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Current Stem Cell Researchs Therapy, 2014, 9, 424-431

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, Pr ince of Wales Hospital, Shetin, Hong Kong SAR, PR China; 2Lui Che Woo Institute of Innovati ve 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, Pr ince of Wales Hosp ital, Sttetin. Hong Kong SAR, PR China; 4The CUH K-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System The Chinese Universi ty of Hong Kong Shenzhen Research Insti tute, Shenzhen, PR China; 5Key Laboratory for Regenerative Medicine, Ministry of Education, School of BiomedicaI Sciences, Faculty ofMedicine, The Chinese Univers ity 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 beneficia l 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 di fferent 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 s tem ce lls (MSCs) . secre tive fa ctors. transplan tation .

INTRODUCTION and HL A-DR surface mo lecu le ; th ird , these cells can be dif­fere ntiate d into osteobl ast s, adipocy tes 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 abili ty 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) secretion of growth factors and cytokl­different iate Into ne ura l cells [2]. germ ce lls [3]. cardiomy o ­nes [B, 9]; 2) suppo rt fo r o ther cell types dur ing tissue regen ­cytes [4], etc. The h isto ry of MSCs could be traced back to era tio n [10 -12]; 3) imm unomodulation properti es [13. 14]; 4) 1970 when Friede ns te in and his co-wo rkers first isolated and differe ntia tio n into specific ce lls for dam aged orga n tissues cultured fib rob last -like clonogenic stromal ce lls from bone [15. 16] (Fig . 1) . However. the cellular effec ts and the trace mar row w hich are multi-po tent progenitor s [5]. These ce lls of MSCs after resto ring transplanta tion appea r to be lack ofcan be easi ly expanded and pro mote tissue repa ir. Thus, the consideration and rem ain inconclusive [16-1 B]. use of MS Cs has been an innovativ e approach in treatmen t

of variou s diseases . Currently. there have been more than Trans planted MS Cs can be labeled with different ma rk­300 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 Na tio na l Institute of Healt h [6]. based on polymerase chain rea ction [19. 20], Y chromosome

staining [21], green flu orescent pr otein labeling [22. 23] and T he Intern a tional Society of Cellu lar Therapy has mad e a so on [24, 25] . With the deve lop me nt of cell tracking tech­d efinition of MSCs based on three minimal criteria : First,

these ce lls can be plasti c-adh erent in a standa rd co ndition: nology, new methods like in vi vo Imaging techn iqu es can be 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

seco nd , these ce lls express CO lOS, C073 and CD9 0, and

o the r organs [28] . In order to ga in so me ins ight into the fate *Address correspondence to this author at the Roo m 904. 9/F, Li Ka Shing and effects of tran sp lan ted allogenei c MSCs, we have re ­Institute of Health Institute,Prince of Wales Hospital, The Chinese Univer­

viewe d availab le liter atures and focused on functi on and fate sity of Hong Kong, Shatin. Hong Kong, SAR, PRChina; Tel; (852) 37636 153; Fax; (852) 2646 3020; E-mail;gangJi @cuhk.edu.hk of in vivo transplantated allogeni c MS Cs .

2212 -3946/14 $58.00+.00 e 2014 Bentham Science Publi shers

Rolesof MesenchymalStem Cellsin TissueRepairand Disease Modification CurrentStem CellResearch& Therapy, 2014, Vol. 9, No.5 425

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-61

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 ep ithelia l cells

Imm uno mo i:lu lat ion

Ma intai n ba lance of TH1/TH 2 and enhance the prolife rati onofTreg cells.

Abilitv of redu cing the preval ence o f GVHD

Inhibitory funct ion s on cytotoxic T cells [Crohn's di sease)

Secret essential factors

Reverse degenerative 13-cell nct ion

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 afte r first produced by Okabe In 1997 [221 . Although GFP has been documented to be biolog ically inert, it may cause di ­lated 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 s taining 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. Magnet ic 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 cell s [35J. Contr ast rea­gents are needed for tracking ce lls, such as lanth anid e chelates [36], superparamagnetic iron oxid e [37], micron -

sized iron oxide particles [38], some unique tracer dye [39] and others [40,41]. Yet these methods s till 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 si tes 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 s tudy 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

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 1999. 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 tibi a 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 pilo t 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.

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 infarct ion. 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.5 427

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 sugges ted 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 trans ­planted 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 2,3­dioxygenase (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 [104-107] . 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 [113-117]. 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

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 auto­Immune 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 [119-124].

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 p­cell 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 (CUHK4 70813), and a grant from China Shenzhen City Sci­ence and Technology Bureau under the Shenzhen City Knowledge Innovation Plan. Basic Research Project (JCYJ2013040l17193581l) 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): 306­316.

[21 Ma L, Feng XY. Cui BL. et al. Human umbilical cord Wharton's jelly-derived mesenchymal stem cells differentiation into nerve­like cells. Chin Med J (Engl) 2005: 118(23): 1987-93.

[3] Huang P. Lin LM, Wu XY, er al. Dlfferenllation of human umbili­cal cord Wharton's Jelly-derived mesenchymal stem cells into germ-lIke cells in vitro. J Cell Biochem 2010: 109(4); 747-54.

[4J Qlan Q. Qlan H. Zhang X. et al. 5-Azacytidine induces cardiac differentiation of human umbilical cord-derived mesenchymal stem cells by activating extracellular regulated kinase. Stem Cells Dev 2012; 21 (I): 67-75.

[51 Friedenste!n AJ, Chailakhjan RK. Lalyklna KS. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3(4): 393-403.

[6J Ikebe C, Suzuki K. Mesenchymal stem cells for regenerative ther­apy: optlmization of cell preparation protocols. Biomed Res Int 2014; 2014: 951512,

[71 Dominici M. Le Blanc K. Mueller 1. et al. Minimal crlleria for defining multi potent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8(4): 315-7.

[8] Chen L, Xu Y, Zhao J. et al. Conditioned medium from hypoxic bone marrow-derived mesenchymal stem cells enhances wound healing in mice. PLoS One 2014; 9(4): e96161.

[91 Yew TL. Hung YT. LI HY. et al. Enhancement of wound healing by human multipotent stromal cell conditioned medium: the paracrine factors and p38 MAPK activation. Cell Transplant 2011; 20(5): 693-706.

[101 lzumida Y. Aoki T. Yasuda D. et al. Hepatocyte growth factor is constitutively produced by donor-derived bone marrow cells and promotes regeneration of pancreatic beta-cells. Biochem Biophys Res Commun 2005; 333(1): 273-82.

[1l] Lin F. Moran A. Igarashi P. Inlrarenal cells. not bone marrow­derived cells, are the major source for regeneration In postischernic kidney. j Clin Invest 2005; 115(7): 1756-64.

[121 Duffield jS. Park KM, Hsiao LL, et al. Restoration of tubular epithelial cells during repair of the postischemlc kidney occurs In­

Rolesof MesenchymalStem Cells in TissueRepair and DiseaseModification CurrentStem Cell Research& Therapy, 2014, Vol. 9, No,5 429

depende ntly of bone marrow-derived stem ce lls . J C lin Inves t 2005 ; 115 (7): 1743 -5 5.

113) Le Blanc K, Tamm lk L. Sundberg B, et al. Mese nchy ma l s lem ce lls Inh ibit and stimulate mixed ly mphocyt e cultures a nd m ito ­genic respon ses inde pendently of the majo r histoco mpati bWty comp lex. Scand J Immunol 2003; 57(1) ; 11-20.

114] Ba i L. Lennon DP. Eaton V. et al. Human bone marrow-der ive d mesenchy mal s tem cells ind uce T h2-polarized Immune resp onse and pro mot e endogenou s repai r In ani ma l models of m ultiple scle­ros is. Glia 2009: 57(11) : 119 2-203.

115J Rya n AE, Lohan P, O'Flynn L, et et. Chon drog enic differentiation increases antidonor immune res ponse to a lloge neic mesenchymal s tern cell transplarnation . Mol T her 20 14: 22(3) : 65 5-6 7.

[16] LI ZH, Liao W, Cui XL, et et. Intr avenous transplan tatio n of allo­ge ne ic bone marrow m esenchy ma l stem ce lls and its directional m igration to the necr otic fe moral head. ln t J Med Scl 201 1; 8 (1): 74-83 .

[17] Takerntya K. Kai H. Yasukawa H, el st. Mesenc hy ma l ste m ce ll ­base d prostacycl in synthase ge ne therapy for pulmonary hype rten­sion rats. Bas ic Res Ca rdlol20 10; 10 5(3) : 409 -17 .

118) Nakamura T. Seklya I. Murieta T, et al. Arth roscop ic, histological and MRI ana lyses of cartilage re pair after a minim ally invasive me thod of tra nspl an tation of allogeneic synOVia l mesenchymal stroma l ce lls Into ca rtilage defects in pigs. Cy tothe rapy 20 12: 14(3): 327-38.

1191 Boeker W, Ross mann O . Docheva D, et al. Quanti tative polym ­erase cha in reaction as a reli able method to determine fu nctional lentiviral titer after ex vivo ge ne transfer in huma n mesen chymal ste m cells. J Cene Med 2007: 9(7); 585 -95.

120] Rollin R. Alvarez-Lafuente R, Marco F, et al. Hu man parvovirus B19, varicella zoster Virus, and human herpesvirus-6 in mesenchy­mal stem cells of patients w ith os teoa rthritis : a na lys is with quanti­tative real-tlrne polymerase cha ln rea ctio n. Osteoarthritis Ca n ilage 2007; 15 (4) : 475-8.

[21] J iang W, Ma A, Wan g T, et al. Horning and d ifferent ia tion of mesen ­chymal stem ce Us deUvered intravenously to ischemic my ocardium in vivo:a time-ser ies study . Pflugers Arch 200 6; 453(1) : 43-52 .

122J Okabe M. Ika wa M. Kominami K. et al. 'Creen mice' as a sou rce of ub iquitous green cells. FEBS Le tt 1997 ; 407 (3) : 3 13-9.

[231 Huang WY, Ara mbuno J. Douglas PS, et al. Tr ansgen ic expression of green fluorescen ce prot ein can cause dil ared card iomyopa thy . Na t Med 2000; 6(5): 482-3.

(24J Amsalem Y. Mar dor Y. Feinberg MS , et a l.Iron-oxide labe ling and outco me of tran spl ant ed mesenchy ma l stem ce lls in the infa rcted my ocardiu m. Circulation 200 7; I i6(1 1 Suppl): 138-45.

[25] Park SK, Won J H, Kim HJ , et al. Co-transplantat ion of human mesenc hy mal stem cell s prom otes human CD34+ cells engraftment in a dose-dependent fashion in NOD/SCm mice. J Korean Med Sci 2007; 22(3): 412-9.

[26] Ni M. Rui YF. Tan Q.et al. Engi nee red sc affold-free tendon lissue produced by tendon-derived s tem ce lls. Biomaterials 20 13; 34(8): 202 4-37.

127J J oo SY. Cho KA , Iung YJ , et st. Bioi maglng for the monit or ing of the in vivo distribution of infused mese nchymal s tem cells In a mouse mode l of tile g ra ft-versus -host reaction. Ce ll Bio i ln t 20 11; 35(4) ; 4 17-21.

1281 Cao J. Denn is JE. Muzic RF, et al. The dynamic in vivodls iribu­lion o f bon e m arrow-deri ved mese nchymal stem ce lls a fter Infu­sio n. Ce lls T issu es O rgans 200 1; 169(1 ): 12-20 _

1291 Dava nl S. Mara nd ln A. Mersin N. et sl. Mesenchyma l progenitor ce lls diffe renlia te in to an endo thelia l phenotype, enhance vasc ular density, and imp rove heart function in a rat cellular cardiomyo­plasty model. Circulation 2003; 108 Suppl l : I1253-8 .

130] Leiker M, Suzuki C , Iyer VS. et al. Assessment of a nuclear affin­ity lab eling method for tracking imp lanted mesenc hyma l stem ce lls. Cell Transplant 2008 ; 17(8) : 9 11-22 .

[31 ] Sun S. Chen C, Xu M, et al. Dlffe renliati on a nd m igra tio n of bone marrow mesenchymal stem cells transpl ant ed through the spleen In rats with portal hypertension . PLoS One 20 13; 8( 12) ; e83 523 .

[32] Shao CH, Chen SL. Dong TF , et al. Tra nsplant a tion of bone mar­row-de rived mesenc hy ma l stem ce lls after regiona l he patic irradla ­tion a me liorates thioacetam lde -Indu ced live r fibrosis in rats . J Su rg Res 20 14: 186(1 ): 408 -16.

133] Yaghoubl SS , Barr io J R. Na ma var i M. et et. Imaging prog ress of herpes simp lex virus type 1 thymid ine kinase s uic ide ge ne therapy

In living subjects wi th pos itron emission tom ograph y . Ca nce r Ge ne Th er 2005 ; 12(3) : 329-39 .

1341 Klcic A, Shen WY, Wilson AS, et al. Diffe rentiation of ma rrow s tromal ce lls lnto pho toreceptors in the rat eye _ J Ne urosct 200 3; 23(2 1): 774 2-9.

[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) : i0 6-9.

[361 Cric h SC , Bianco ne L, Gan talupp i V, et al. Improved rout e for the vlsuallzatlon of ste m cells labeled with a Cd-Eu-chelate as dua l (MRl a nd Ilu oresce nce) agent. Magn Reson Med 200 4; 51(5) : 93 8 ­44 .

137) Kust er mann E. Himm elreich U. Kandal K, et al. Efflclent s tem cell labeling fo r MR I studies. Contrast Media Mol Imaging 2008 ; 3(1) ; 27 -37 .

[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): 1150-7.

[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): 2333 ­8.

(40) Yamada M, Yang P. In vitro labellng of hum an embryonic s tem ce lIs for magnetic resonance imagi ng. J Vis Ex p Z008; 17. pii : 82 7.

[41) Be rge r C, Rausch M, Sc hm idt P, et al. Feas ibility and limits of magneticall y labeling pr ima ry cu ltured rat T cetis w ith femm oxldes co upled with comm only used transfeclion age nts. Mo l Imagi ng 2006 ; 5(2) : 93 -104 .

[42] So hni A. Verfaillie CM. Mesenchymal Stem Cells Migration Hom ­ing a nd Tr ac king . Stem Ce lls Int 2013; 2013: 130763.

[43] Zhao H, Feng J , Seide l K. et al. Secretion of shh by a ne urovascu­lar bu ndl e niche supports mesenchymal s tem ce ll homeostas is in the adul t mous e inc iso r. Ce ll Stem Cell 2014 ; 14 (2): 160 -73 .

[44] Livet J. Weissman TA. Kan g H . et al. Transgenic stra tegies fo r combinato ria l ex pression of Iluo rescent proteins In the nervous sys­tem. Natu re 200 7; 450(7166) : 56-62 .

[451 Ng uyen PK. Riegler J and W UJC . Ste m ce ll imagi ng : from bench 10 beds ide. Cell Stem Ce ll 20 14; 14(4) : 431 -44 .

[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 pracr lce. Blomater lals 2007; 28(29): 4240· 50 .

[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 Sc i Mater Med 20 11; 22(3 ) : 14 1-5 1.

[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 osteogenes is imperfecta. Nat Med 1999 ; 5(3) : 309 · 13.

[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 ito rs . Scie nce 1998; 279(5356) : 1528-30.

[501 Ch am berla in C , Fox J, As hton B, et al. Co ncise review; meson­chy mal stem cells ; their pheno type, differ enti at ion capacity , im mu ­nolo gical fea tures , and po ten tial for homing. Stem Cells 200 7; 25 (1 I) : 2739 -49 .

[51) PereIra RF , Hal fo rd KW , O' Ha ra MD , et al. Cultured ad herent ce lls from marr ow can se rve as long-l asting precu rsor ce lls for bon e. carti lage , an d lung in Irradia ted m ice. Proc Nall Acad Sci USA 1995 ; 92(1I) : 485 7-61.

[521 Ric her t L. C olubi c S, Guedes RL, et al. Characle rizallon of exopo lysaccha rides prod uced by cyanobacteria isolated from Poly ­nesian microbial ma ls. Curr Mic robio l 2005; 51 (6); 379-84.

[53) C ranero-Molto F , We is JA. Miga MI, et al. Regenerative effects of transplanted mes enc hy mal ste m ce lls in fracture healing. S tem Cell s 2009 : 27(8) : 1887-98.

[54] Orti z LA , Gam be llJ F, McBr ide C. et al. Mesenchymal stem ce ll engraftment in lu ng Is e nhanced in response to bleomycin expos ure and am eliorates its fibrotic effects. Pro c Natl Acad Sci USA 200 3; 100 (14) : 8407-11.

[551 Ch en Y. Xiang LX , Shao JZ, et al. Rec run rnent of end ogenou s bon e marrow mese nc hyma l stern ce lls towa rds lnju red live r. J Ce ll Mol Med 2010 ; 14 (613) ; 1494-508 .

[561 Mah mood A. Lu D, Lu M , et al. Treatm ent of tra uma tic brai n In ­j ury In ad ul t rats with in travenous ad mlnls trano n of hum an bo ne marrow s troma l cells . Neu rosurgery 2003 : 53 (3): 697-702; discu s ­s ion 70 2-3.

-

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 regenera tive medicine. Transplant Proc 2006 ; 38(3) : 967 ·9.

158] Qulntavalla J . Uzial-Fusi S . Yin J . et al. Fluorescently label ed mesenchym al s tem ce lls (MSCS) mainta in mu ltilineag e potential and can be de tec ted fo llow ing Implantatlon into ar ticular cartilage defec ts. B ioma te rla ls 2002 ; 23 (1): 109-19.

159] 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 s tudy and a rand omi sed controlled IriaL Lancet 2002 : 360 (933 1): 427- 35.

160J Lian Q. Zhang Y. Zh ang J, et al. Func tio nal mesenchym al stem cells der ived from human Induced plur ipo tent stem cells atte nuate limb Ischem ia in mice . Circ ula tion 2010: 121 (9): 1113-23.

161] Madonna R, Pizzi SO , Tart are A, et al. Tr ansplantauon o f mesen ­chy mal ce lls improves peripheral limb ischem ia in diabetic rat s . Mol Blot ech nol 2014: 56(5) : 438-48.

162) Huan g WH , Che n HL, Huang PH, et al. Hypoxic mesen chymal stem cell s eng ra ft and a meliora te limb Ischaemia in allogeneic re­cipients . Cardl ovasc Res 2014: 101 (2) : 26 6-76 .

1631 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 s tudy . PLoS One 2013 : 8 (8): e69299 .

[64] Curley GF , Ansari B, Hay es M, eral . Effects of intratracheal mes­enchymal stro mal cell therapy during recov ery and resoluti on after ventilator-ind uced lun g Injury. Anesthesi ology 20 13: 118 (4): 924 ­32 .

1651 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) : 228- 34.

166 1 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 20 13 : 183(2) : 907- 15.

167J 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 201 3 ; 33 (8): 1872 -80.

1681 Richardson 10 , Bert as o AG. Psaltis Pl . et s l. Impact of timing and dose of mes en chymal s troma l ce ll therapy in a preclinical model of acute my ocardial infarcti on . J Card Fall 20 13: 19(5): 342 -53 .

[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 , apop­tos is. a nd hippoca mpal da ma ge in brain of a spo ntaneous s troke mod eL Free Radle Bioi Med 20 14: 70 : 141-54.

1701 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): 474-81.

1711 Coquery N, Blesch A, St roh A , et al . lntrahippocampal tra nsp lanta­tion of mesenchymal stro ma l ce lls promotes neuroplastlci ty. Cy­to the rapy 20 12; 14(9) : 1041·53.

172] ROjas M. Park er RE, Thorn N, et al. Infusion of freshl y isolated autologous bone marrow derived mononuclear cells prev en ts endo ­toxin-induced lung Injury In an ex-vivoperfused swine model. Ste m Ce ll Res Th er 20 13: 4 (2) : 26.

173J Wang T. Tang W, Sun S, et s t. Intra venou s infus ion of bone ma r ­row mesenchy mal stem ce lls Improves brain function after resusci­tation from ca rd iac arrest , Crit Care Mcd 2008: 36 (11 Suppl): S486-91.

174] 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): 32 1-9.

175] Ma J, Both SK, Ji W, et et. Adipose tissu e-d erived mesen chymal stem cell s as monocultures o r cocultures with human umbilica l vein end oth eli al c ells: perfor mance in vitro and In rat cra nial de­fects. J Biom ed Maler Res A 20 14; 102(4) : 1026 -36.

176J Pedersen TO . Blo is AL, Xu e Y. el st. Oste ogen ic stimulatory c on­dilions enhance growth and maturation of endo the lial ce ll mi­crovascular networks in c ulture with mesen chymal stem cells. J Tissue En g 20 12: 3(1) : 204 17314124432 36.

1771 Wise AF. William s TM. Kle wie r ME. et al. Human mesen chym al s tem 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) : FI222-35.

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 200 2: 105(1 ): 93·8 .

[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: 86-8.

[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): 289-99.

[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) : 9-20 .

[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) : 700-6.

[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): 375-83 .

[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) : 662- 71.

[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 u­lates 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): 378 -8 4.

[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) : 11247-56.

[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) : 382- 7.

[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 201 3 ; 17(9): 1136 · 45 .

[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) : 3- 10.

[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: 647 107 .

[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): e253-7.

[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 Patho1 201 3 : 6 (5) : 83 1-40.

[96J Ka ibori M , Adachi Y, Shrrno T . et al . Stimulati on of liver regenera­Uon 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) : 1107 -9.

[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 20 12; 178 (1): 63-70.

[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; 2 2 (10) : 1785 -99.

[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 in ­jury. Kidney 1012005 ; 67( 5) : 1772-84 .

[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 In ­jury mu ri ne model. Pathol ogy 2008 : 40 (1) : 52-7.

[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 200 5 : 68 (6) : 2572· 81.

Roles ofMesenchymal Stem Cells in Tissue Repair and Disease Modification Currenl Stem Cell Research s Therapy, 2014. Vol. 9, No.5 431

11 02) 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): 26-3 3.

11031 Boec kh M, Nic hol s WC , Marr KA. Long -ter m ca re after hem a ­topoletic-cell transplantation In adu lts . N Eng l J Med 200 2 : 347(20) : 1625-6: a uthor re ply 1625 -6.

1104) Do rronsoro A , Fe rnandez-Rueda J , Fechter K, et al. Human Mes ­enchy 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: 203643.

[1051 Larocca RA , Moraes-Vieira PM , Bassi EJ, et 81. Adipose tissue ­de rived mesenchy mal stern cells incre ase skin allograft s urvival and Inhibit Th-17 immu ne response. PLoS On e 2013 : 8(10): e76396.

[1061 Shi M. Liu ZW. Wa ng FS . Imm unom od ulatory prope rties and Iherapeu tic ap plicalJon of mesenc hymal stern cells. Clln Exp lrn­muno12011 ; 164(1) : 1-8.

[107] Yagl H, So to-C ulie rre z A. Parekkad an B, et al. Mesenchyma l stem ce lls : Me chanisms of immunomodulallon and hom ing . Cell Trans­plan1 20 10; 19(6) : 667-79.

[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): 105 -9.

1109J 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): 5 1-8 .

IllOj UcceJII A . Moretta L and Pistoia V . Mese nchymal ste rn cell s in hea lth an d d isease . Nat Rev Imm uno 12008 : 8 (9): 726 -36 .

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 surv ival of mice exposed to le thal total bod y Irra diation: a poten tial immunolog ical mec hanis m. Chin Me d J (Eng!) 20 14 : 127(3) : 475-82 .

II 121 Tob in LM . Healy ME. Eng lish K . et al. Hu man mesenc hymal stem cells su ppress donor CD4(+) T cell proliferation and red uce parhol ­ogy in a humanized mo use model of acute graft -ve rsus-host dts ­ease. Clin Ex p Im munol 20 13; 172( 2): 333 -48.

[113] Va nikar AV a nd Trivedi HL. Stem cell tran splantation in living donor ren al tran spl antation fo r minimization of immunosuppr es ­s ion. Transplantation 2012; 94(8) : 845-50.

11141 Vanlkar AV . Tr ive dI HL. Feroze A. et 81. Effect of co ­trans planta tio n of mesen chy mal ste m ce lls and he matopoie tic s tem ce lls as compared to hematop oietic stem ce ll tran splantatio n alone in renal tra nsplan talion 10 achieve donor hypo-r esponsiveness . In t Uro l Ne phro l 201 1; 43 (1): 225 -32 .

[115) Zhou HP. Yi DH, Yu SQ . et al. Ad m inistratio n of don or-derived me se nchy mal s lem ce lls can prolo ng the survival of rat ca rdiac al ­log raft . Transpl an t Proc 2006 ; 38(9): 3046-51 .

[116] Fo rbes C M, Sturm MJ, Leong RW, et et. A phase 2 study of allo ­geneic mesenchym al stromal ce lls for lum inal Crohn's d isease re­frac tory to bio log ic therapy . Cll n C as troeruerol Hepa lol 2014 : 12(1) : 64 -71.

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 init ial c lin ical trials . Curr O pin Organ Tr ansplant 201 3: 18(6): 672 -8 1.

[118] Koc h M , Lehnhardt A, Hu X , et al. Isogene iC MSC applica tion In a rat model of acu te rena l allog ra ft rejec tion modula tes imm une re ­

s ponse but does not prol ong allograft survi va l. Transpl Immun ol 20 13: 29 (1-4) : 43 -50.

[119] Sui W . Hou X. Che W . et al. Hem atopoietic and mesenchy mal ste m cell transplantat ion fo r severe a nd refractory system ic lupus eryt hematosus. Clln Inununo1201 3; 148 (2) : 186-97.

[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 tria l (FAIT I : fistula Advanced T herapy Tr ial I) an d long-term ev alua tion . Dis Co lon Rectum 20 12; 55(7) : 76 2-72 .

[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): 79-86.

[122] Kassis 1, Vaknin-Dernbinsky A, Ka russ ls D. Bone marrow mesen­chyma l 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): 63-8 .

[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 s tudy . J Neu ro immunol20 10: 227 (1-2) : 185-9.

[124J Krabbe C, Zim mer J . Meyer M. Neu ra ltra nsdlfferen liatlon of mes ­enc hymal stern ce lls--a c ritica l review. A PMIS 2005: I J3(1 1-12) : 831 -44 .

[125] Con nick P, Kola ppan M, Crawley C, et al. Autologo us mesenchy ­mal stem cell s fo r the treatment of secondary progressive mulliple sclerosis: a n open- la be l phase 2a proof-of-con cept stud y . Lan cet Neuro l 2012 ; II (2) : 150-6.

[126) Be lingheri M. Lazza ri L. Parazzt V. et al. Allogeneic mesen chymal stem ce ll Infus ion for th e sta bilization of foca l segmental glomeru ­losclerosis. Biologica ls 2013 ; 41(6): 439 -45.

[127) Gu Z, Aki ya ma K, Ma X, et et. Transplantation of umbili cal co rd mes enchyma l s te rn cell s allevtates lupus neph ritis in MRLllpr mice . Lupus 2010 : 19 (13) : / 502-14.

[128J Bo uguen G and Peyri n-B iroulet L. Surgery fo r ad ult Crohn's dis ­ease : what is the ac tua l risk? Gu t 20 I 1; 60 (9) : 1178-8 1.

[129) Kud o K. Liu Y, Ta kahas hi K, et al. Transplanta tion of mesenchy ­mal stem ce lls to prevent rad iation-induced in tes tinal injUry in mice . J Radiat Res 20 10: 5 1(1): 73-9.

[1301 Brand S. Crohn 's disease : Th l , Th l7 or both? The change of a para­digm: new immuno logical and genetic tnsjglns hnpUcate Thl 7 ce lls in the pathogenesis of Crohn'sdisease. Gilt 2009 : 58 (8): 1152-67.

[13 1] Lee RH , Seo MJ, Reger RL, el al. Mul tlpots nt s tromal ce lls 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): 17438- 43.

(132) Se mon t A. Mouisedd lne M, Franco is A. el al. Mesenchym al ste m cells improve smal l In tesllnal inte grity through regu lati 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 signifi ­can t transdifferenllatl on of bone marrow Into pancreat ic beta -cells in vivo. Dlabetes 2004 : 53(3) : 6 16-23 .

[13 4] Urban VS, Kiss J . Kov acs J , et st. Mese nc hym a l s tem cells cooper­at e with bone marrow celJs in therapy of diabetes. S tem Cells 2008: 26 (1) : 244- 53.

Received : April 11, 2014 Revised : June 04. 2014 Acc epted: June 07. 2014