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Application of mesenchymal stem cells in human diseases
Chapter 2
Application of mesenchymal stem cells in human diseases Wenyan Zhou1, Yun Xu2 1 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC; 2Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC
Introduction: background and driving forces Adult tissue stem cells lose pluripotency through aging and disease, which hinders normal tissue function. Mesenchymal stem cells (MSCs), found in a variety of adult tissues, have the ability to differentiate into various mesenchymal lineages in vitro and also show a mighty immunomodulatory ability; these properties make MSCs potential therapy candidates for tissue engineering and regeneration medicine.
History of mesenchymal stem cells Friedenstein transplanted bone fragments and found that nonhematopoietic mesenchymal tissue could form in the heterotopic area; he named the cells osteoblasts (Friedenstein et al., 1968). Subsequently, a number of studies were carried out to confirm the colony formation and plastic adherent ability (Friedenstein et al., 1970, 1976). Similar cells were found in human bone marrow (Castro-Malaspina et al., 1980); these cells with the capability of selfrenewal and in vitro multilineage differentiation potential were named “mesenchymal stem cells” by Caplan (Caplan, 1991). The next decade, a series of studies focused on verifying the stem cell properties of MSCs, but not until 1997 was the in vivo bone formation capacity of human bone marrow MSCs (BMSCs) verified (Kuznetsov et al., 1997). Ever since the nomenclature MSCs was adopted, the correctness of the name has been a matter of concern. According to the antigen expression of the adherent cells of bone marrow, “mesenchymal” was accredited, but there is no uniform answer to which antigen (a single antigen or a small panel of antigens) could be used to define “stem” (Horwitz and Keating, 2000). To solve this puzzle, the International Society for Cellular Therapy (ISCT) gave a new Mesenchymal Stem Cells in Human Health and Diseases. https://doi.org/10.1016/B978-0-12-819713-4.00002-5 Copyright © 2020 Elsevier Inc. All rights reserved.
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terminology, mesenchymal stromal cells, to all of the plastic-adherent mesenchymal cells, no matter the tissue origin, and only when the stemness is demonstrated by clearly stated criteria can these cells be called mesenchymal stem cells (Horwitz et al., 2005), but the acronym MSC is still kept in use. The next year, the ISCT issued minimal criteria to define human MSCs (here referring to mesenchymal stromal cells), including adherence to plastic, specific surface antigen expression, and multipotent differentiation potential (Dominici et al., 2006). Although the ISCT had proposed the difference between mesenchymal stromal cells and MSCs, these two terminologies were still confused. Researchers use the minimal criteria to define MSCs without evidence of stem cell activity (Le et al., 2007; Soleimani and Nadri, 2009). During the next decade, investigators cared more about the function of MSCs; transplantation of MSCs can enhance the engraftment of hematopoietic stem cells (HSCs) (Chao et al., 2012; Le et al., 2007). Due to their multipotential capacity, MSCs can be used to repair tissue injury (Han et al., 2015; Martino et al., 2016). Since the highly active cytokine-secreting property was found, the role of MSCs in immunomodulation and homeostasis maintenance has been studied (Davies et al., 2017; Zhao et al., 2015). This makes MSCs a potential therapeutic cell, which may become a commercialized product, so it is vital to produce MSCs in batches as a standard therapeutic during largescale proliferation. In 2016, the ISCT made a statement on this issue, highlighting that culture conditions can influence MSC functions, so the clinical application should be the guidance for large-scale proliferation, to optimize the culture system (Martin et al., 2016).
Function of mesenchymal stem cells Mesenchymal stem cells as seed cells participate in tissue regeneration Mesenchymal stem cells for myocardial injury MSCs were treated with hypoxia, preconditioned for 24 h, and tested in a monkey’s infarcted heart. Ninety days after the first injection the infarct size and left ventricular (LV) function, as well as cardiomyocyte proliferation, vascular density, and myocardial glucose uptake, were significantly improved compared with the control group (Hu et al., 2016a,b). Human MSCs treated with 5% O2 were administered intravenously into mice with LV dysfunction. LV ejection fraction and infarct size were significantly improved in the MSC group after 21 days (Luger et al., 2017). A double-blind, placebo-controlled, dose-ranging trial was conducted in 53 patients. The result showed that the forced expiratory volume in 1 s and LV ejection fraction were improved in patients treated with human MSCs (Hare et al., 2009).
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Mesenchymal stem cells for osteoarthritis, lower back pain, and cartilage repair Chondrogenic progenitor cell-based stem cell therapy has been studied for cartilage regeneration in osteoarthritis (OA) (Koelling and Miosge, 2009). In an animal model tumor necrosis factor a (TNFa) inducing leucine-rich a2glycoprotein 1 (LRG1) secretion contributed to angiogenesis coupling with aberrant bone formation; the LRG1 inhibitor lenalidomide could be a potential therapeutic approach for OA treatment (Wang et al., 2017). Recombinant Atsttrin, which expressed by MSCs is a novel TNFa blocker and play a chondroprotective role in ameliorating OA development (Xia et al., 2015). Human MSCs injected intraarticularly were activated to express high levels of Hedgehog and trigger type II collagen to enhance rat meniscal regeneration (Horie et al., 2012). Delayed fracture union can be prevented by MSCs mixed with platelet-rich plasma (Liebergall et al., 2013). Orozco et al. presented a phase I/II study of 12 patients with clinical and objective follow-up coverage for 1 year after intraarticular MSC injection. MSC administration appears to be safe, and the result showed that 65%e78% of patients exhibited rapid and progressive improvement and most of them emerged with improvement of cartilage quality (Orozco et al., 2013). Two-year follow-up results showed that the quality of cartilage had further improved (Orozco et al., 2014). 71% of patients with degenerative disc disease transplanted with MSCs exhibited rapid improvement of pain and disability, but without disc height recovery (Orozco et al., 2011). How to prolong the cells’ intraarticular longevity became a focus of attention. MSC pretreatment with inflammatory factors or hypoxia does not influence migration or adhesion to osteoarthritic cartilage and synovium (Leijs et al., 2017). Alternative approaches should be developed to improve the therapeutic effect. Mesenchymal stem cells for pulmonary disease A phase I study has shown that in severe chronic obstructive pulmonary disease patients, combined one-way endobronchial valve insertion and MSC treatment can decrease levels of circulating C-reactive protein at 30 and 90 days, as well as the BODE (body mass index, airway obstruction, dyspnea, exercise) index and modified Medical Research Council score (de Oliveira et al., 2017). A phase II study showed that bronchopulmonary dysplasia patients receiving intratracheal transplantation with allogeneic human umbilical cord blood-derived MSCs have lower severity than the control group (Chang et al., 2014). MSCbased therapies were used to treat acute respiratory distress syndrome (ARDS) patients; serious adverse events (SAEs) were subsequently observed in three of nine patients, even they thought those SAEs were not related to the MSCs. Phase II is already under way to treat ARDS (Wilson et al., 2015).
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Mesenchymal stem cells for liver disease Adipose-derived MSCs (ADSCs) and BMSCs seeded in regenerated silk fibroin (RSF) scaffolds were evaluated in a CCl4-induced liver injury mouse model. Results showed that neovascularization, a bile canaliculus-like structure, and some hepatocyte-like cells were observed after transplantation of RSF MSCs (Xu et al., 2017). A phase II trial evaluated the effects of BMSCs transplanted in cirrhotic patients. Three and six months after surgery patients exhibited partial improvement of liver function (El-Ansary et al., 2012). Thirty to fifty million MSCs were injected into eight patients with end-stage liver disease. According to the results, serum albumin, bilirubin, and liver function score were all improved (Kharaziha et al., 2009). In 54.5% of alcoholic cirrhosis patients histological improvements were observed after BMSC injection, and the levels of transforming growth factor b1 (TGFb), type I collagen, and a-smooth muscle actin were decreased (Jang et al., 2014). MSC transplantation can be used as a potential treatment for liver injury. Mesenchymal stem cells for gastrointestinal disease Silanized hydroxypropylmethylcellulose hydrogeleloaded ADSCs improve colonic epithelial structure as well as hyperpermeability in a rat model of radiation-induced severe colonic damage (Moussa et al., 2017). Crohn’s disease patients were given intravenous infusions of allogeneic MSCs weekly for 4 weeks. Forty-two days after the first MSC administration, 8/15 had clinical remission, and 7/15 had endoscopic improvement (Forbes et al., 2014). In a phase III randomized, double-blind controlled trial using ADSCs for complex perianal fistulas in Crohn’s disease, 212 patients were randomly divided into two groups with MSCs or placebo. After 24 weeks, a significant remission was found in the MSC group compared with the placebo group (53 of 107 vs. 36 of 105) (Pane´s et al., 2016). Mesenchymal stem cells as modulators participate in tissue homeostasis and regeneration MSCs usually work through systemic infusion to cure disease. Although this method can show the effectiveness of treatment, there is little direct evidence that MSCs differentiate into injured tissue cells, so there must be another mechanism by which MSCs cure diseases. In a review, Horwitz and Dominici summarized the role of MSCs cytokine secretion in tissue regeneration (Horwitz and Dominici, 2008), and since then, more and more studies have begun to focus on the secretome of MSCs. BMSCs are the earliest kind of MSCs that appear to have the tissue regulation function, mainly in the maintenance of HSC microenvironment. Human MSCs have been demonstrated to reconstitute a functional human hematopoietic microenvironment in NOD-SCID mice (Muguruma et al., 2006). CD146þ
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MSCs are thought to be the specific population that contributes to hematopoietic maintenance, as they have the capability of forming a hematopoietic niche in heterotopic sites after transplantation and highly express angiopoietin-1, which is a pivotal molecule of the HSC niche (Sacchetti et al., 2007). However, in 2016 a study reported that CD146þ MSCs can only form bone after transplantation, suggesting that mouse CD146þ cells are osteo-progenitors committed to osteoblastic fate, and they identified a Sca1þ population that could generate CD146þ cells as the progenitor of the HSC niche (Hu et al., 2016a,b). This divergence may be due to differences in cell species; human and mouse MSCs may possess different characteristics. Since MSCs can secrete a variety of chemotactic factors and express low level of major histocompatibility complex II, the immunomodulatory ability of MSCs has drawn much attention in this field. Considerable literature shows that MSCs are involved in both innate immune and adaptive immune responses, through interaction with monocytes, polarization of macrophages, and promoting the formation of regulatory T cells, not just suppressing the immune response, but also displaying proinflammatory effects depending on the specific inflammatory environment. The innate immune system is the first line of nonspecific defense to resist invasion by pathogenic germs, during which the Toll-like receptors (TLRs) play an important role. TLRs are a group of receptor molecules expressed on the surface of innate effector cells, which can recognize danger signals such as lipopolysaccharide (LPS), double-stranded RNA, and endotoxin when tissue is injured (Kawai and Akira, 2011; Medzhitov, 2001). MSCs express abundant TLRs, especially TLR3 and TLR4 (Hwa et al., 2006; Pevsner-Fischer et al., 2007). An interesting study demonstrated that TLR3 and TLR4 play different roles in the immunomodulatory properties of MSCs. In their research, TLR3-primed MSCs show an antiinflammatory profile (MSC2), while TLR4-primed MSCs are proinflammatory (MSC1) (Waterman et al., 2010). However, that is not always the case. By using poly(I:C) and LPS to stimulate TLR3 and TLR4, respectively, of MSCs, both methods can inhibit T cell modulatory activity by impairing Notch signaling (Liotta et al., 2008). On the other hand, both TLR3 and TLR4 activation of MSCs can increase T regulatory cell induction; that is to say, both TLR3-primed and TLR4-primed MSCs show antiinflammatory characteristics (Rashedi et al., 2017). Different experiments may use different concentrations of TLR ligands to stimulate MSCs, which may influence the proinflammatory and antiinflammatory properties of MSCs (Ren et al., 2008), and as the molecular mechanisms of TLR-primed immunomodulatory actions remain unclear, this may be the cause of divergence. Macrophages are an important population in the immune response. They interact with MSCs to participate in tissue repair (Wang et al., 2015). At the early stage of infection or injury, macrophages respond rapidly and release inflammatory factors to kill pathogens. At this stage, the levels of
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inflammatory factors in the tissue are relatively low; MSCs perceive the low inflammatory level, and are polarized into the proinflammatory type MSC (MSC1), releasing growth factors such as interleukin-6 (IL-6) and IL-8 to enhance inflammation. When there are sufficient levels of proinflammatory cytokines, MSCs adopt the antiinflammatory type (MSC2) and release TGFb, IL-10, and indoleamine 2,3-dioxygenase, which polarize the proinflammatory macrophages (M1) to antiinflammatory macrophages (M2). In a model of colitis and sepsis, ADSCs induced a distinct regulatory activation state of macrophages, which possess potent immunomodulatory ability and therapeutic potential in inflammatory bowel diseases and sepsis (Anderson et al., 2013). In addition, through an extracellular vesicle-mediated mitochondrial transfer mechanism, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype (Morrison et al., 2017).
Controversy over and expectations for mesenchymal stem cells There is still a lot of controversies about MSCs, although they show numerous benefits. A most basic question is, what is the MSCs? Mesenchymal stromal cells and mesenchymal stem cells are always confused. Since there is no clear definition to distinguish between the two terminologies, they are used to refer to the same cell population, which defined by the ISCT in 2006 (Dominici et al., 2006). According to this manual, researchers use CD73, CD90, and CD105 to judge whether the cells they cultured are MSCs. However, there is the problem that using the conventional panel of CD markers to characterize MSCs has its limitations, especially when large-scale amplification is needed. During MSC expansion, replicative senescence will accumulate (Yang et al., 2017), but the CD markers (CD73, CD90, CD105) are rarely affected (Kundrotas et al., 2016), it is inaccurate to predict the function of MSCs according to these markers. What’s more, different researchers use different markers to identify subpopulations of MSCs, such as CD146, Nestin, and PDGFR-a, but without a definite hierarchical relationship like the hematopoietic system. A vast number of documents indicate that MSCs exist in various tissues of the body, but the difference between MSCs derived from different tissues is still not clear Scientists never stop exploring the in situ form of MSCs. Thus provoking another controversy. In 2008, Crisan and colleagues found that MSCs possess a perivascular localization for the first time (Crisan et al., 2008). In this research they isolated pericytes and found that cultured pericytes show multipotency as well as MSC markers. Caplan also made his point that all MSCs were pericytes (Caplan, 2008, 2017). Another work using lineage tracing demonstrated that pericytes never contribute to tissue regeneration and wound healing during aging and injury (Guimara˜es-Camboa et al., 2017). It is still difficult to make a conclusion about what is the relationship between MSCs
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and pericytes. It could be said that some pericytes but not all can develop into MSC-like cells during in vitro culture, and cell property will change with long term in vitro culture. All the efforts of MSCs researchers have been made to better utilize MSCs for disease treatment, and the results of several clinical trials with MSCs are inspiring (Butler et al., 2017; Staff et al., 2016). There are several factors need to be considered in MSCs clinical application. For example, it is necessary to choose a suitable tissue source and culture condition for MSCs when treating a specific disease. Moreover, both the safety and the effectiveness are important for the clinical applications of MSCs. In addition, tracking the results of clinical trials is important no matter the results are, positive or not.
Conclusion In summary, MSCs possess huge clinical application prospects, for their strong activities in tissue regeneration, immunoregulation, and other paracrine effects. However, until now scientists have not given a universal definition of MSCs. Moreover, MSCs are proved to be a heterogeneous cell population with the advancing research. Thus new technologies, such as single-cell RNA sequencing, proteomics, and epigenomics, should be adopted to investigate the complexity of MSCs. So far, the clinical application of MSCs is largely behind the level of laboratory research. Therefore, the combination of basic research and clinical trials is a significant factor to improve the development of MSCs. In future studies, new technologies should be used to encode the heterogeneity of MSCs, and appropriate clinical trials are needed to clarify the curative effect of MSCs. The prospects of MSCs are worth expecting.
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14 Mesenchymal Stem Cells in Human Health and Diseases Liebergall, M., Schroeder, J., Mosheiff, R., Gazit, Z., Yoram, Z., Rasooly, L., Daskal, A., Khoury, A., Weil, Y., Beyth, S., 2013. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol. Ther. 21, 1631e1638. Liotta, F., Angeli, R., Cosmi, L., Filı`, L., Manuelli, C., Frosali, F., Mazzinghi, B., Maggi, L., Pasini, A., Lisi, V., Santarlasci, V., Consoloni, L., Angelotti, M.L., Romagnani, P., Parronchi, P., Krampera, M., Maggi, E., Romagnani, S., Annunziato, F., 2008. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 26, 279e289. Luger, D., Lipinski, M.J., Westman, P.C., Glover, D.K., Dimastromatteo, J., Frias, J.C., Albelda, M.T., Sikora, S., Kharazi, A., Vertelov, G., Waksman, R., Epstein, S.E., 2017. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ. Res. 120, 1598e1613. Martin, I., De Boer, J., Sensebe, L., 2016. A relativity concept in mesenchymal stromal cell manufacturing. Cytotherapy 18, 613e620. Martino, M.M., Maruyama, K., Kuhn, G.A., Satoh, T., Takeuchi, O., Mu¨ller, R., Akira, S., 2016. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nat. Commun. 7, 11051. Medzhitov, R., 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135e145. Morrison, T.J., Jackson, M.V., Cunningham, E.K., Kissenpfennig, A., McAuley, D.F., O’Kane, C.M., Krasnodembskaya, A.D., 2017. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am. J. Respir. Crit. Care Med. 196 (10), 1275e1286. Moussa, L., Pattappa, G., Doix, B., Benselama, S.L., Demarquay, C., Benderitter, M., Se´mont, A., Tamarat, R., Guicheux, J., Weiss, P., Re´thore´, G., Mathieu, N., 2017. A biomaterial-assisted mesenchymal stromal cell therapy alleviates colonic radiation-induced damage. Biomaterials 115, 40e52. Muguruma, Y., Yahata, T., Miyatake, H., Sato, T., Uno, T., Itoh, J., Kato, S., Ito, M., Hotta, T., Ando, K., 2006. Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood 107, 1878e1887. Orozco, L., Soler, R., Morera, C., Alberca, M., Sa´nchez, A., Garcı´a-Sancho, J., 2011. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92, 822e828. Orozco, L., Munar, A., Soler, R., Alberca, M., Soler, F., Huguet, M., Sentı´s, J., Sa´nchez, A., Garcı´a-Sancho, J., 2013. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95, 1535e1541. Orozco, L., Munar, A., Soler, R., Alberca, M., Soler, F., Huguet, M., Sentı´s, J., Sa´nchez, A., Garcı´a-Sancho, J., 2014. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results. Transplantation 97, e66e68. Pane´s, J., Garcı´a-Olmo, D., Van Assche, G., Colombel, J.F., Reinisch, W., Baumgart, D.C., Dignass, A., Nachury, M., Ferrante, M., Kazemi-Shirazi, L., Grimaud, J.C., de la Portilla, F., Goldin, E., Richard, M.P., Leselbaum, A., Danese, S., 2016. Expanded allogeneic adiposederived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388, 1281e1290.
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Pevsner-Fischer, M., Morad, V., Cohen-Sfady, M., Rousso-Noori, L., Zanin-Zhorov, A., Cohen, S., Cohen, I.R., Zipori, D., 2007. Toll-like receptors and their ligands control mesenchymal stem cell functions. Blood 109, 1422e1432. Rashedi, I., Go´mez-Aristiza´bal, A., Wang, X.H., Viswanathan, S., Keating, A., 2017. TLR3 or TLR4 activation enhances mesenchymal stromal cell-mediated Treg induction via Notch signaling. Stem Cells 35, 265e275. Ren, G., Zhang, L., Zhao, X., Xu, G., Zhang, Y., Roberts, A.I., Zhao, R.C., Shi, Y., 2008. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2, 141e150. Sacchetti, B., Funari, A., Michienzi, S., Di, C.S., Piersanti, S., Saggio, I., Tagliafico, E., Ferrari, S., Robey, P.G., Riminucci, M., Bianco, P., 2007. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324e336. Soleimani, M., Nadri, S., 2009. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat. Protoc. 4, 102e106. Staff, N.P., Madigan, N.N., Morris, J., Jentoft, M., Sorenson, E.J., Butler, G., Gastineau, D., Dietz, A., Windebank, A.J., 2016. Safety of intrathecal autologous adipose-derived mesenchymal stromal cells in patients with ALS. Neurology 87, 2230e2234. Wang, M., Zhang, G., Wang, Y., Liu, T., Zhang, Y., An, Y., Li, Y., 2015. Crosstalk of mesenchymal stem cells and macrophages promotes cardiac muscle repair. Int. J. Biochem. Cell Biol. 58, 53e61. Wang, Y., Xu, J., Zhang, X., Wang, C., Huang, Y., Dai, K., Zhang, X., 2017. TNF-a-induced LRG1 promotes angiogenesis and mesenchymal stem cell migration in the subchondral bone during osteoarthritis. Cell Death Dis. 8, e2715. Waterman, R.S., Tomchuck, S.L., Henkle, S.L., Betancourt, A.M., 2010. A new mesenchymal stem cell (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One 5, e10088. Wilson, J.G., Liu, K.D., Zhuo, H., Caballero, L., McMillan, M., Fang, X., Cosgrove, K., Vojnik, R., Calfee, C.S., Lee, J.W., Rogers, A.J., Levitt, J., Wiener-Kronish, J., Bajwa, E.K., Leavitt, A., McKenna, D., Thompson, B.T., Matthay, M.A., 2015. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir. Med. 3, 24e32. Xia, Q., Zhu, S., Wu, Y., Wang, J., Cai, Y., Chen, P., Li, J., Heng, B.C., Ouyang, H.W., Lu, P., 2015. Intra-articular transplantation of atsttrin-transduced mesenchymal stem cells ameliorate osteoarthritis development. Stem Cells Transl. Med. 4, 523e531. Xu, L., Wang, S., Sui, X., Wang, Y., Su, Y., Huang, L., Zhang, Y., Chen, Z., Chen, Q., Du, H., Zhang, Y., Yan, L., 2017. Mesenchymal stem cell-seeded regenerated silk fibroin complex matrices for liver regeneration in an animal model of acute liver failure. ACS Appl. Mater. Interfaces 9, 14716e14723. Yang, F., Yang, L., Li, Y., Yan, G., Feng, C., Liu, T., Gong, R., Yuan, Y., Wang, N., Idiiatullina, E., Bikkuzin, T., Pavlov, V., Li, Y., Dong, C., Wang, D., Cao, Y., Han, Z., Zhang, L., Huang, Q., Ding, F., Bi, Z., Cai, B., 2017. Melatonin protects bone marrow mesenchymal stem cells against iron overload-induced aberrant differentiation and senescence. J. Pineal Res. Zhao, K., Lou, R., Huang, F., Peng, Y., Jiang, Z., Huang, K., Wu, X., Zhang, Y., Fan, Z., Zhou, H., Liu, C., Xiao, Y., Sun, J., Li, Y., Xiang, P., Liu, Q., 2015. Immunomodulation effects of mesenchymal stromal cells on acute graft-versus-host disease after hematopoietic stem cell transplantation. Biol. Blood Marrow Transplant. 21, 97e104.
Application of mesenchymal stem cells in human diseases Wenyan Zhou1, Yun Xu2 1 Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC; 2Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PRC
Introduction: background and driving forces Adult tissue stem cells lose pluripotency through aging and disease, which hinders normal tissue function. Mesenchymal stem cells (MSCs), found in a variety of adult tissues, have the ability to differentiate into various mesenchymal lineages in vitro and also show a mighty immunomodulatory ability; these properties make MSCs potential therapy candidates for tissue engineering and regeneration medicine.
History of mesenchymal stem cells Friedenstein transplanted bone fragments and found that nonhematopoietic mesenchymal tissue could form in the heterotopic area; he named the cells osteoblasts (Friedenstein et al., 1968). Subsequently, a number of studies were carried out to confirm the colony formation and plastic adherent ability (Friedenstein et al., 1970, 1976). Similar cells were found in human bone marrow (Castro-Malaspina et al., 1980); these cells with the capability of selfrenewal and in vitro multilineage differentiation potential were named “mesenchymal stem cells” by Caplan (Caplan, 1991). The next decade, a series of studies focused on verifying the stem cell properties of MSCs, but not until 1997 was the in vivo bone formation capacity of human bone marrow MSCs (BMSCs) verified (Kuznetsov et al., 1997). Ever since the nomenclature MSCs was adopted, the correctness of the name has been a matter of concern. According to the antigen expression of the adherent cells of bone marrow, “mesenchymal” was accredited, but there is no uniform answer to which antigen (a single antigen or a small panel of antigens) could be used to define “stem” (Horwitz and Keating, 2000). To solve this puzzle, the International Society for Cellular Therapy (ISCT) gave a new Mesenchymal Stem Cells in Human Health and Diseases. https://doi.org/10.1016/B978-0-12-819713-4.00002-5 Copyright © 2020 Elsevier Inc. All rights reserved.
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terminology, mesenchymal stromal cells, to all of the plastic-adherent mesenchymal cells, no matter the tissue origin, and only when the stemness is demonstrated by clearly stated criteria can these cells be called mesenchymal stem cells (Horwitz et al., 2005), but the acronym MSC is still kept in use. The next year, the ISCT issued minimal criteria to define human MSCs (here referring to mesenchymal stromal cells), including adherence to plastic, specific surface antigen expression, and multipotent differentiation potential (Dominici et al., 2006). Although the ISCT had proposed the difference between mesenchymal stromal cells and MSCs, these two terminologies were still confused. Researchers use the minimal criteria to define MSCs without evidence of stem cell activity (Le et al., 2007; Soleimani and Nadri, 2009). During the next decade, investigators cared more about the function of MSCs; transplantation of MSCs can enhance the engraftment of hematopoietic stem cells (HSCs) (Chao et al., 2012; Le et al., 2007). Due to their multipotential capacity, MSCs can be used to repair tissue injury (Han et al., 2015; Martino et al., 2016). Since the highly active cytokine-secreting property was found, the role of MSCs in immunomodulation and homeostasis maintenance has been studied (Davies et al., 2017; Zhao et al., 2015). This makes MSCs a potential therapeutic cell, which may become a commercialized product, so it is vital to produce MSCs in batches as a standard therapeutic during largescale proliferation. In 2016, the ISCT made a statement on this issue, highlighting that culture conditions can influence MSC functions, so the clinical application should be the guidance for large-scale proliferation, to optimize the culture system (Martin et al., 2016).
Function of mesenchymal stem cells Mesenchymal stem cells as seed cells participate in tissue regeneration Mesenchymal stem cells for myocardial injury MSCs were treated with hypoxia, preconditioned for 24 h, and tested in a monkey’s infarcted heart. Ninety days after the first injection the infarct size and left ventricular (LV) function, as well as cardiomyocyte proliferation, vascular density, and myocardial glucose uptake, were significantly improved compared with the control group (Hu et al., 2016a,b). Human MSCs treated with 5% O2 were administered intravenously into mice with LV dysfunction. LV ejection fraction and infarct size were significantly improved in the MSC group after 21 days (Luger et al., 2017). A double-blind, placebo-controlled, dose-ranging trial was conducted in 53 patients. The result showed that the forced expiratory volume in 1 s and LV ejection fraction were improved in patients treated with human MSCs (Hare et al., 2009).
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Mesenchymal stem cells for osteoarthritis, lower back pain, and cartilage repair Chondrogenic progenitor cell-based stem cell therapy has been studied for cartilage regeneration in osteoarthritis (OA) (Koelling and Miosge, 2009). In an animal model tumor necrosis factor a (TNFa) inducing leucine-rich a2glycoprotein 1 (LRG1) secretion contributed to angiogenesis coupling with aberrant bone formation; the LRG1 inhibitor lenalidomide could be a potential therapeutic approach for OA treatment (Wang et al., 2017). Recombinant Atsttrin, which expressed by MSCs is a novel TNFa blocker and play a chondroprotective role in ameliorating OA development (Xia et al., 2015). Human MSCs injected intraarticularly were activated to express high levels of Hedgehog and trigger type II collagen to enhance rat meniscal regeneration (Horie et al., 2012). Delayed fracture union can be prevented by MSCs mixed with platelet-rich plasma (Liebergall et al., 2013). Orozco et al. presented a phase I/II study of 12 patients with clinical and objective follow-up coverage for 1 year after intraarticular MSC injection. MSC administration appears to be safe, and the result showed that 65%e78% of patients exhibited rapid and progressive improvement and most of them emerged with improvement of cartilage quality (Orozco et al., 2013). Two-year follow-up results showed that the quality of cartilage had further improved (Orozco et al., 2014). 71% of patients with degenerative disc disease transplanted with MSCs exhibited rapid improvement of pain and disability, but without disc height recovery (Orozco et al., 2011). How to prolong the cells’ intraarticular longevity became a focus of attention. MSC pretreatment with inflammatory factors or hypoxia does not influence migration or adhesion to osteoarthritic cartilage and synovium (Leijs et al., 2017). Alternative approaches should be developed to improve the therapeutic effect. Mesenchymal stem cells for pulmonary disease A phase I study has shown that in severe chronic obstructive pulmonary disease patients, combined one-way endobronchial valve insertion and MSC treatment can decrease levels of circulating C-reactive protein at 30 and 90 days, as well as the BODE (body mass index, airway obstruction, dyspnea, exercise) index and modified Medical Research Council score (de Oliveira et al., 2017). A phase II study showed that bronchopulmonary dysplasia patients receiving intratracheal transplantation with allogeneic human umbilical cord blood-derived MSCs have lower severity than the control group (Chang et al., 2014). MSCbased therapies were used to treat acute respiratory distress syndrome (ARDS) patients; serious adverse events (SAEs) were subsequently observed in three of nine patients, even they thought those SAEs were not related to the MSCs. Phase II is already under way to treat ARDS (Wilson et al., 2015).
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Mesenchymal stem cells for liver disease Adipose-derived MSCs (ADSCs) and BMSCs seeded in regenerated silk fibroin (RSF) scaffolds were evaluated in a CCl4-induced liver injury mouse model. Results showed that neovascularization, a bile canaliculus-like structure, and some hepatocyte-like cells were observed after transplantation of RSF MSCs (Xu et al., 2017). A phase II trial evaluated the effects of BMSCs transplanted in cirrhotic patients. Three and six months after surgery patients exhibited partial improvement of liver function (El-Ansary et al., 2012). Thirty to fifty million MSCs were injected into eight patients with end-stage liver disease. According to the results, serum albumin, bilirubin, and liver function score were all improved (Kharaziha et al., 2009). In 54.5% of alcoholic cirrhosis patients histological improvements were observed after BMSC injection, and the levels of transforming growth factor b1 (TGFb), type I collagen, and a-smooth muscle actin were decreased (Jang et al., 2014). MSC transplantation can be used as a potential treatment for liver injury. Mesenchymal stem cells for gastrointestinal disease Silanized hydroxypropylmethylcellulose hydrogeleloaded ADSCs improve colonic epithelial structure as well as hyperpermeability in a rat model of radiation-induced severe colonic damage (Moussa et al., 2017). Crohn’s disease patients were given intravenous infusions of allogeneic MSCs weekly for 4 weeks. Forty-two days after the first MSC administration, 8/15 had clinical remission, and 7/15 had endoscopic improvement (Forbes et al., 2014). In a phase III randomized, double-blind controlled trial using ADSCs for complex perianal fistulas in Crohn’s disease, 212 patients were randomly divided into two groups with MSCs or placebo. After 24 weeks, a significant remission was found in the MSC group compared with the placebo group (53 of 107 vs. 36 of 105) (Pane´s et al., 2016). Mesenchymal stem cells as modulators participate in tissue homeostasis and regeneration MSCs usually work through systemic infusion to cure disease. Although this method can show the effectiveness of treatment, there is little direct evidence that MSCs differentiate into injured tissue cells, so there must be another mechanism by which MSCs cure diseases. In a review, Horwitz and Dominici summarized the role of MSCs cytokine secretion in tissue regeneration (Horwitz and Dominici, 2008), and since then, more and more studies have begun to focus on the secretome of MSCs. BMSCs are the earliest kind of MSCs that appear to have the tissue regulation function, mainly in the maintenance of HSC microenvironment. Human MSCs have been demonstrated to reconstitute a functional human hematopoietic microenvironment in NOD-SCID mice (Muguruma et al., 2006). CD146þ
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MSCs are thought to be the specific population that contributes to hematopoietic maintenance, as they have the capability of forming a hematopoietic niche in heterotopic sites after transplantation and highly express angiopoietin-1, which is a pivotal molecule of the HSC niche (Sacchetti et al., 2007). However, in 2016 a study reported that CD146þ MSCs can only form bone after transplantation, suggesting that mouse CD146þ cells are osteo-progenitors committed to osteoblastic fate, and they identified a Sca1þ population that could generate CD146þ cells as the progenitor of the HSC niche (Hu et al., 2016a,b). This divergence may be due to differences in cell species; human and mouse MSCs may possess different characteristics. Since MSCs can secrete a variety of chemotactic factors and express low level of major histocompatibility complex II, the immunomodulatory ability of MSCs has drawn much attention in this field. Considerable literature shows that MSCs are involved in both innate immune and adaptive immune responses, through interaction with monocytes, polarization of macrophages, and promoting the formation of regulatory T cells, not just suppressing the immune response, but also displaying proinflammatory effects depending on the specific inflammatory environment. The innate immune system is the first line of nonspecific defense to resist invasion by pathogenic germs, during which the Toll-like receptors (TLRs) play an important role. TLRs are a group of receptor molecules expressed on the surface of innate effector cells, which can recognize danger signals such as lipopolysaccharide (LPS), double-stranded RNA, and endotoxin when tissue is injured (Kawai and Akira, 2011; Medzhitov, 2001). MSCs express abundant TLRs, especially TLR3 and TLR4 (Hwa et al., 2006; Pevsner-Fischer et al., 2007). An interesting study demonstrated that TLR3 and TLR4 play different roles in the immunomodulatory properties of MSCs. In their research, TLR3-primed MSCs show an antiinflammatory profile (MSC2), while TLR4-primed MSCs are proinflammatory (MSC1) (Waterman et al., 2010). However, that is not always the case. By using poly(I:C) and LPS to stimulate TLR3 and TLR4, respectively, of MSCs, both methods can inhibit T cell modulatory activity by impairing Notch signaling (Liotta et al., 2008). On the other hand, both TLR3 and TLR4 activation of MSCs can increase T regulatory cell induction; that is to say, both TLR3-primed and TLR4-primed MSCs show antiinflammatory characteristics (Rashedi et al., 2017). Different experiments may use different concentrations of TLR ligands to stimulate MSCs, which may influence the proinflammatory and antiinflammatory properties of MSCs (Ren et al., 2008), and as the molecular mechanisms of TLR-primed immunomodulatory actions remain unclear, this may be the cause of divergence. Macrophages are an important population in the immune response. They interact with MSCs to participate in tissue repair (Wang et al., 2015). At the early stage of infection or injury, macrophages respond rapidly and release inflammatory factors to kill pathogens. At this stage, the levels of
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inflammatory factors in the tissue are relatively low; MSCs perceive the low inflammatory level, and are polarized into the proinflammatory type MSC (MSC1), releasing growth factors such as interleukin-6 (IL-6) and IL-8 to enhance inflammation. When there are sufficient levels of proinflammatory cytokines, MSCs adopt the antiinflammatory type (MSC2) and release TGFb, IL-10, and indoleamine 2,3-dioxygenase, which polarize the proinflammatory macrophages (M1) to antiinflammatory macrophages (M2). In a model of colitis and sepsis, ADSCs induced a distinct regulatory activation state of macrophages, which possess potent immunomodulatory ability and therapeutic potential in inflammatory bowel diseases and sepsis (Anderson et al., 2013). In addition, through an extracellular vesicle-mediated mitochondrial transfer mechanism, MSCs promote an antiinflammatory and highly phagocytic macrophage phenotype (Morrison et al., 2017).
Controversy over and expectations for mesenchymal stem cells There is still a lot of controversies about MSCs, although they show numerous benefits. A most basic question is, what is the MSCs? Mesenchymal stromal cells and mesenchymal stem cells are always confused. Since there is no clear definition to distinguish between the two terminologies, they are used to refer to the same cell population, which defined by the ISCT in 2006 (Dominici et al., 2006). According to this manual, researchers use CD73, CD90, and CD105 to judge whether the cells they cultured are MSCs. However, there is the problem that using the conventional panel of CD markers to characterize MSCs has its limitations, especially when large-scale amplification is needed. During MSC expansion, replicative senescence will accumulate (Yang et al., 2017), but the CD markers (CD73, CD90, CD105) are rarely affected (Kundrotas et al., 2016), it is inaccurate to predict the function of MSCs according to these markers. What’s more, different researchers use different markers to identify subpopulations of MSCs, such as CD146, Nestin, and PDGFR-a, but without a definite hierarchical relationship like the hematopoietic system. A vast number of documents indicate that MSCs exist in various tissues of the body, but the difference between MSCs derived from different tissues is still not clear Scientists never stop exploring the in situ form of MSCs. Thus provoking another controversy. In 2008, Crisan and colleagues found that MSCs possess a perivascular localization for the first time (Crisan et al., 2008). In this research they isolated pericytes and found that cultured pericytes show multipotency as well as MSC markers. Caplan also made his point that all MSCs were pericytes (Caplan, 2008, 2017). Another work using lineage tracing demonstrated that pericytes never contribute to tissue regeneration and wound healing during aging and injury (Guimara˜es-Camboa et al., 2017). It is still difficult to make a conclusion about what is the relationship between MSCs
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and pericytes. It could be said that some pericytes but not all can develop into MSC-like cells during in vitro culture, and cell property will change with long term in vitro culture. All the efforts of MSCs researchers have been made to better utilize MSCs for disease treatment, and the results of several clinical trials with MSCs are inspiring (Butler et al., 2017; Staff et al., 2016). There are several factors need to be considered in MSCs clinical application. For example, it is necessary to choose a suitable tissue source and culture condition for MSCs when treating a specific disease. Moreover, both the safety and the effectiveness are important for the clinical applications of MSCs. In addition, tracking the results of clinical trials is important no matter the results are, positive or not.
Conclusion In summary, MSCs possess huge clinical application prospects, for their strong activities in tissue regeneration, immunoregulation, and other paracrine effects. However, until now scientists have not given a universal definition of MSCs. Moreover, MSCs are proved to be a heterogeneous cell population with the advancing research. Thus new technologies, such as single-cell RNA sequencing, proteomics, and epigenomics, should be adopted to investigate the complexity of MSCs. So far, the clinical application of MSCs is largely behind the level of laboratory research. Therefore, the combination of basic research and clinical trials is a significant factor to improve the development of MSCs. In future studies, new technologies should be used to encode the heterogeneity of MSCs, and appropriate clinical trials are needed to clarify the curative effect of MSCs. The prospects of MSCs are worth expecting.
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14 Mesenchymal Stem Cells in Human Health and Diseases Liebergall, M., Schroeder, J., Mosheiff, R., Gazit, Z., Yoram, Z., Rasooly, L., Daskal, A., Khoury, A., Weil, Y., Beyth, S., 2013. Stem cell-based therapy for prevention of delayed fracture union: a randomized and prospective preliminary study. Mol. Ther. 21, 1631e1638. Liotta, F., Angeli, R., Cosmi, L., Filı`, L., Manuelli, C., Frosali, F., Mazzinghi, B., Maggi, L., Pasini, A., Lisi, V., Santarlasci, V., Consoloni, L., Angelotti, M.L., Romagnani, P., Parronchi, P., Krampera, M., Maggi, E., Romagnani, S., Annunziato, F., 2008. Toll-like receptors 3 and 4 are expressed by human bone marrow-derived mesenchymal stem cells and can inhibit their T-cell modulatory activity by impairing Notch signaling. Stem Cells 26, 279e289. Luger, D., Lipinski, M.J., Westman, P.C., Glover, D.K., Dimastromatteo, J., Frias, J.C., Albelda, M.T., Sikora, S., Kharazi, A., Vertelov, G., Waksman, R., Epstein, S.E., 2017. Intravenously delivered mesenchymal stem cells: systemic anti-inflammatory effects improve left ventricular dysfunction in acute myocardial infarction and ischemic cardiomyopathy. Circ. Res. 120, 1598e1613. Martin, I., De Boer, J., Sensebe, L., 2016. A relativity concept in mesenchymal stromal cell manufacturing. Cytotherapy 18, 613e620. Martino, M.M., Maruyama, K., Kuhn, G.A., Satoh, T., Takeuchi, O., Mu¨ller, R., Akira, S., 2016. Inhibition of IL-1R1/MyD88 signalling promotes mesenchymal stem cell-driven tissue regeneration. Nat. Commun. 7, 11051. Medzhitov, R., 2001. Toll-like receptors and innate immunity. Nat. Rev. Immunol. 1, 135e145. Morrison, T.J., Jackson, M.V., Cunningham, E.K., Kissenpfennig, A., McAuley, D.F., O’Kane, C.M., Krasnodembskaya, A.D., 2017. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am. J. Respir. Crit. Care Med. 196 (10), 1275e1286. Moussa, L., Pattappa, G., Doix, B., Benselama, S.L., Demarquay, C., Benderitter, M., Se´mont, A., Tamarat, R., Guicheux, J., Weiss, P., Re´thore´, G., Mathieu, N., 2017. A biomaterial-assisted mesenchymal stromal cell therapy alleviates colonic radiation-induced damage. Biomaterials 115, 40e52. Muguruma, Y., Yahata, T., Miyatake, H., Sato, T., Uno, T., Itoh, J., Kato, S., Ito, M., Hotta, T., Ando, K., 2006. Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment. Blood 107, 1878e1887. Orozco, L., Soler, R., Morera, C., Alberca, M., Sa´nchez, A., Garcı´a-Sancho, J., 2011. Intervertebral disc repair by autologous mesenchymal bone marrow cells: a pilot study. Transplantation 92, 822e828. Orozco, L., Munar, A., Soler, R., Alberca, M., Soler, F., Huguet, M., Sentı´s, J., Sa´nchez, A., Garcı´a-Sancho, J., 2013. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95, 1535e1541. Orozco, L., Munar, A., Soler, R., Alberca, M., Soler, F., Huguet, M., Sentı´s, J., Sa´nchez, A., Garcı´a-Sancho, J., 2014. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results. Transplantation 97, e66e68. Pane´s, J., Garcı´a-Olmo, D., Van Assche, G., Colombel, J.F., Reinisch, W., Baumgart, D.C., Dignass, A., Nachury, M., Ferrante, M., Kazemi-Shirazi, L., Grimaud, J.C., de la Portilla, F., Goldin, E., Richard, M.P., Leselbaum, A., Danese, S., 2016. Expanded allogeneic adiposederived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet 388, 1281e1290.
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