Targeting Macrophages As a Candidate for Tissue Regeneration

Macrophages and Tissue Regeneration Zhang et al. Curr. Issues Mol. Biol. (2018) 29: 37-48. caister.com/cimb Snapshot: Targeting Macrophages as a Candidate for Tissue Regeneration Jing Zhang1,2,3, Yang Yang4, Zhi Yang4,5, Tian Li4,5 and Fulin Chen1,2,3* Introduction Macrophages, also known as "big eaters" due to 1Lab of Tissue Engineering, College of Life their phagocytic capacity, were first annotated by Sciences, Northwest University, 229 Taibai North Mechnikov in the late 18th century (Fraga et al., Road, Xi'an, 710069, P. R. China 2017; Tauber, 2003; Wan et al., 2017). They are a 2Provincial Key Laboratory of Biotechnology of specific mononuclear cell group abundant in almost Shaanxi, 229 Taibai North Road, Xi'an, 710069, P. every organ of higher animals. In mammals, R. China macrophages can derive from the yolk sac, fetal 3Key Laboratory of Resource Biology and liver, and bone marrow (Geissmann et al., 2010; Biotechnology in Western China Ministry of Wynn et al., 2013). Their differentiation is Education, 229 Taibai North Road, Xi'an, 710069, P. orchestrated by multiple growth factors (GFs) R. China. (Gordon, 2003; Sica et al., 2012). Tissue-resident 4College of Life Sciences, Northwest University, 229 macrophages, usually originating from the bone Taibai North Road, Xi'an, 710069, P. R. China marrow hematopoietic progenitors, has the ability of 5Department of Biomedical Engineering, The Fourth self-renewing (Geissmann et al., 2010; Jenkins et Military Medical University, 169 Changle West Road, al., 2011; Schulz et al., 2012; Davies et al., 2013). Xi'an 710032, China Generally, they are divided into two phenotypes, classically activated M1 macrophages and * Correspondence: [email protected] alternatively activated M2 macrophages, which refer to the state activated by Th1 and Th2 lymphocytes DOI: https://dx.doi.org/10.21775/cimb.029.037 or with interferon-gamma (INF-γ) and interleukin 4 (IL-4), respectively (Goerdt et al., 1999; Gordon, Abstract 2003; Sica et al., 2012). This phenomenon is Macrophages are a specific mononuclear cell group described as heterogeneity or polarization. abundant in almost every organ of higher animals. This group is a pivotal part of the immune system Tissue regeneration plays an important role in and is involved in immune responses against cardiovascular diseases (Sengupta et al., 2010; exogenous antigen invasion. Recently, Wang et al., 2013), cerebrovascular diseases accumulating evidence has demonstrated that (Wang et al., 2013), and neoplasms (Jin et al., macrophages participate in wound repair and tissue 2017), three major killers among human across the regeneration. In this review, we will first introduce world (Jiang et al., 2017; Li et al., 2017; Liang et al., the influences of regeneration after injury in various 2017; Lv et al., 2017; Ma et al., 2017; Wu et al., tissues and organs among macrophage-depleted 2018; Xin et al., 2018; Zhang et al., 2018). The animal models. Second, the possible relationship primary function of a macrophage is to serve as the between macrophages and reparation capacities effector of the innate immune system (Saini et al., will be discussed. Finally, we provide a general idea 2016; Jackaman et al., 2017; Liang et al., 2017; about the roles of macrophages in the injury- Rahimifard et al., 2017; Ren et al., 2017). regeneration process and then discuss the current Accompanied by monocytes, macrophages occupy challenges and prospects of their clinical the front line of innate defense against exogenous application. The information compiled here may be antigens. They are highly flexible cells that exhibit useful for regenerative research and may promote dramatic changes in phenotypes in response to macrophages as a therapeutic target in regenerative stimuli from neighboring tissues/cells and/or the medicine. external environment. They promptly infiltrate into !37 Macrophages and Tissue Regeneration Zhang et al. the pathogen invasion site of the organism, clear Scientists have discovered that macrophages are debris, and secrete chemokines and cytokines to involved in the repair of brain vascular rupture and initiate inflammation procedures, drive acquired regeneration of peripheral nerves. Because vascular immune responses and subsequently promote injury endothelial growth factor (VEGF) is one of the key resolution from a morbid status (Gordon et al., 2005; factors in angiogenesis (Pollard, 2009; Fantin et al., Hume, 2006; Hume, 2008; Geissmann et al., 2010; 2010), Cattin and co-researchers (Cattin et al., Hume et al., 2012; Wynn et al., 2013). Additionally, 2015) used the Cre system and created transgenic macrophages fulfill indispensable functions in the mice in which the production of VEGFα in patterning and formatting of tissues during macrophages is inhibited. In the abovementioned developmental and mature stages. They are work, they found that the loss of VEGFα did not involved in erythropoiesis (Kawane et al., 2001), inhibit macrophage recruitment during the early hematopoiesis (Gordy et al., 2011)(Gordy et al., stage of nerve regeneration. However, a reduction 2011), angiogenesis (Rao et al., 2007; Machnik et in vascularization was observed in mutant animals, al., 2009; Fantin et al., 2010; Stefater III et al., leading to the restraint of Schwann cells (SCs) at 2011), osteogenesis (Niida et al., 1999; Pollard, the stump site. Consequently, these cells failed to 2009), and neural homeostasis (Pollard, 2009; form tube-like structures, which are necessary to Erblich et al., 2011). Furthermore, macrophages direct axons back to their original targets. maintain metabolic homeostasis in adult mammalian Meanwhile, by studying transgenic zebrafish models organs, such as adipose tissue, the liver, and the (Liu et al., 2016), another group demonstrated that pancreas (Weisberg et al., 2003; Odegaard et al., in some cases, following cerebrovascular rupture, 2007; Kang et al., 2008; Olefsky et al., 2010; macrophages were recruited by extracellular ATP Nguyen et al., 2011; Odegaard et al., 2013). and formed direct physical adhesions with both However, chronically activated macrophages lead to epithelial ends. With the help of mechanical forces, a prolonged inflammatory reaction, which triggers both the broken ends of cerebral vessels could be substantial adjunctive tissue destruction. Indeed, successfully reconnected, and a functional vessel these unregulated macrophages contribute to was then restored (Figure 1, Table 1). Thus, various chronic inflammatory and autoimmune macrophages promote the migration of SC and diseases, including atherosclerosis, asthma, maintain the homeostasis of peripheral neural rheumatoid arthritis, and fibrosis (Kamada et al., network by secreting cytokines, making physical 2008; Hansson et al., 2011; Libby et al., 2011; ligation, and assisting neovessel formation. Murray et al., 2011). Apart from the disease- promoting effect, clinical and experimental evidence Fracture healing has demonstrated that macrophages participate in Macrophages have also been involved in bone tumor initiation, progression, and metastasis (Marelli healing. Schlundt et al. produced unilateral closed et al., 2017; Yao et al., 2017). fractures in 8-week-old mice (Schlundt et al., 2015). They used a well-developed medical intravenous In this review, we aimed to mainly focus on the injection method to selectively deplete mouse mechanism by which macrophages contribute to macrophages. This fabulous work was performed by tissue/organ injury repair. We will first introduce the Dutch scientists VanRooijen and Van Nieuwmegen influences of regeneration after injury in various in 1984. The approach is to introduce an effector tissues and organs among macrophage-depleted molecule, liposome-carried dichloromethylene animal models. Second, the possible relationship diphosphonate, specifically called clodronate between macrophages and reparation capacities liposome, into the organism (Van Rooijen et al., will be discussed. Finally, we provide a general idea 1984). This compound has been shown to have about the roles of macrophages in the injury- high affinity for calcium and, thus, adheres to the regeneration process. Collectively, this review will mononuclear phagocyte system (MPS). At the serve as a comprehensive reference and hopefully cellular and molecular levels, the accumulated aid in the design of future research and provide a intracellular effectors caused a "liposome-mediated potential therapeutic target in therapeutic methods. macrophage suicide" effect, leading to the death of the macrophages (Figure 2). This novel method is Macrophage depletion and tissue regeneration reversible and less toxic, demonstrating effective elimination of macrophages in various organs, such Blood vessel rupture and/or nerve regeneration as the spleen, lung, and testis (Van Rooijen et al., Physical damage of the brain is usually 1985; Thepen et al., 1989; van Rooijen et al., 1989; accompanied by the rupture of blood vessels. Delemarre et al., 1990; Van Rooijen et al., 1990; !38 Macrophages and Tissue Regeneration Zhang et al. Fig 2. Figure 1. Roles of macrophage in regeneration. Accumulated studies have demonstrated that macrophage participated in regeneration in different organisms. In human, macrophage is able to promote regeneration of bone fracture, vessel rupture, and skin wound. Besides, it can also promote ap- pendage growth of zebrafish and newt. 29 Table 1. Summary of macrophage involvement and function in different regeneration processes. Organ/tissue/body parts Model Mechanism

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