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Melatonin Plays Critical Role in Mesenchymal Stem Cell-Based Regenerative Medicine in Vitro and in Vivo Chenxia Hu and Lanjuan Li*

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Melatonin Plays Critical Role in Mesenchymal Stem Cell-Based Regenerative Medicine in Vitro and in Vivo Chenxia Hu and Lanjuan Li* Hu and Li Stem Cell Research & Therapy (2019) 10:13 https://doi.org/10.1186/s13287-018-1114-8 REVIEW Open Access Melatonin plays critical role in mesenchymal stem cell-based regenerative medicine in vitro and in vivo Chenxia Hu and Lanjuan Li* Background Abstract Recently, mesenchymal stem cells (MSCs) have emerged as promising sources for restoring tissue and organ func- Although stem cells have emerged as promising tion; however, there are many potential safety hazards for sources for regenerative medicine, there are many their clinical application, including an availability shortage, potential safety hazards for their clinical application, senescence, sensitivity to toxic environments, and poten- including tumorigenicity, an availability shortage, tial tumorigenicity. Moreover, heterogeneity exists in the senescence, and sensitivity to toxic environments. isolation and cultivation procedures among laboratories, Mesenchymal stem cells (MSCs) have various and the definition of MSCs remains unclear according to advantages compared to other stem cells, including current comments from Sipp et al. [1]. Herein, we termed embryonic stem cells (ESCs) and induced pluripotent MSCs according to the criteria from the International stem cells (iPSCs); thus, MSCs have been intensely Society for Cellular Therapy (ISCT). (i) MSCs must be investigated in recent studies. However, they are plastic-adherent when maintained in standard culture placed in a harsh environment after isolation and conditions. (ii) MSCs must express CD105, CD73, and transplantation, and the adverse microenvironment CD90 and lack expression of CD45, CD34, CD14, or substantially reduces the viability and therapeutic CD11b; CD79alpha or CD19; and HLA-DR surface effects of MSCs. Intriguingly, melatonin (MT), which is markers. (iii) MSCs must differentiate in vitro into os- primarily secreted by the pineal organ, has been teocytes, chondrocytes, and adipocytes [2]. Although found to influence the fate of MSCs during various the nature and functions of MSCs remain unclear, non- physiological and pathological processes. In this clonal stromal cultures obtained from the bone mar- review, we will focus on the recent progress made row and other tissues that contain a subpopulation of regarding the influence of MT on stem cell biology stem cells are currently serving as sources of putative and its implications for regenerative medicine. In MSCs for therapeutic purposes, largely due to findings addition, several biomaterials have been proven to that they might be effective in the treatment of several significantly improve the protective effects of MT on diseases [3]. In addition, MSC-based treatment is powerful MSCs by controlling the release of MT. Collectively, MT and can regenerate organ function through the secretion will be a promising agent for enhancing MSC activities of cytokines and other anti-inflammatory mechanisms [4]. and the regenerative capacity via the regulation of However, various adverse factors in vitro and in vivo will reactive oxygen species (ROS) generation and the reduce the stemness of MSCs and commonly hinder the release of immune factors in regenerative medicine. differentiation process of MSCs. Once MSCs are isolated Keywords: Melatonin, Mesenchymal stem cell, from their original tissues or organs, they rapidly lose their Regenerative medicine, In vitro, In vivo, Protection, vitality because of inappropriate ex vivo conditions, and Therapy shortened telomerase activity and disturbance of the secretome also disturb their morphology [5]. Long-term in vitro culture leads to a decreased colony-forming cap- * Correspondence: [email protected] acity, reduced proliferation ability, unstable cellular DNA, Collaborative Innovation Center for Diagnosis and Treatment of Infectious and a shortened cell lifespan [6, 7]. A sufficient number of Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious active MSCs can compensate for missing organ functions Diseases, School of Medicine, First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China induced by wound, ischemia, drugs, high glucose, sepsis, © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Hu and Li Stem Cell Research & Therapy (2019) 10:13 Page 2 of 11 etc. [8–12]; however, the in vitro life span of MSCs is lim- potential modulator of MSC fate in vitro and in vivo ited by the harsh microenvironment, which thus leads to (Fig. 1). In the near future, MT will be a promising an insufficient cell source [6]. On the other hand, trans- agent for controlling MSC fate via the regulation of planted MSCs can secrete beneficial cytokines within the ROS generation and release of immune factors in re- injured area, while more than 80–90% of implanted cells generative medicine. are sentenced to apoptosis or death 72 h after injection by the harsh microenvironment in vivo [13]. Moreover, trans- MT and related agents are promising factors that plantation of MSCs decreases their survival and prolif- participate in MSC biology eration rates because the low blood supply and collagen Mammals secrete a low level of MT during the daytime, density of tissue cannot provide sufficient nutrition or and the basal level is lower than 10pg/mL, while the growth factors; concurrently, oxidative stress and chronic level of MT is adjusted to higher values (up to 120 pg/ inflammation are substantially increased and impair mL) at night [26]. MT is not only a hormone secreted MSC activities in vivo [14]. by the pineal gland but can also be synthesized by other Under physiological conditions, MSCs will undoubt- tissues, including the retina, harderian gland, gastrointes- edly produce basal reactive oxygen species (ROS) to tinal tract, testes, and lymphocytes [27]. MT is hypothe- maintain cell proliferation and differentiation, while in- sized to originate from the mitochondria of eukaryotic complete oxidation of oxygen in vitro and in vivo re- cells [28, 29]; it has been demonstrated that the MT con- sults in excessive production of ROS and DNA damage centration is highest in the cell membrane, followed by in MSCs and impairs the normal function of MSCs via the mitochondria, nucleus, and cytosol, at the cellular multiple apoptosis-related pathways [15, 16]. Extremely level [30]. Given that mitochondria are the major target of high ROS levels generated by hydrogen peroxide free radicals and the primary intracellular ROS-producing (H2O2), hydroxyl radicals, and superoxide anion will in- organelle, the lipophilicity of MT is beneficial for exerting duce oxidative stress in MSCs [17]. The excessive ROS its protective effects in vivo [31]. Due to its detoxification induced by a stressful microenvironment impairs the and anti-inflammatory properties, MT rescues mitochon- self-renewal, proliferation, and differentiation capacity drial dysfunction [32], cellular senescence [33], and aging of MSCs [18]; moreover, aging significantly upregulates [34, 35]. With respect to energy metabolism, MT signifi- the level of oxidative stress and thus limits the quantity cantly upregulates the level of mitochondrial respiration and quality of MSC daughter cells [19]. Recently, mela- and ATP production, while it inhibits mitochondrial per- tonin (MT) has been isolated from the pineal organ meability transition pores through the activation of cop- and shown to participate in regulating multiple physio- per, zinc superoxide dismutase (CuZnSOD) within the logical functions, including sleep promotion, circadian intermembrane space [29, 36, 37]. rhythms, and neuroendocrine processes [20, 21]. The Although MT effectively exerts broad free radical scav- administration of MT substantially improves the ma- enging activity without receptors in vivo, the antioxidant nipulation advantages of MSCs ex vivo and in vivo; in activity of MT also requires assistance from specific re- general, MT serves as a component of the homeostatic ceptors [38, 39]. Two specific G-protein-coupled recep- and cell-protective agents, which protect MSCs from tors, MT1 and MT2 in mammals, bind calmodulin and oxidation, inflammation, apoptosis, ischemia, and aging consequently activate nitric oxide synthase (NOS) [40] for regulating MSC differentiation and protection in and participate in regulating the functions of MSCs different organs and tissues [22, 23]. The antioxidant [31, 41]. Aside from these two main receptors, MT capacity of MSCs could be particularly relevant in the also interacts with other receptors, including the non- case of immune and inflammatory components. Im- mammalian MT receptor subtype MT3, the nuclear portantly, MT is involved in the detoxification of ROS receptor ROR/RZR, and calmodulin [42, 43]. However, and free radical intermediates because it plays a critical the detailed expression level of MT receptors should be role in the release of antioxidant enzymes, including determined according to the stem cell type and the catalase, glutathione reductase, superoxide dismutase,
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