The Roles of Mesenchymal Stem Cells in Tissue Repair and Disease Modification

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1 SendOrders for Reprintsto 424 Current Stem Cell Researchs Therapy, 2014, 9, The Roles of Mesenchymal Stem Cells in Tissue Repair and Disease Modification Tianyi Wu 1. 2,3, Yang Liu I. 2,3, Bin Wang l. 2,3 and Gang Li 1. 2,3.4,5,* I Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese Uni versity of Hong Kong, Prince of Wales Hospital, Shetin, Hong Kong SAR, PR China; 2Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China; 3Stem Cells and Regenerative Medicine Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Sttetin. Hong Kong SAR, PR China; 4The CUH K-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, PR China; 5Key Laboratory for Regenerative M edicine, Ministry of Education, School of BiomedicaI Sciences, Faculty ofmedicine, The Chinese University ofhong Kong, Hong Kong SAR, PR China Abstract: Mesenchymal stem cells (MSCs) are multi-potent cells which have been widely used for tissue regeneration and immunomodulalion. The infusion of autologous and allogenic MSCs has been proved to be safe and effective in tissue repair and disease modu lation. The inherent homing ability of MSCs ensures the transplanted cells migrating into the damaged tissue areas, but only a small percentage of the transplanted (allogenic) MSCs survive for long. However. the beneficial effects of MSCs transplantation could be noted within 1-2 days that are unlikely due to their proliferation and differentiation. The regulatory roles of MSCs in tissue repair are rather more important than their direct involvement of repair processes. The most important effect of transplanted MSCs is their immunomodulation function through crosstalk with the immune cells or the paracrine actions. The active factor secreted by MSCs may val}' in the different disease conditions or tissue niches, and are under dynamic changes in various local environments. To understand and define the MSCs secretion factors in various disease settings could be a future research direction. and the findings could lead to potential new MSCs-based therapeutic products. Keywords: Fa te. lmrnunomodulation, mesen chym al stem ce lls (MSCs). secretive fa ctors. transplantation. INTRODUCTION and HL A-DR surface mo lecu le ; third, these cells can be differe ntiate d into osteobl ast s, adipocytes and chondro blasts Mesenc hym al ste m cells (MSCs) are multi -potent cell s [7]. Recent ly. research ers have proved the pot ent ial of using which hav e the ability to differentiate into multiple cell MSCs for different organ regeneration and immunoregul a typ es. includ ing os teoblasts, chondrocytes, and adipocytes tion. The effects of MS Cs treatm ent s is contributed by the l l l It also has been proved that MSCs have the potential to fo llowtng factors: 1) se cretion of growth factors and cytokldifferent iate Into ne ura l cells [2]. germ ce lls [3]. cardiomy o cytes [4], etc. The histo ry of MSCs could be traced back to nes [B, 9]; 2) support fo r other cell types dur ing tissue regen 1970 when Friede nste in and his co-wo rkers first isolated and era tio n [10-12]; 3) imm unomodulation properties [13. 14]; 4) cultured fib rob last -like clonogenic stromal ce lls from bone differe ntia tio n into specific ce lls for dam aged orga n tissues marrow w hich are multi-po tent progenitors [5]. These ce lls [15. 16] (Fig. 1). However. the cellular effec ts and the trace can be easily expanded and pro mote tissue repair. Thus, the of MSCs after resto ring transplanta tion appea r to be lack of use of MS Cs has been an innovativ e approach in treatmen t consideration and rem ain inconclusive [16-1 B]. of variou s diseases. Currently. there have been more than Trans planted MS Cs can be labeled with different ma rk 300 clinical trials using MSCs listed on the website of the ers, and tracing of transpl ant ed MSC cell lin eage can be United Sta tes Natio na l Institute of Healt h [6]. based on polymerase chain rea ction [19. 20], Y chromosome T he Intern ational Society of Cellu lar Therapy has mad e a staining [21], green flu orescent pr otein labeling [22. 23] and d efinition of MSCs based on three minimal criteria: First, so on [24, 25]. With the develop me nt of cell tracking tech these ce lls can be plasti c-adh erent in a standa rd co ndition: nology, new methods like in vivo Imaging techn iqu es can be seco nd, these ce lls express CO los, C073 and CD9 0, and used for deep tiss ue an d lon g-term tracin g [26. 27]. It has lack of C045, CD 34. COI4 or CDIlb, CD79alpha or CD I9 been proved that systemic injection of MSCs reaches the lungs before redi s tributed to the liver, bo ne mar row and othe r organs [28]. In order to gain so me insight into the fate *Address correspondence to this author at the Roo m /F, Li Ka Shing and effects of tran sp lanted allogenei c MSCs, we have re Institute of Health Institute,Prince of Wales Hospital, The Chinese Univerviewe d availab le liter atures and focused on function and fate sity of Hong Kong, Shatin. Hong Kong, SAR, PRChina; Tel; (852) ; Fax; (852) ; of in vivo transplantated allogeni c MS Cs /14 $ e 2014 Bentham Science Publishers

2 Rolesof MesenchymalStem Cellsin TissueRepairand Disease Modification CurrentStem CellResearch& Therapy, 2014, Vol. 9, No Imm uno mo i:lulat ion Osteogenesis Imperfeeta Femoral head necrosis Cartilage defect Limb ischaemia Releasing repair factors IL-Ii, 1l-8 and CXCLl Myocardial Infarction Release of VEGF, HGF, G ( SF, FGF-2. TGF-6 1 Diabetes Differentiat e into endotnettot cells Chronic kidney Injury homin g" to the sites of Inflamm at ion, and different iate Int o kidn ey epit helial cells Ma intai n ba lance of TH1/TH 2 and enhance the prolife rati onoftreg cells. Abilitv of redu cing the pre val ence o f GVHD Inhibitory funct ion s on cytotoxic T cells [Crohn's di sease) Secret essential factors Reverse degenerative 13-cell nction Fig. (1), Diagram illustrates the applications of autologous and allogenic MSCs in tissue regeneration and immunomodulation, and their potential underlying mechanisms. The Tracking Methods of MSCs In Vivo In vivo imaging and labeling meth ods are important tools for tracking cells. Fluorescence Imaglng is a suitable and easy way for visualizing labeled cells both in vitro and in vivo. The green fluorescent protein (GFP) transgenic animals and cells, which can be seen in a dark enviro nment, were most widely used for cell transplantation experimen ts after first produced by Okabe In 1997 [221. Although GFP has been documented to be biologically inert, it may cause dilated card iomyopathy in GFP transgenic mous e [23]. DNA binding dyes like DAPI can provide a fluor escence Imaging after staining and be applicabl e for live cell labeling [291. But, DAPI has been proved to have growth-inhibitory effec t on MSCs and possess ability to affec t MSC s differenti ation 130). Transplanted ce lls ca n also be s tained and track ed with red fluore scent Oil [31, 32). Whil e these labelin g method s need an additional staining progress during resuspen slon and cannot be tested by bio- assay. Another approach for trackin g MSC s is to overexpress some reporter gen es, then using spec ific antibody against the gene products incorporated in the genomic DNA su ch as bromodeoxyuridine (BrdU), p-galactosid ase, luclferase a nd thymidine kinase [33, 341. Other means of more advanced techniques have also been devel oped in ord er to track a longterm changes of the transplanted MSCs in vivo. Magnetic resonance imaging (MRI); single-photon em issi on CT (SPECT) and positron emission tom ography (PET), are very effective ways to obtain three-dimensional Image in vivo and some of these technologies have been successfully used for therapeutic tracing of transplanted cells [35J. Contr ast reagents are needed for tracking cells, such as lanth anid e chelates [36], superparamagnetic iron oxid e [37], micronsized iron oxide particles [38], some unique tracer dye [39] and others [40,41]. Yet these methods still face many challenges like false positive signals, lack of whole body scan or a fast tracer decay [42]. Recently, a lineag e tracing syst em has been employed to investigate tbe neuronal commitment role of MSC [43). In this system, Cre is driven by a lineage specific promoter. Meanwhile, on the other cassate, follow ed Rosa 26 promoter is a stop codon flan ked by loxp sites and a report gene (LacZ). A very delicat e example is simultaneously elaborate multiple fluor escent prot ein [44] based on different Cre-loxp co mbination. By changing the promoter sequence before Cre protein. this sys tem could be a very flexible and useful method to trace the role of MSC in varies model and circumstance. Although all present image technologies of cell tracking have different disadv antages [45]. there is no universal tracer for MSCs tracking in vivo, and to choose a most reliable way of labeling the transplanted MSCs is essential for study ing the fate and function of MSCs in vivo. The Use of MSCs in Repairing of Musculoskeletal System The gold standard for clinical treatment of large musculoskeletal tissues injury Is to restore or replace the damage tissues through surgical procedures. Numbers of therapies have been developed for managing bone defects, and it is clear that the bone formation or the healing of the defe ct can be enhanced by MSCs cell therapy. However, none of current therapeutic treatments have proved to be fully successful [46]. There are multiple ways of cell implanting duri ng lissue regeneration, together with vehicles or scaffolds which are also known as systemic application or local application. The survival of cells after implantation and the total number

3 426 CurrentStem Cell Research & Therapy, 2014, Vol.9, No.5 Wuetal. of cells delivered are the key factors of success [47]. But results from most studies proved that only 5% of transplanted cells survived after 2 weeks of their administration. In Horwitz and his co-workers has proved the therapeutic effects of transplantation of allogeneic MSC into three children with osteogenesis imperfect [48]. This study also demonstrated the migrating capacity of allogeneic MSC which lead the transplanted MSCs migrating to the bone In these osteogenesis imperfecta childr en. This ability was first known as the "homing" cap acity which marrow-derived MSCs can migrate and incorporate to musculoskeletal tissues of the recip ient animals \49-51]. The following studies suggested that the mob ilization of autologous MSCs can be induced by trauma [52]. And researchers also determined that the transplanted MSCs can migrate to the injury area. MSCs expressing Firefly tuctterese were systemically injected into the mouse with stabilized tibia fracture. 1 day after transplantation, MSCs were found In the lungs. The MSCs started to localize in the fracture area on the day 3 of transplantation and this fluorescence lasted about 14 days. The followtng study confirmed this "homing" capacity is dependent on the presence of CXCR4 and the cell number reached a saturation point on day 7 of transplantation. The histology and mechani cal analyses confirmed the improvement of fracture healing by more cartilage and newly mineralized bone for malion [53]. In another study, researchers Intravenously injected allogeneic MSCs into femoral head necrosis animals and traced for 6 weeks. Labeled MSCs reached the peak point at 6 weeks in the necrotic area of femoral heads while these cells were not seen after 2 weeks after transplantation in normal animals [161. Trauma condition stimulated the migration of MSCs have also been confirmed conditions in other animal models such as brain injury, lung injury, liver injury and burn injury ect [54-57]. Chondrogenic differentiation is important characteristic of MSCs. The underlying mechanism using MSC cartilage repair are: (1) MSCs attenuates inflammatory reaction at the injury areas ; (2) cartilage injury area defects replaced by chondrogenic MSCs [15]. A fluorescent dye CMTMR [5 [[[4-chloromethyl] benzoyl]aminoj-tetramethylrhodamlne] was flrst used by Quintavalla to label goat MSCs and implanted into the cartilage defect area with loaded on gelatin sponge scaffold [581. During 14 days of implantation. the number of fluore scence labeled MSCs reduced over lime. The implanted MSCs are found around the defect area and 6 mm away from the original defect. Compared with the scaffold cultured in vitro. over 70% of cells released from the implanted scaffold showed no fluorescence indicating that cells from the underlying bone marrow or the surrounding environment were recruited into the sponge scaffold during the healing progress. The cartilage healing cannot complete through implantation of allogeneic MSCs alone. Another study used Oil-labeled MSCs to repair the cartilage defect in pigs. Labeled cells were seen In the defected area at I week. but not at 4 and 12 weeks. The cartilage repair progress lasted for at least 3 months, so that the transplantation of allogeneic MSCs may act indirectly paracrine releasing repair factors for Improving cartilage repair rather than directly repair the defect area [18]. Local injection of MSCs directly into the ischaemic area is a potential treatment for arterial occlu sion and the limb ischaemia. In a pilot study. autologous bone marrowmononuclear cells were injected locally into the ischaemic limbs. In all 45 legs. ankle-brachial pressure index level. transcutaneous oxygen pressure, rest pain and pain-free walking time were all significantly improved in 4 weeks and sustained at 24 weeks. The enhanced angiogenesis was due to the secreted angiogenic cytokines and the improved function of endothelial cells [59]. Lian also found MSCs. derived from human pluripotent stem cells, have the significant therapeutic efficacy in 11mb ischemia model of mouse [60J which indicated that the function of transplanted MSCs can successfully apply across species. It was confirmed that the secreting of IL-5, IL-8 and CXCLl from MSCs is important for enhancing function [9J. In diabetic rat models. the ischemic muscle metabolism neovasculogenesis were improved following MSCs transplantation and incorporation of MSCs to vessels was not observed, suggesting that neovasculallzation induced by transplantatlon should be mediated through paracrine factors [61]. Another study confirmed that MSCs expressed and secreted higher level of bfgf. VEGF-A. IL-6 and ll-8 under hypoxic conditlon which can induce angiogenesis. cell migration. proliferation and so on [8]. Further study confirmed that transplanted MSCs could reduce the cytotoxicity and accumulation of natural killer cells under such hypoxic situation [621. There were reports that MSCs could secret some crucial growth factors like BMP-2 for osteogenesis during bone heallng progress; TGF-J3 for chondrogenesis during cartilage healing. etc. MSCs could also secrete many cytokines that could regulate Inflammatory responses during injury. It is uncl ear which ones of these paracrine factors are the most important factors as they are mixture and constantly changing. During the regeneration of organs. the regulatory function of MSCs is more complex. and the factors secreted by MSCs are dynamic and responsive to the local environment. The Use of MSCs inorgan Regeneration The use of MSCs transplantation for treating lung [63. 64], liver [65. 66]. heart [57, 68] and brain Injury [69, 70], has been tested in animal models. The therapeutic mechanisms are mainly due to modulating against the inflammatory responses while the engraftment or differentiation properties of MSCs were not involved [71-74]. GFP-Jabeled MSCs have been found crossed the blood-brain barrier and then engrafted to injured areas the hippocampus in rats [74]. The results suggested that the implanted MSCs can survive only a short-term in the brain (20 days) but promote a longterm change in hippocampal plasticity [72]. Results from another study showed that the labeled MSCs accumulated in the lung of rats with pulmonary hypertension compared with normal rats. After 14 days of transplantation. the number of MSCs was decreased from 7.5% to 4.2% indicating that these MSCs cannot survive too long in vivo [17]. As the most of organs are greatly vascularized tissues, the co-culturing of endothelial cells and MSCs can maximum simulate the co-existence of cells of normal tissues, which may promote the cell functions during reparation [75.

4 Rolesof Mesenchymalstem Cellsin TissueRepairand Disease Modification 76J. A higher level of bioch emical factors can be easily detected after co-culture in vitro, this increasing secretion can also be proved after transplanted in vivo [77-79]. The cros stalk of MSCs and endothelial cells or other cells can be bidirectional in vitro. Th e cell-cell interaction function and the higher level of factors can also improve osteogenesis function of MSCs [80]. MSCs have been proved to have therapeutic benefit for myocardial infarction. MSCs secreted factors and regulated the function of cardiomyocytes and immature cells during repair [81-83]. Vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), granulocyte colony stimulating factor (G-CSF), fibroblast growth factor (FGF-2) and transforming growth factor beta 1 (TGF-~l) have been identified as key factors of cardioprotection released by MSCs [84]. Some researchers reported that engrafted MSCs could differentiate into cardiomyocytes in vivo after local injection in addition to their secretion of paracrine factors [78, 79]. Following MSCs injection into the heart, most of transplanted MSCs were found In the lungs, liver, and spleen, only a small part of MSCs disperse within myocardium suggesting that the local integration at the injured area may not be necessary in myocardial repair progress [85]. It has been proved that transplantation of allogeneic MSCs was useful for managing acute myocardial infarction and the improved heart function last more than 4 weeks even after the transplanted MSCs disappeared [24, 86, 87]. Benefit of MSCs was also associated with the time and dose of injection [68, 74, 88J. However, large amount of MSCs injection can lead to massive pulmonary infarction and shall be avoided [88]. In 1999, Tomita injected both MSCs and 5-aza cytidine treated MSCs were injected into the myocardial scar tlssue 3 weeks after cryoinjury on the left ventricular wall, and found that only 5-azacytidine treated MSCs can inhibit ventricular scar formation and improve the contractile function, the MSCs transplantations have been proved to increase the capillary density [89]. But 5-azacytidine pre-differentiated MSCs Increased their immunogenicity and only survived in the first few weeks, while the untreated MSCs could exert a longer-term survival [90]. The transplanted MSCs were capable of increasing blood vess el density and blood flow which are beneficlal in protecting the myocytes from further ischemic damage [91]. A significant increase of VEGF level has been found after MSCs transplantation in rat hearts and the transplanted MSCs were further found in the newly formed blood vessels [92]. The higher expression of active factors by transplanted MSCs has also been found in other disease conditions. In the diabetic rats, both intramuscularly injected and subcutaneously injected MSCs can be detected in the wound area, and reached the peak point on day 5: MSCs granulation tissue formation and epithelialization of other cells in the wound area [931 were seen. The trace of labled-mscs showed that they can be differentlated into endothelial cells and form collagen fibers in the blood vessels afte r 4 weeks transplantation [94]. The same prote ctlve effects of allogeneic MSCs on liver was also proved in both acute and chronic liver injury models [95-97]. The result of Moslem's study indicated that human pluripo tent stem cell derived MSCs also can be an alternative cell source for mice liver repair [98]. CurrentStem CellResearch& Therapy, 2014, Vol. 9, No In chronic kidney Injury, MSCs have been found "homing" to the sites of inflammation during kidney injury and can be differentiated into kidn ey epithelial cells [99, 100]. Similar to the mechanism of MSCs promoting myocardial repair, current data suggested that direct kidney cell differentiation by allogeneic MSCs is not the case in kidney repair [11, 12]. Broekema traced labelled MSCs during kidney Injury repair, MSCs were first found within the peritubular capillaries and interstitium; 8 days later, MSCs were found within tubules and only about 2-2.5% of recovered tissues were derived from the labelled MSC [101]. On the other hand, the paracrine function of the transplanted MSCs playa more Important role in kidney injury repair [l 02]. It has been proved that MSCs-derived GM-CSF, EGF, CXCLl, IL-6, IL-8, MCP-I, PDGF-AA, and CCL5 can be identified wh ich may promote repair of kidney injury by promoting macrophage polarization, while which of these factors is the most import ant one still remains unknown [77J. The Immunomodulatory Function of MSCs In Vivo Activation and proliferation of T lymphocytes are the main cause of allogeneic transplant rejection [103]. MSCs are lack of some immune response-related surface antigens including CD40, CD40L, CD80 and CD86, hence the transplanted allogeneic MSCs don 't trigger acute immune attack. When co-culturing with peripheral blood lymphocytes, allogeneic MSCs don't cause lymphocyte proliferation [13]. The immune suppressive function of MSCs against T lymphocytes may be due to the contact between the cells and the cytokines secreted by MSCs, such as indole amine 2,3 dioxygenase (IDO), prostaglandin E2 (PGE2), transforming growth factor-beta (TGF -P), hepatocyte growth factor (HGF), interleukln-l0 (IL-lO), human leukocyte antigen -G (HLA -G5), etc [ ]. It is also found that MSCs can help to maintain balance of TH IfTH2 and enhance the proliferation of Treg cells [14]. After 48h of MSCs transplanted into sensitized and non-sensitized rats, the MSCs can be detected mainly in spleen of sensitized ones while in non sensitized rats the MSCs were mainly found in the bone marrow, where MSCs exert their immunemodulatory functions [108]. MSCs have also been used in treating autoimmune diseases such as autoimmune encephalltls, inflammatory bowel diseases and graft versus host diseases [109, 110]. MSCs transplantation improved the survival of mice with the lethal dosage radiation-induced injury and attenuated radlationinduced hematopoietic toxicity, indicating the potential immuneprotective role of MSCs [Ill]. Graft-versus-host disease (GVHD) is a series of severe complications during allogeneic tissue/organ transplant which is due to the attack form donor T cells. MSCs have been proved to have the ability of reduclng the prevalence of GVHD [112]. The use of MSCs instead of immunosuppressive drugs during solid organ transplantation has proved to be safe and effective again st GVHD. In the patients with kidney transplantation, the infusion of MSC can improve graft survival and reduce the dose of immunosuppression [ ]. Koch et st. compared the Intra-arterial and intravenous MSCs and found that many animals died following Intra-arterial injection because MSCs may block the capillary

5 428 Current Stem Cell Research & Therapy, 2014, Vol. 9, No.5 system of kidney or other abdominal organs. Whereas the intravenous injection of MSCs is relatively safe. The reason for this is the directly reaching to the capillary system of MSC through intra-arterial injection [118]. The graft protection function of MSCs is T cell related. with the increase of Treg cells and the reduction of T-memory cells [41]. MSCs is capable of reversing mir-155 expression which can led to Th2 differentiation induced by organ transplantation [116]. However, the multi-potentiality of MSCs did have the ability of restoring vessel endothelium in systemic lupus erythematosus [119J. Now. the using of MSCs as treatment for auto Immune diseases such as Crohn's disease, ulcerative colitis. multiple sclerosis, amyotrophic lateral sclerosis, systemic lupus erythematosus has been accepted as an alterative clinical therapy method [ ]. Focal segmental glomerulosclerosis is known as a dysregulation of the immune system resulting in renal failure. A 13-years-old boy. who presented an immediate recurrence after transplantation. received allogeneic MSCs infusion 3 times and was fully recovered and remain stable after a follow up of 22 months [125]. This renoprotection function of Infusion MSCs was also detected in patients of systemic lupus erythematosus [126]. More importantly. multiple transfusions of MSCs provided a better strategy compared to that of single dose infusion [119]. Nearly a quarter of patients suffering form Crohn's disease need major abdominal surgery [127]. The rational of using MSCs for the treatment of Crohn's disease is based on their inhibitory functions on cytotoxic T cells. which is highly active in Crohn's disease patients [128]. The transplantation of MSCs Improved the intestinal injury and inhibit ulceration through regulating the intestinal epithelial cell niches directly or indirectly [129, 130]. It is believed that immune response also plays an important role in the development of diabetes. The transplantation of MSCs can successfully depress autoimmunity against islets and enhance survival of islets. Also. transplanted MSCs has been proved to lower blood glucose levels in diabetic animals [131]. However. these results showed the infusion of MSCs had no significant effect on pancreatic p-cell differentiation [132]. It is known that transplanted MSCs can secret essential factors for pancreatic tissue regeneration, such as HGF [133J and MSCs could reverse degenerative p cell function through their immunosuppressive property [10]. Allogeneic. labeled MSCs can only be detected in pancreas and kidney in MSCs-treated diabetic mice. whereas no MSCs was seen in the lung, liver. and spleen [134]. SUMIVIARY The beneficial function of transplanted MSCs has already been proved in many therapeutic areas. such as hematopoietic reconstitution. Immunomodulation, hepatic regeneration and cardiac reperfuslon. The inherent homing ability of MSCs ensures the transplanted cells migrating into the damaged tissue areas, but only a small percentage of the transplanted (allogenic) MSCs survival for long. The beneficial effects of MSCs transplantation could only be noted within I -2 days which is not sufficient for cellular growth, division and differentiation. During last few years, the using of MSCs has had a great change. Researchers paid more and more attention on their regulatory role instead of their differ- Wuetal. entiation ability. The regulatory function of transplanted MSCs includes both immunomodulation function and secretion function. Both of these two functions may change according to the disease conditions or tissue niches. To understand and define the MSCs secretion factors in various disease settings could be future research direction. The findings could lead to potential new MSCs-based therapeutic products. CONFLICT OF INTEREST The authors confirm that this article content has no conflict of interest. ACKNOWLEDGEMENTS This work is supported by a grant from Hong Kong Government Research Grant Council. General Research Fund (CUHK ), and a grant from China Shenzhen City Science and Technology Bureau under the Shenzhen City Knowledge Innovation Plan. Basic Research Project (JCYJ l l) to Gang Li. This study was also supported in part by SMART program, Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong. This research project was made possible by resources donated by Lui Che Woo Foundation Limited. REFERENCES [11 Knight MN, Hankenson KD. Mesenchymal Stem Cells in Bone Regeneration. Adv Wound Care (New Rochelle) 2013; 2(6): [21 Ma L, Feng XY. Cui BL. et al. 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Diffe rentiation of ma rrow stromal ce lls lnto pho toreceptors in the rat eye _ J Ne urosct 200 3; 23(2 1): [35] Koo reman NG, Ra nso hoff JD, Wu JC. Tra ck ing ge ne and ce ll fate for therapeuti c gain. Nat Ma ter 2014 : 13 (2) : i [361 Cric h SC, Biancone L, Gan talupp i V, et al. Improved rout e for the vlsuallzatlon of ste m cells labeled with a Cd-Eu-chelate as dual (MRl a nd Ilu oresce nce) agent. Magn Reson Med 200 4; 51(5) : ) Kust er mann E. Himm elreich U. Kandal K, et al. Efflclent s tem cell labelin g fo r MR I studies. Contrast Media Mol Imaging 2008 ; 3(1) ; [38] Sha piro EM, Gonzalez -Perez 0, Manuel Garcia-Ve rdugo J, el al. Magnetic resonan ce imag ing of the migration of neuronal prec ursors generated in the ad ult rode nt bra in. Neuroimage 200 6; 32 (3): [39) Carnbhir SS, Ba rrio JR. Phelps ME. et st. Imagin g adenoviraldi rec ted rep o rter ge ne ex pression In Ilvlng anima ls w ith pos itron e miss ion to mography. Proc Nail Aca d Sc i USA 19 99; 96 (5): (40) Yamada M, Yang P. In vitro labelln g of hum an embryonic s tem ce lis for magnetic resonance imagi ng. J Vis Ex p Z008; 17. pii : [41) Be rge r C, Rausch M, Sc hm idt P, et al. Feas ibility and limits of magneticall y labeling pr ima ry cultured rat T cetis w ith femm oxldes co upled with comm only used transfeclion age nts. Mo l Imagi ng 2006 ; 5(2) : [42] So hni A. Verfaillie CM. Mesenchymal Stem Cells Migration Hom ing a nd Tr ac king. Stem Ce lls Int 2013; 2013: [43] Zhao H, Fen g J, Seide l K. et al. Secretion of shh by a ne urovascular bu ndl e niche supports mesenchymal stem ce ll homeostas is in the adul t mous e inc iso r. Ce ll Stem Cell 2014 ; 14 (2): [44] Livet J. Weissman TA. Kan g H. et al. Transgenic stra tegies fo r combinatorial ex pression of Iluorescent proteins In the nervous system. Natu re 200 7; 450(7166) : [451 Ng uyen PK. Riegler J and W UJC. Ste m ce ll imagi ng : from bench 10 bedside. Cell Stem Ce ll 20 14; 14(4) : [461 Ca nce dda R, Giannon i P a nd Mas trog iacom o M. A tissue eng ineer ing a pproach to bo ne rep air in large an ima l models and in c linica l pracrlce. Blomaterlals 2007; 28(29): [471 Eber li D, Atala A, Yoo JJ. One and four lay er acellular bla dder mat rix for fasc ial tissu e reco nstruction. J Mater Sci Mater Med 20 11; 22(3 ) : [48] Horwi tz EM, Prock op DJ. Fitzpat rick LA. et al. TranspJan tability and Iherapeut ic effects of bone marrow-derived mesenchymal ce lls In children wit h osteogenesis imperfecta. Nat Med 1999 ; 5(3) : [49J Fe rrari G, Cuse lla-de Angelis C, Coletta M, et al. M uscl e regenera tion by bon e ma rro w-de rived myogenic progen itors. Scie nce 1998; 279(5356) : [501 Ch am berla in C, Fox J, As hton B, et al. Co ncise review; mesonchymal stem cells; their phenotype, differenti ation capacity, immu nolo gical fea tures, and po ten tial for homing. 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7 - 430 Current Stem Cell Research & Therapy. 2014, Vol. 9, No.5 [57] Mansilla E. Marin GH. Drago H, et al. Bloodstream cells phe notypically ide nlica l lo hum an mesenchym al bone mar row stern ce lls circulate in large am oun ts unde r the Influence of acute large sk in damage: new evidence for their use In regenerative medicine. Transplant Proc 2006 ; 38(3) : ] Qulntavalla J. Uzial-Fusi S. Yin J. et al. Fluorescently label ed mesenchym al stem ce lls (MSCS) mainta in mu ltilineag e potential and can be de tec ted follow ing Implantatlon into ar ticular cartilage defects. B ioma te rlals 2002; 23 (1): ] Tateishi-Yuyama E. Matsu bara H, Mur ohara T. et al. Th erapeulic angiogenesi s for patients with limb Isch a emia by aut ologous trans plantation of bone-marrow ce Us: a pilot study and a rand omi sed controlled IriaL Lancet 2002 : 360 (933 1): J Lian Q. Zhang Y. Zh ang J, et al. Functio nal mesenchym al stem cells der ived from human Induced plur ipotent stem cells atte nuate limb Ischemia in mice. Circ ula tion 2010: 121 (9): J 161] Madonna R, Pizzi SO, Tart are A, et al. Tr ansplantauon o f mesenchy mal ce lls improves peripheral limb ischem ia in diabetic rats. Mol Blot ech nol 2014: 56(5): ) Huan g WH, Che n HL, Huang PH, et al. Hypoxic mesen chymal stem cells eng ra ft and a meliora te limb Ischaemia in allogeneic recipients. Cardl ovasc Res 2014: 101 (2): Moodley Y, Vag hj ian l V, C ha n J, et al. Anti-inflammatory e ffec ts of adult stem ce lls in su sta ined lung inj ury: a compara tive study. PLoS One 2013 : 8 (8): e [64] Curley GF, Ansari B, Hayes M, eral. Effects of intratracheal mesenchymal stro mal cell therapy during recov ery and resolution after ventilator-ind uced lun g Injury. Anesthesiology 20 13: 118 (4): Li DL, He X H, Zhang S A. el af. Bone marrow-derived mesenchymal stem ce lls promote hep atic regenerati on after part ial hepatectomy In rats. Pathoblology 20 13; 80(5) : Du Z, Wei C. Cheng K, el al. Mesenchymal stem ceil- cond itioned med ium red uces liver Injury an d enhances regenerallon In red ucedsize rat live r tran spl antation. J Surg Res : 183( 2) : J Katare R, Riu F, Ra wlin son J, eral. Peri vascular deli very of encap sulated mesenchymal stem cells improves postischemic angiogenesis via paracrine activation of VEGF A, Arte rioscle r Thromb Vase Bioi ; 33 (8): Richardson 10, Bert as o AG. Psaltis Pl. et s l. Impact of timing and dose of mes en chymal stroma l ce ll therapy in a preclinical model of acute my ocardial infarcti on. J Card Fall 20 13: 19(5): [69] Calio ML, Marinho OS, Ko GM. el ai, Transplantation of bone marrow me se nchymal stem ce lls decr ease s oxidative s tress, apoptosis. a nd hippoca mpal da ma ge in brain of a spo ntaneous s troke mod el Free Radle Bioi Med 20 14: 70 : van Velth oven CT. Kavelaars A. Helj nan C1. Mesenchy m al stem cells as a treatment for neonatal isch em ic brain damage. Pediatr Res 201 2; 7 1(4 PI 2): Coquery N, Blesch A, Stroh A, et al. lntrahippocampal transp lantation of mesenchymal stro ma l ce lls promotes neuroplastlci ty. Cytothe rapy 20 12; 14(9) : ] ROjas M. Park er RE, Thorn N, et al. Infusion of freshl y isolated autologous bone marrow derived mononuclear cells prev en ts endotoxin-induced lung Injury In an ex-vivoperfused swine model. Ste m Ce ll Res Th er 20 13: 4 (2) : J Wang T. Tang W, Sun S, et st. Intra venou s infus ion of bone ma r row mesenchy mal stem ce lls Improves brain function after resuscitation from ca rdiac arrest, Crit Care Mcd 2008: 36 (11 Suppl): S ] Wolf D. Reinhard A, Secki nger A. et s l. Dose-dependent effects of intravenous a llog eneic mesenchymal stem ce lls in (he Infarcted porcin e heart. S tem Cell s Dev 2009 ; 18(2): ] Ma J, Both SK, Ji W, et et. Adipose tissu e-d erived mesen chymal stem cell s as monocultures or cocultures with human umbilica l vein endoth elial cells: perfor mance in vitro and In rat cra nial defects. J Biom ed Maler Res A 20 14; 102(4) : Pedersen TO. Blo is AL, Xu e Y. el st. Oste ogen ic stimulatory c ondilions enhance growth and maturation of endothe lial ce ll microvascular networks in c ulture with mesen chymal stem cells. J Tissue En g 20 12: 3(1) : Wise AF. William s TM. Kle wier ME. et al. Human mesen chym al stem ce lls alter ma crophage ph eno typ e and promote rege ne ratio n via homing to the kidn ey followtng ischemla-reperfus ion inj ury. Am J Phy sio l Renal Physiol 2014: 306(10) : FI Wuelal. [78J TOlOa C, Pitte nger MF. Cah ill KS. et et. Huma n mesenc hyma l s tem ce lls differentiat e to a cardtomyocyre phenotyp e In the adult muri ne heart. C ircu latio n 2002: 105(1 ): [79] Orll c 0, Kajstura J, Chimenti S, e! al. Bon e marrow stem ce lls regen erate infarcted my oca rdiu m. Pedlatr Tran splant 2003; 7 Suppl 3: [801 Ho ng M. 10 H. An keny RF, el al. Influence of mesen ch ymal stern cel ls on the respons e of endothelial ce Us to lamina r /low and shear stress. Cells Tissu es Organs 201 3: 198(4): [81] W oll ert KC, Drexler H. Cell-based therapy for heart failure, Cu rr Opln Card iol 2006 ; 2 1(3) : 234-9, [82] Plnenger MF. Martin B1. Mes enchymal st em ce lls and their po tential as ca rd iac therapeuti cs. Cir c Res 2004; 95 (1) : [83] Iso Y, Spees J L, Serrano C, et al. Mult ipolent human stromal cells Impr ove cardiac function after my ocardial infarcti on In mice with out long-term engraftrnent, Blochem Blophy s Res Commun 2007: 354 (3): [841 Cr isostomo PR, Wa ng M. Markel TA. etet. Stem ce ll mechanisms and parac rine effects: potential in ca rd iac su rger y. Shack 2007 : 28 (4): [85] Imantslu Y. Saito A, Komoda H, el al. Allo genic mesenchym al ste rn cell transpl antation has a therap eutic effe ct in acute myc car dial infarction La rats. J Mol Ce li Cardlol2008 ; 44(4) : [86] W illiams AR. Su nc lo n V Y, McCall F. et al. Dur ab le scar s ize redu cti on due to alloge ne ic me senchymal stem ce ll therapy reg u lates whole-chamb er remodelin g. J Am Heart Assoc 2013: 2( 3) : eoooi40. [871 W ang T, Tang W. Su n S, et et. Mesen ch ymal st em ce lls improv e out comes of cardiopulmonary res uscitation in myo cardial infarcted rats. J Mol Celi Ca rdio l 2009 ; 46 (3): [88J Everaert BR. Be rgw erf I, De Voch t N, et al. Multimodal in vivo imagin g reveals limit ed allograft survival, intra pulmonary ce ll tra pp ing and minimal evide nce for isc he mia-d irected BMSC hom Ing. BM C Blotechnol 20 12; 12: 93. [89) Tom ita S, Li RK, We ise l RD, et sl. Au tolo go us lransp lanta tion of bone marrow cell s imp ro ves damaged heart fun clion. Circulation 1999; 100(19 Suppl) : [90] Xia C, Cao J. Imagin g the survival and utility of pre-differentiated a lloge neic MSC In isc hem ic heart. Blochem Blophys Res Commun 20 13; 438(2) : [91] Li P, Li SH, Wu J. et al. Interleukln-Bdownregula tion with mesenchym al s tem cell differentiation result s In lass of immunoprivllege. J Cell Mol Med ; 17(9): [92] Ta ng YL, Zhao Q. Z han g YC, et al. Au to logous mesen ch ymal stem ce ll tran spl antation Indu ce VEGF and ne ovascularizalio n in isch em ic myocard ium. Regul Pept 20 04; 117(1) : [93] W an J, Xia L, Liang W, et al. Transplantation o f bone marrowderived mesenchymal stem cell s promotes del ay ed wound healing in d iabetic rats. J Diab etes Res 2013 : 201 3: [94J Fang S M, Du DY. Li YT, el et. A llogene ic bon e mar row mesen chy ma l stern cells tran spl an tation for stabll lzing and repa iring of ath erosclerotic ruptured plaque. Th rom b Res 201 3; 131 (6): e [95] Xagorari A. Siotou E, Yi angou M, et al. Protective effec t of mes enchymal s tem cell -conditioned medium on hepati c ce ll apo ptos is afte r acute liver injury.lnt J C lin Exp Patho : 6(5) : [96J Ka ibori M, Adachi Y, Shrrno T. et al. Stimulati on of liver regenera Uon afte r hep atec tomy in mice by injeclion of bon e marrow mesen chymal stem cells via the porta l vein. Tr ansplant Proc 20 12; 44(4) : [97] Se kl T, Yokoyama Y. Nagasaki H. el al. Ad ipose tissue-deri ved mesenchymal stem ce ll transplantation promotes hepatic rege ne ralio n aft er hepa tic Isch emia-re perfu sion and sub sequent hepatactomy in rats. J Surg Res 2012; 178 (1): [981 Mosl em M, ValoJerdi MR, Poumasr B. el al. Therapeuti c potential of hu man ind uced plur ipotent stem ce ll-de rived mes enchymal stem ce lls In m ice w ith leth al fulminant hepat ic failure. Cell Tran spl ant 20 13; 22 (10) : [991 To gel F, Isaa c J, Hu Z, et aj. Renal S DF- I signals mo bil ization and homin g of CXCR4 -pos itive cells to the kidney aft er ischemic injury. Kidney ; 67( 5) : [100] Wong CY, Cheong S K, Mok PL. et al. D ifferentiation of hum an me senchymal s te m cell s into mesangial cells In post-glom eru lar Injury mu ri ne model. Pathol ogy 2008 : 40 (1): [IOJ] Bro ek em a M, Harm se n MC, Koe rts JA, et al. Deter minants of tubular bone marrow-derived cell engr aftment after re nal ische rnla/rep erfusion in rats. Kidney In t : 68 (6) :

8 Roles ofmesenchymal Stem Cells in Tissue Repair and Disease Modification Currenl Stem Cell Research s Therapy, Vol. 9, No ) Asa numa H, Me ld rum DR, Meldrum KK. Therape utic applications of mesenchy mal stem cells 10 repair kidn ey Inj ury. J Urol 20 10: 184 (I): Boec kh M, Nic hols WC, Marr KA. Long -ter m ca re after hem a topoletic-cell transplantation In adu lts. N Eng l J Med : 347(20) : : a uthor re ply ) Dorronsoro A, Fe rnandez-rueda J, Fechter K, et al. Human Mesenchy mal Stromal Ceil-Media ted Imrnunoregulauon: Me chan isms of Ac lion and Clinical A ppllcatlons. Bon e Ma rrow Res 20 13: 20 13: [1051 Larocca RA, Moraes-Vieira PM, Bassi EJ, et 81. Adipose tissuede rived mesenchy mal stern cells incre ase skin allograft s urvival and Inhibit Th-17 immune response. PLoS On e 2013 : 8(10): e [1061 Shi M. Liu ZW. Wa ng FS. Imm unom od ulatory prope rties and Iherapeu tic ap plicaljon of mesenchymal stern cells. Clln Exp lrnmuno12011 ; 164(1) : 1-8. [107] Yagl H, So to-c ulie rre z A. Parekkad an B, et al. Mesenchymal stem ce lls: Me chanisms of immunomodulallon and hom ing. Cell Transplan ; 19(6) : [1081 Xu LH, Fang JP. Hong DL. et al. Ap plication o f mesenchymal s troma l ce lls In bo ne marrow tra nsp lanlatio n for se nsitized reci pients. Ac la Haematol 20 12; 127 (2): J Ren G. Chen X. Do ng F, et st. Concise review: mesenchymal stem ce lls and tra nsl ational medic ine: emerging Issues. Stem Ce lls Tra nsl Med 20 12: 1( 1): IllOj UcceJII A. Moretta L and Pistoia V. Mesenchymal stern cells in hea lth an d d isease. Nat Rev Imm uno 12008: 8 (9): II I I I Qiao S, Ren H. Shi Y, et st. Allogeneic compact bo ne-d eriv ed mes enchymal stem cell tran splant ation Increases survival of mice exposed to le thal total bod y Ira diation: a potential immunolog ical mec hanis m. Chin Me d J (Eng!) : 127(3) : II 121 Tobin LM. Healy ME. Eng lish K. et al. Hu man mesenc hymal stem cells su ppress donor CD4(+) T cell proliferation and red uce parhology in a humanized mo use model of acute graft -ve rsus-host dtsease. Clin Ex p Im munol 20 13; 172( 2): [113] Va nikar AV a nd Trivedi HL. Stem cell tran splantation in living donor ren al tran spl antation for minimization of immunosuppr ess ion. Transplantation 2012; 94(8): Vanlkar AV. Tr ive di HL. Feroze A. et 81. Effect of co trans plantatio n of mesen chy mal ste m ce lls and he matopoie tic stem ce lls as compared to hematop oietic stem ce ll tran splantation alone in renal tra nsplan talion 10 achieve donor hypo-r esponsiveness. Int Uro l Ne phrol 201 1; 43 (1): [115) Zhou HP. Yi DH, Yu SQ. et al. Ad m inistratio n of don or-derived mese nchymal slem ce lls can prolo ng the survival of rat cardiac allograft. Transpl an t Proc 2006; 38(9): [116] Fo rbes C M, Sturm MJ, Leong RW, et et. A phase 2 study of allogeneic mesenchym al stromal ce lls for lum inal Crohn's disease refrac tory to bio log ic therapy. Cll n C as troeruerol Hepa lol 2014 : 12(1) : II 17J Pileggi A. Xu X, Tan J. et 81. Mesenchymal stromal (stem) ce lls to impr ove so lid organ transplant ou tcome: lesson s from the initial c linical trials. Curr O pin Organ Tr ansplant 201 3: 18(6): [118] Koc h M, Lehnhardt A, Hu X, et al. IsogeneiC MSC applica tion In a rat model of acu te rena l allog ra ft rejec tion modulates imm une response but does not prol ong allograft survi val. Transpl Immunol 20 13: 29 (1-4) : [119] Sui W. Hou X. Che W. et al. Hem atopoietic and mesenchy mal ste m cell transplantation fo r severe a nd refractory system ic lupus eryt hematosus. Clln Inununo1201 3; 148 (2): [120] Herreros MD. Ca rcia -Arra nz M, G uada lajara H. et al. Autologou s expa nded adi pose- derived st em cells for the trea tment of complex cry ptoglandu lar perianal fis tu las : a pha se III randomized clinical trial (FAIT I : fistula Advanced T herapy Trial I) an d long-term ev alua tion. Dis Co lon Rectum 20 12; 55(7) : [121] Carcia-Olmo 0, He rre ros D, Pascual I, et et. Exp anded adiposede rived stern cells for the treatment of co mplex perianal fistula: a phase II clinical trial. Dis Colon Rectum 2009: 52 (1): [122] Kassis 1, Vaknin-Dernbinsky A, Karussls D. Bone marrow mesenchymal stem cells: age nts of imm unomodulauon a nd ne uroprolec lio n. C urr Stem Ce ll Res Ther 20 1 I; 6(1): [123 ] Ya rnou t B. Houran i R, Salt l H. et al. Bone ma rrow mesenchy mal ste m cell trans plantation in patients with mu ltiple sclerosis : a pilot study. J Neu roimmunol20 10: 227 (1-2): [124J Krabbe C, Zim mer J. Meyer M. Neu ra ltra nsdlfferenliatlon of mesenc hymal stern ce lls--a c ritica l review. 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The change of a paradigm: new immuno logical and genetic tnsjglns hnpucate Thl7 ce lls in the pathogenesis of Crohn'sdisease. Gilt 2009 : 58 (8): [13 1] Lee RH, Seo MJ, Reger RL, el al. Mul tlpots nt stromal cells from human marrow home to and promote repair of pancreatic islets and rena l glomeruli In diab etic NODlscld mice. Proc Nat! Acad Sci USA 200G: 103(4G): (132) Se mon t A. Mouisedd lne M, Franco is A. el al. Mesenchym al ste m cells improve small Intesllnal inte grity through regulati on of endog enous epithelia l cell homeostasis. Cell Death Differ 20 I 0: 17(6): 952-GI. [133] Lec hner A, Yang YG, Blacken RA, et al. No evidence for significan t transdifferenllatl on of bone marrow Into pancreat ic beta -cells in vivo. Dlabetes 2004 : 53(3): [13 4] Urban VS, Kiss J. Kov acs J, et st. Mese nc hym a l stem cells cooperate with bone marrow celjs in therapy of diabetes. Stem Cells 2008: 26 (1): Received : April 11, 2014 Revised: June Accepted: June

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