cooper-White J.J., Concise review: new frontiers in microRNA-based tissue regeneration, Stem cells translational medicine (2014) 969-76 [200] Nakasa T., Ishikawa M., Shi M., Shibuya H., Adachi N., Ochi M., Acceleration of muscle regeneration by local injection of muscle•specific specific microRNAs microRNAs in in rat rat skeletal skeletal muscle muscle injury model, Journal of cellular and molecular medicine 14 (2010) 2495-505 [201] Zhang Y., Wang Z., Gemeinhart R.A., Progress in microRNA delivery, Journal of Controlled Release 172 (2013) 962-74 [202] Gori M., Trombetta M., Santini D., Rainer A., Tissue engineering and microRNAs: future perspectives in regenerative medicine, Expert opinion on biological therapy 15 (2015) 1601-22 [203] Li J., Kooger R., He M., Xiao X., Zheng L., Zhang Y., A supramolecular hydrogel as a carrier to deliver microRNA into the encapsulated cells, Chemical Communications 50 (2014) 3722-4 [204] Morishita Y., Imai T., Yoshizawa H., Watanabe M., Ishibashi K., Muto S., Nagata D., Delivery of microRNA-146a with polyethylenimine nanoparticles inhibits renal fibrosis in vivo, International journal of nanomedicine 10 (2015) 3475-88 [205] van der Pol E., Boing A.N., Harrison P., Sturk A., Nieuwland R., Classification, functions, and clinical relevance of extracellular vesicles, Pharmacological reviews 64 (2012) 676-705 [206] S E.L.A., Mager I., Breakefield X.O., Wood M.J., Extracellular vesicles: biology and emerging therapeutic opportunities, Nature reviews Drug discovery 12 (2013) 347-57 [207] Silva A.M., Teixeira J.H., Almeida M.I., Gonỗalves R.M., Barbosa M.A., Santos S.G., Extracellular vesicles: immunomodulatory messengers in the context of tissue repair/regeneration, European Journal of Pharmaceutical Sciences (2016) [208] Teixeira J.H., Silva A.M., Almeida M.I., Barbosa M.A., Santos S.G., Circulating extracellular vesicles: Their role in tissue repair and regeneration, Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis 55 (2016) 53-61 [209] Fais S., O'Driscoll L., Borras F.E., Buzas E., Camussi G., Cappello F., Carvalho J., Cordeiro da Silva A., Del Portillo H., El Andaloussi S., Ficko Trcek T., Furlan R., Hendrix A., Gursel I., Kralj-Iglic V., Kaeffer B., Kosanovic M., Lekka M.E., Lipps G., Logozzi M., Marcilla A., Sammar M., Llorente A., Nazarenko I., Oliveira C., Pocsfalvi G., Rajendran L., Raposo G., Rohde E., Siljander P., van Niel G., Vasconcelos M.H., Yanez-Mo M., Yliperttula M.L., Zarovni N., Zavec A.B., Giebel B., Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine, ACS nano 10 (2016) 3886-99 [210] Marote A., Teixeira F.G., Mendes-Pinheiro B., Salgado A.J., MSCs-Derived Exosomes: Cell-Secreted Nanovesicles with Regenerative Potential, Front Pharmacol (2016) 231 [211] Li T., Yan Y., Wang B., Qian H., Zhang X., Shen L., Wang M., Zhou Y., Zhu W., Li W., Xu W., Exosomes derived from human umbilical cord mesenchymal stem cells alleviate liver fibrosis, Stem cells and development 22 (2013) 845-54 [212] Hyun J., Wang S., Kim J., Kim G.J., Jung Y., MicroRNA125b-mediated Hedgehog signaling influences liver regeneration by chorionic plate-derived mesenchymal stem cells, Sci Rep (2015) 14135 [213] Phinney D.G., Di Giuseppe M., Njah J., Sala E., Shiva S., St Croix C.M., Stolz D.B., Watkins S.C., Di Y.P., Leikauf G.D., Kolls J., Riches D.W., Deiuliis G., Kaminski N., Boregowda S.V., McKenna D.H., Ortiz L.A., Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs, Nature communications (2015) 8472 [214] Lee C., Mitsialis S.A., Aslam M., Vitali S.H., Vergadi E., Konstantinou G., Sdrimas K., Fernandez-Gonzalez A., Kourembanas S., Exosomes mediate the cytoprotective action of 40 mesenchymal stromal cells on hypoxia-induced pulmonary hypertension, Circulation 126 (2012) 2601-11 [215] Qin Y., Wang L., Gao Z., Chen G., Zhang C., Bone marrow stromal/stem cell-derived extracellular vesicles regulate osteoblast activity and differentiation in vitro and promote bone regeneration in vivo, Sci Rep (2016) 21961 [216] Alvarez-Erviti L., Seow Y., Yin H., Betts C., Lakhal S., Wood M.J., Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes, Nature biotechnology 29 (2011) 341-5 [217] Huleihel L., Hussey G.S., Naranjo J.D., Zhang L., Dziki J.L., Turner N.J., Stolz D.B., Badylak S.F., Matrix-bound nanovesicles within ECM bioscaffolds, Science Advances (2016) e1600502 [218] Alvarez M.M., Liu J.C., Trujillo-de Santiago G., Cha B.-H., Vishwakarma A., Ghaemmaghami A., Khademhosseini A., Delivery strategies to control inflammatory response: Modulating M1-M2 polarization in tissue engineering applications, Journal of Controlled Release (2016) [219] Kim Y.-H., Furuya H., Tabata Y., Enhancement of bone regeneration by dual release of a macrophage recruitment agent and platelet-rich plasma from gelatin hydrogels, Biomaterials 35 (2014) 214-24 [220] Glowacki A.J., Gottardi R., Yoshizawa S., Cavalla F., Garlet G.P., Sfeir C., Little S.R., Strategies to direct the enrichment, expansion, and recruitment of regulatory cells for the treatment of disease, Annals of biomedical engineering 43 (2015) 593-602 [221] Glowacki A.J., Yoshizawa S., Jhunjhunwala S., Vieira A.E., Garlet G.P., Sfeir C., Little S.R., Prevention of inflammation-mediated bone loss in murine and canine periodontal disease via recruitment of regulatory lymphocytes, Proceedings of the National Academy of Sciences 110 (2013) 18525-30 [222] Nikolich-Zugich J., Aging of the T cell compartment in mice and humans: from no naive expectations to foggy memories, Journal of immunology 193 (2014) 2622-9 41 Statement of significance Most regenerative strategies have not yet proven to be safe or reasonably efficient in the clinic In addition to stem cells and growth factors, the immune system plays a crucial role in the tissue healing process Here, we propose that controlling the immune-mediated mechanisms of tissue repair and regeneration may support existing regenerative strategies or could be an alternative to using stem cells and growth factors The first part of this review we highlight key immune mechanisms involved in the tissue healing process and marks them as potential target for designing regenerative strategies In the second part, we discuss various approaches using biomaterials and drug delivery systems that aim at modulating the components of the immune system to promote tissue regeneration 42 Figure Fish Regenerative capacity Amphibians Fetal Reptiles Birds Neonatal Mammals Adult Immune competence Figure A Number of immune cells mobilized after TISSUE INJURY Tissue resident immune cells Neutrophils Tissue γδT cells macrophages Time hours B T cells Monocytes and Macrophages 1-3 days 1-2 weeks Initial immune response FIBRIN CLOT Tissue macrophage Tissue stem cell Dead neutrophil Tissue debris DAMPs MMPs Arginase Inflammatory cytokines IL-1, IL-6, IFN-γ, TNF-α, Growth factors Proteases CXCL8, IFN-γ, TNF-α, IL-1, CCL2 Inflammatory monocyte IL-4, IL-10, IL-13, Inflammatory macrophage (M(IFN-γ)) CELL MOBILIZATION PROLIFERATION DIFFERENTIATION Growth factors PDGF VEGF IGF-1 Tissue stem cell CX3CL1 Tissue repair macrophage (M(IL-4)) Monocyte ANGIOGENESIS Blood Blo od ves vessel sel Neutrophil C Monocyte D Impaired healing, scarring or fibrosis Regeneration ECM DEPOSITION TNF-α IL-1, Tissue stem cell Profibrotic MMPs TIMPs TNF-α, IFN-γ, T helper or CD8+ Inflammatory macrophage (M(IFN-γ)) Pro-fibrotic macrophage (M(IL-4)-like) Tissue macrophage T cell Tissue stem cell TGF-β PDGF, Growth factors Amphiregulin, IL-10, Scar forming myofibroblast Regulatory T cell T helper SCARRING Tissue macrophage Monocyte Pericyte IGF-1 IL-4, IL-10, Anti-inflammatory anti-fibrotic macrophage (M(IL-10)-like)) T helper INFLAMMATION VASCULAR PERMEABILITY γδT cell ANGIOGENESIS Pericyte Stem/ progenitor cell Figure Pro-inflammatory modulators Physicochemical properties Crosslinking DAMPs Degradability Inflammatory molecules e.g.: TNF-α SDF-1, PGE2 Chemokines Hydrophobicity Topography Synthetic vs naturally derived Anti-inflammatory modulators Anti-inflammatory cytokines e.g.: IL-10, IL-4, NF-κB inhibitors Chemokines siRNAs Pro-resolving mediators Anti-inflammatory miRNAs Extracellular vesicles Anti-TNF-α Biomaterial / Delivery system Injured tissue Regeneration Blood or lymphatic vessel Anti-fibrotic macrophage A AT CON Inflammatory macrophage IO V O N SE FL M TI ER A IN Neutrophil M Regulatory T cell ON TI A RIZ LA PO H Tissue macrophage γδT cell N PH Monocyte AS E T helper T cell S RE OL I UT O N P *Graphical Abstract Controlling the IMMUNE SYSTEM to induce TISSUE REGENERATION Injured tissue PROinflammatory modulators ANTIinflammatory modulators Physicochemical properties Controlled Immune system Biomaterial / Delivery system ... and regeneration of various tissues Promoting tissue regeneration by modulating the immune system In the first part of this review, we have seen that the immune system greatly influences tissue. .. systems that aim at modulating the components of the immune system to promote tissue repair and regeneration The main actors of the immune response following tissue injury An immune response almost... Abstract The immune system plays a central role in tissue repair and regeneration Indeed, the immune response to tissue injury is crucial in determining the speed and the outcome of the healing