Accepted Manuscript Title: Organ-specific migration of mesenchymal stromal cells: Who, when, where and why? Author: Anne S. Cornelissen Marijke W. Maijenburg Martijn A. Nolte en Carlijn Voermans PII: DOI: Reference:

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Please cite this article as: Cornelissen Anne S, Maijenburg Marijke W, Voermans Martijn A.Nolte en Carlijn.Organ-specific migration of mesenchymal stromal cells: Who, when, where and why?.Immunology Letters http://dx.doi.org/10.1016/j.imlet.2015.06.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Elsevier Editorial System(tm) for Immunology Letters Manuscript Draft Manuscript Number: IMLET-D-15-00129R1 Title: Organ-specific Migration of Mesenchymal Stromal Cells: Who, When, Where and Why? Article Type: SI: MSCS and immunity Keywords: Mesenchymal stromal cells, migration, homing, engraftment, bone marrow, chemokines Corresponding Author: Dr. Carlijn Voermans, Ph.D Corresponding Author's Institution: First Author: Anne S Cornelissen Order of Authors: Anne S Cornelissen; Marijke W Maijenburg, Ph.D; Martijn A Nolte, Ph.D; Carlijn Voermans, Ph.D Abstract: Mesenchymal stromal cells (MSC) represent a type of multipotent cells that can differentiate to various mesenchymal lineages. MSC can be isolated from different tissues and require ex vivo expansion to exert their regenerative and immunosuppressive function for various clinical applications. The efficacy of these MSC-based therapies at least partly depends on migration and specific homing towards the site where the cells are needed. MSC express a wide variety of integrins, chemokine- and growth factor receptors, though culture-expansion dramatically alters their migratory and engraftment potential. However, it has become clear that tissue damage and/or inflammation can enhance the efficacy of MSC homing. In this review, we focus on the migratory potential of MSC to target organs, including bone marrow, bone, spleen & lymph nodes, intestine and heart, and the underlying molecular mechanisms in various preclinical and clinical settings. Better understanding of directed MSC migration will offer new perspectives to modulate MSC expansion and/or clinical protocols to improve their efficacy upon transplantation.

Abstract

Organ-specific Migration of Mesenchymal Stromal Cells: Who, When, Where and Why? Anne S. Cornelissen, Marijke W. Maijenburg, Martijn A. Nolte en Carlijn Voermans*

Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

*

Corresponding author:

Carlijn Voermans, PhD Department of Hematopoiesis Sanquin Research and Landsteiner Laboratory AMC/UvA Plesmanlaan 125 1066 CX Amsterdam The Netherlands Phone: +31 20 512 3377 Fax: +31 20 512 3474 [email protected]

Abstract Mesenchymal stromal cells (MSC) represent a type of multipotent cells that can differentiate to various mesenchymal lineages. MSC can be isolated from different tissues and require ex vivo expansion to exert their regenerative and immunosuppressive function for various clinical applications. The efficacy of these MSC-based therapies at least partly depends on migration and specific homing towards the site where the cells are needed. MSC express a wide variety of integrins, chemokine- and growth factor receptors, though culture-expansion dramatically alters their migratory and engraftment potential. However, it has become clear that tissue damage and/or inflammation can enhance the efficacy of MSC homing. In this review, we focus on the migratory potential of MSC to target organs, including bone marrow, bone, spleen & lymph nodes, intestine and heart, and the underlying molecular mechanisms in various preclinical and clinical settings. Better understanding of directed MSC migration will offer new perspectives to modulate MSC expansion and/or clinical protocols to improve their efficacy upon transplantation.

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*Highlights

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1. Introduction Mesenchymal stromal cells (MSC) are multipotent stem cells and comprise a heterogeneous population of cells. MSC were first isolated from bone marrow (BM) [1], but they can also be obtained from various other adult and fetal tissues, such as adipose tissue (AT) and cord blood (CB) [2,3] (Figure 1). MSC are characterized by their adherence to plastic, the expression of certain surface markers and their ability to in vitro differentiate into osteoblasts, chondroblasts and adipocytes [4]. Ex-vivo expanded MSC are interesting candidates for cellular therapies due to their regenerative and immunosuppressive capacities. MSC are already used in clinical trials to improve hematopoietic recovery after stem cell transplantation [5]. They are also administered for regenerative treatments such as the treatment of large bone fractures [6], osteogenesis imperfecta [7], myocardial infarction [8] and muscular dystrophy [9]. Besides their regenerative capacities, MSC can also be applied to dampen immune responses in the case of graft-versus-host disease (GvHD) [10], inflammatory bowel disease (IBD) [11], arthritis [12] and diabetes [13]. MSC comprise a rare population of 0.001-0.01% of all nucleated cells in the BM [14]. For clinical trials it is required to massively ex-vivo expand MSC to obtain sufficient cell numbers. The average dose that is given to patients with GvHD varies between 0.4-9x106 cells per kg body weight [15]. A major drawback is that ex vivo expansion of MSC decreases their homing capacity [16]. MSC express a wide range of integrins and adhesion molecules and can respond to a wide variety of chemotactic stimuli (Table 1). Although MSC migration follows the same principles as leukocyte migration [17–19], the homing/engraftment potential is limited as MSC show very low engraftment and most MSC become entrapped in the vascularization of the lungs after intravenous infusion [20,21]. However, MSC are able to transmigrate trough endothelium and therefore can extravasate and migrate towards their

destination [22]. Whether homing and/or engraftment of MSC is absolutely necessary remains controversial and this may be injury and/or tissue specific. We previously found that only a very small percentage of MSC were able to migrate in vitro towards different chemotactic stimuli. Interestingly MSC seem to have the whole migratory machinery as actin rearrangement and increased paxillin phosphorylation were observed in most MSC upon stimulation. This indicates that responding to migratory cues is not restricted to migrating MSC [23]. Probably other mechanisms are involved to induce MSC migration. When infused into irradiated mice, François and colleagues observed homing of MSC to injured sites [24]. In another study, immunodeficient mice were treated with human MSC after acute myocardial infarction. No engraftment of MSC was observed despite the improvement of fibrosis and cardiac function [25]. This may suggest that the capacity of MSC to secrete soluble factors or vesicles rather than engrafting and transdifferentiating plays an important role in tissue repair. A new emerging concept is the „hit and run‟ concept‟; MSC can rapidly pass their beneficial effects to other cells (e.g. macrophages and regulatory T cells), which then in turn can mediate immunomodulation and tissue repair [25–27]. There is some evidence that MSC can circulate in minute quantities in peripheral blood under physiological conditions [28], though this remains controversial [29]. Circulating MSC could be detected in patients with major skin burns and in patients with bone fractures [29–31]. Moreover, in a murine model it was shown that MSC are mobilized from the BM during inflammation [32]. On the other hand, Hoogduijn and colleagues could not detect circulating MSC in patients with end-stage kidney or liver failure or in patients that showed rejection after heart transplantation [33]. We have previously reviewed the possibilities to improve the migration potential of culture-expanded MSC [34]. However, not much is known about migration of MSC to specific target organs. Therefore, we will focus in this review on migration of MSC to target organs in

preclinical and clinical settings, in which they are currently applied to improve the outcome of a variety of diseases (Figure 1).

2. MSC migration towards the bone marrow MSC are an important constituent of the BM microenvironment, where they support hematopoiesis via direct cell-cell interactions with hematopoietic cells, and release of soluble factors [35]. Evidence for the important role of MSC in supporting hematopoiesis came in 1966 from Friedenstein et al who showed that transplantation of MSC resulted in the generation of structures (ossicles) which replicated the histological features of bone. In these structures the stroma is of donor origin whereas the hematopoietic cells are derived from the host [36]. More recently, it was shown that BM-derived perivascular, human mesenchymal progenitors are uniquely capable of forming the hematopoietic microenvironment upon transplantation into heterotopic ossicles in immunodeficient mice [37]. Culture-expanded BM-derived MSC (intravenously injected) are nowadays the first source of choice for clinical applications, therefore it would be logical to assume that at least part of these MSC migrate to the BM after transplantation. However, Rombouts and Ploemacher demonstrated in 2003 that MSC loose there homing capacity already after 24 hours of culture, while primary non-cultured BM-derived MSC were able to effectively home to BM in irradiated mice [16]. It has been demonstrated that simultaneous intravenous injection of cultureexpanded donor MSC and hematopoietic stem cells (HSC) accelerates recovery of hematopoiesis after myeloablative therapy in animal models and in man [5,38], though the observed percentages of MSC in BM were low (80%) did not alter the BM homing of MSC in unconditioned animals, but caused a significant increase in homing to BM and spleen of animals that had received prior irradiation [44]. Chen et al observed the same in vitro and in vivo correlation for CXCR4 transduced murine MSC transplanted into irradiated BALB/c mice [45]. Moreover Bobis-Wozowikz described that transplantation of CXCR4-transduced human AT-MSC into nonobese NOD/SCID mice led to increased engraftment (0.3% to 0.7% after 24hrs) into BM in comparison to GFP-transduced AT-MSC [46]. Together these data indicate that the CXCL12/CXCR4 axis plays an important role in homing of MSC to the BM, and prior treatment. Moreover, irradiation and chemotherapy increases CXCL12 production in BM [47], which may explain the necessity of pretreatment for boosting MSC migration and engraftment in BM. Yet, expression of other homing molecules on MSC is also important when targeting MSC to the BM, such as hematopoietic cell E-selectin/L-selectin ligand (HCELL), a special glycoform of CD44 that improves MSC homing towards BM by enhanced E-selectin binding [48]. Furthermore, as MSC are a heterogenic population of cells, it is important to consider differences in the migatory capacity of MSC subsets. As such, human MSC expressing the stromal cell antigen Stro-1 are better capable of entering the BM and spleen of NOD/SCID mice than Stro-1 negative

cells, though the latter provide better hematopoietic support [49]. Furthermore, we recently determined new BM-derived MSC subsets based on the expression of CD146 and CD271 that express different amounts of CXCR4 [50]. The homing potential or migratory capacity of these newly defined primary MSC is hardly studied due to the limited number of cells available. Yet, it will be interesting to determine the migration potential of these MSC subsets using new sophisticated methods to study migration with low cell numbers, as this may identify cells with superior migration capacity and engraftment potential compared to cultureexpanded MSC, thereby yielding better therapeutic efficacy.

3. MSC migration towards the bone Since the discovery of their osteogenic potential, MSC are used in clinical trials to treat patients with bone defects such as osteogenesis imperfecta [7,51], osteoarthritis [52] and bone fractures [6,53]. MSC can be administered either intravenously, via intra-bone injections or intra-articular injections [51,54,55]. There is evidence that systemically infused MSC can home to the fracture site [55–58]. However, therapeutic efficacy of systemically administered MSC varies enormously [55–58]. It was already shown by different research groups that MSC can actively migrate out of the BM [59,60]. Circulating MSC could be detected in peripheral blood of patients with bone fractures [30]. However one could argue that this is caused by mechanical disruption of the bone rather than active recruitment from the BM. Haasters and colleagues found a reduced migration potential in vitro of human MSC from osteoporotic patients primarily caused by downregulation of integrin α2 [61]. These findings may underlie the reduced fracture healing observed in osteoporotic individuals [62]. Regarding the heterogeneity of MSC, it has been shown that MSC expressing CD271 (the low-affinity nerve growth factor receptor) [63] were recruited to the fracture site in injured mice upon intravenous injection [64]. However, there was no detectable difference in callus formation or callus size when compared to PBS-injected controls [64]. Intra-articular injected

GFP-labeled MSC were found to integrate in cartilage and were involved in the reparative process of cartilage in osteoarthritic donkeys [54]. Interestingly, intrafemoral injections of MSC could induce homing and bone formation in dogs with mandibular defects [55]. In a study with rats, mechanical stimulation of the fracture was performed to further increase bone formation. Mechanical stimulation 10 days after the occurrence of the fracture resulted in more mineral, less cartilage and greater mechanical properties of the bone compared to stimulation at other time points or unstimulated fractures. Surprisingly, infused GFP-positive MSC were found in osteotomies, except in the group that was stimulated 10 days after surgery. These results show that (timing of) mechanical stimulation dramatically affects migration of MSC to the fracture site [65]. Intramedullary and intravenous injections with

CXCR4-transduced

MSC

showed

improved

BM

homing

and

retention

in

immunocompetent mice. Interestingly, MSC transduced with CXCR4 and Cbfa-1, genes involved in migration and bone formation respectively, showed increased restoration of bone mass and strength in osteoporotic mice [66]. Also ectopic CD49d expression on MSC was found to increase homing to the bone [67]. In a recent study by Xu and colleagues, Sryrelated high-mobility group box 11 (Sox11) overexpressing MSC were found to increase trilineage differentiation, migration, ectopic bone formation and that systemic administration could accelerate bone fracture healing in rats. Sox11 was found to induce BMP/Smad signaling and Runx2 and CXCR4 expression [68]. These studies demonstrate that recruitment of MSC to bone can be enhanced in order to therapeutically employ their osteogenic potential.

4. MSC migration towards the spleen and lymph nodes Homing of MSC to secondary lymphoid organs such as lymph nodes (LNs) and spleen is highly relevant when MSC are applied for their immunosuppressive capacity. Freshly isolated, non-cultured, non-purified BM-MSC from eGFP-transgenic mice efficiently entered the spleen of syngeneic recipients within 24 hours after iv injection, where they

could engraft and expand, but this potential was dramatically decreased when the cells were cultured for 24 hours [16]. Yet, as ex vivo expansion is still a necessity for MSC-based therapies, most subsequent studies have used culture-expanded MSC. As such, when expanded BM-derived murine MSC, that were radioactively-labelled and transgenically expressing DS-Red, were injected in untreated WT recipients, a small amount of radioactivity could be found in the spleen after 24 hours. However, no DS-Red-expressing MSC could be cultured from the recipient spleens at either 5 min, 1, 24 or 72 hours after injection, suggesting that the donor-MSC did not survive in the spleens and that the detected radioactivity was due to uptake of dead cells by local phagocytes [69]. Although homing of culture-expanded MSC to the spleen may thus not be very efficient, this can be improved in three different ways. First, injecting MSC intra-arterially rather than intravenously improves seeding of the spleen, as it prevents entrapment of the cells in the lung [69–71]. Second, sublethal (abdominal) irradiation of the recipient strongly increases both the homing and engraftment of MSC in the spleen [16,24]. Third, efficiency of MSC migration to the spleen is high under pro-inflammatory conditions, as has been shown in experimental autoimmune encephalomyelitis [72], acute ischemic kidney injury [70], and Trypanosoma cruzi infection [73,74]. Apart from these studies in animal models, culture-expanded human MSC can also home to and engraft the human spleen: in vivo tracking of radioactively-labeled MSC in patients with advanced liver cirrhosis revealed that MSC homing to the spleen increased from 2-10% immediately post-infusion to 30-42% on day 10 [75]. Moreover, MSC-chimerism has been detected in human spleens of female patients that died from infectious complications one year after receiving an allogeneic BM transplantation as a treatment of hematological diseases and a transplantation of MSC from third-party male donors [76]. Whether the capacity of MSC to enter and engraft the spleen is also important for their therapeutic efficacy is not yet known. In the steady state, the ability of MSC to enter LNs correlates with their expression of CCR7, a chemokine receptor that is essential for high

endothelial venule-based entry into LNs [77,78]. Different degrees of CCR7-expression have been reported for culture-expanded MSC [79–81], which may relate to differences in passage number and purity of MSC. Yet, transfection of MSC with CCR7 can boost MSC homing to LNs, thereby intensifying their in vivo immunomodulatory effect, without inhibiting immunity to leukemia [82]. CCR7+ MSC localized in close proximity with T cells in LNs, but also in spleen, suggesting that the expression of CCR7 also allows MSC to enter the white pulp, the lymphoid area of the spleen [82]. Comparable to the spleen, MSC can enter lymph nodes upon inflammation. Ex vivo expanded GFP-MSC are found in inguinal, mesenteric and pancreatic LNs 7 and 65 days after injection in diabetic C57BL/6 mice, where they restore the balance between autoaggressive and regulatory T cells and improve diabetes [83]. CFSE-labelled MSC were found to migrate to pancreatic LNs upon injection in diabetic-prone NOD mice and prevent the induction of diabetes by cotransferred diabetogenic T cells [84]. Furthermore, 3 days after transplantation, ex vivo expanded GFP-MSC could be found in LNs draining the eye after cornea transplantation, whereas LNs at the contra-lateral, non-transplanted site contained far fewer MSC [85]. In conclusion, MSC are able to enter both spleen and lymph nodes, but this is strongly influenced by the condition of the cells (e.g. culture-expansion or not) and the status of the recipient.

5. MSC migration towards the intestine MSC have already been applied to patients with IBD [11,86,87]. A lot of studies prove therapeutic efficacy, though migration of MSC towards the intestine is often not studied in clinical trials. Interestingly, MSC can be recruited to sites of inflammation induced by bacterial infections. Li et al showed that epithelial cells infected with Staphylococcus aureus secrete cytokines that can induce migration of MSC via nuclear factor-kappa B (NF-κB)dependent signaling [88]. Also the route of administration may play an important role: rats with experimental trinitrobenzene sulfonic acid (TNBS) induced colitis were intravenously or

intraperitoneally injected with Tc-99m labeled MSC. As expected, intravenously injected cells accumulated in the lungs, liver, kidneys and bladder of rats, whereas intraperitoneally administered MSC accumulated in the lamina propria, submucosa and muscular layers of the colon. Intraperitoneally injected MSC reduced endoscopic and histopathological severity of colitis [89]. However, other studies show that systemically infused MSC could also home to the inflamed colon and effectively ameliorate colitis. Chen and colleagues showed effective migration of GFP-labeled MSC towards the colon of TNBS-treated mice [90]. Liang and colleagues showed migration of human umbilical cord blood derived-MSC to the inflamed colon after systemic infusion into mice [91]. The CXCR4/CXCL12 axis plays an important role in MSC migration. It was shown that levels of CXCR4 and CXCL12 are up-regulated in patients with inflammatory bowel disease [92]. Lentiviral over-expression of CXCR4 in MSC resulted in enhanced homing to the inflamed colon and amelioration of disease severity in TNBS-treated rats [93]. Also pretreatment of MSC with interferon-gamma was found to increase homing and therapeutic efficacy in TNBS-induced colitis in mice compared to unstimulated MSC [94]. Finally, due to the low engraftment potential of MSC to the intestines, it has been suggested that their therapeutic effect is at least partially endocrine/paracrine. Conditioned MSC media that was generated under hypoxic conditions contained gut pleiotropic factors and promoted intestinal repair [95]. Although homing to the intestines may thus not be required for the therapeutic effect of MSC, boosting MSC migration into the tissue may further support these therapies as it will lead to higher local concentrations of the mediating factors.

6. MSC migration towards the heart Recruitment of MSC towards the heart could be important for enhancing tissue repair after myocardial infarction. It was already shown that intravenously infused MSC are safe and efficacious in treatment of myocardial infarctions [96]. There are also clinical trials in

which MSC were administered intracoronary [97,98] or intramyocardially [97]. However in many trials homing and engraftment of MSC into the heart was not studied. In a study from Assis in which they administered 99mTc-HMPAO labeled MSC to rats more MSC were detected in the myocardium of infarcted hearts compared to unaffected hearts. Seven days after injection MSC were still detectable but only in infarcted regions of the heart [99]. Freymann and colleagues injected MSC into swines with myorcardial infarction either intravenously, intracoronary or endocardially. Only 6% of the intracoronary infused MSC (and less for the other infusion methods) persisted in the heart two weeks after infusion [100]. Many studies were performed aiming to improve homing of MSC towards the heart. Remote ischemic postconditioning (RIPostC) (cycles of occlusion and reperfusion) can also enhance retention of infused cells in the myocardium. In a study from Jiang and colleagues male rat MSC were intravenously infused in female rats with myocardial infarction after RIPostC. RIPostC increased CXCL12α levels and significantly increased the MSC retention in the myocardium. Administration of a CRCR4 blocking antibody attenuated this enhancement suggesting that the CXCR4-CXCL12 axis may play an important role in MSC homing to the infarcted myocardium [101]. A possible explanation of the impaired migration comes from an in vitro study from Vogel et al in which they found that activated platelets inhibit recruitment of MSC to apoptotic cardiac myocytes and fibroblasts [102]. Because of the low retention rates it has been suggested that mainly soluble factors secreted by MSC are involved in cardiac repair [103,104]. A new emerging concept in the MSC field are extracellular vesicles (EVs) that contain RNAs and proteins [105–107]. Fractionation studies of conditioned MSC media revealed that EVs are a component of this conditioned media and have a cardioprotective role [106,107]. It will be important to determine the molecular mechanism by which EVs exert their protective effect in the heart,

but also in other organs, and to what extent this relates to the function of the MSC themselves.

7. MSC migration towards tumors A tumor microenvironment has many characteristics of a persistent wound. Cytokines and other factors released by tumor cells or the microenvironment are potent attractors for many cells types, including MSC. The main factors found to be secreted are IFN-γ, TNF-α, IL-6, IL-8, TGF-β, HGF, PDGF, VEGF and CXCL12 [108]. Many groups have shown that MSC can migrate to various types of tumors, such as gliomas [109], multiple myeloma [110], hepatocellular carcinomas [111], breast cancers [112], colon carcinomas [113], ovarian cancers [114] and lung carcinomas [115]. This is both important and complex as MSC can have pro- as well as anti-tumor properties [116]. MSC can have anti-tumor properties in several types of cancers [117–119]. When infusing MSC into mice, reduced lymphoma, melanoma and breast cancer growth could be observed, as well as a reduction of metastasis [118–120]. Potential working mechanisms of these anti-tumor effects of MSC are MSC-mediated down regulation of the Wnt/β-catenin signaling pathway or down regulation of the Akt pathway [121,122]. To further employ the anti-tumor effects of MSC, several studies with genetically engineered MSC were performed in animal models. Different approaches were used to reduce tumor growth and invasion. For example immunostimulatory molecules (IFN-α [123], IFN-γ [124]), anti-angiogenic molecules (IFN-α [123]), agents that active CTLs and NK cells (CX3CL1 [115], IL-12 [125]) and apoptosis inducing molecules (TRAIL [126], IFN-α [123]) were introduced into MSC. A novel approach by Sun and colleagues selectively targets glioma cells by delivery of the immunotoxin EphrinA1-PE38 by MSC. Glioma cells overexpress the EphA2 receptor and binding of EphrinA1-PE38 to this receptor leads to inhibition of tumor growth [127].

In contrast, others have shown that MSC also can exhibit pro-tumor effects such as inhibition of tumor apoptosis [128], stimulation of angiogenesis [129] increasing tumor cell proliferation [130], immune response suppression [131], stimulation of epithelial-tomesenchymal transition [132] and metastasis of tumor cells [112]. MSCs can also differentiate into supportive stromal cells [133]. Quante and colleagues showed that around 20% of the carcinoma-associated fibroblasts, cells that contribute to tumor progression, originate from cells from the bone marrow in a mouse model of gastric cancer [133].

The main conclusion is that MSC can promote and/or inhibit tumor growth and invasion. One should therefore be really careful using MSC for the treatment of patients with malignancies. Migration of MSC towards tumors is not a very efficient process as a lot of MSC do not reach their target site [18,134]. However, actual entry of MSC into the tumors may not be required, as paracrine signaling from MSC can affect tumors even without MSC tumor engraftment [131]. Moreover, genetically engineered MSC can also end up in other parts of the body where they cause undesired effects: IL-6 secreted from senescent MSC was found to promote proliferation and migration of breast cancer cells, instead of reducing tumor growth [135]. Next to the role of soluble mediators, there may also be a role for MSCderived exosomes on tumor growth, though this remains controversial, as both inhibitory and enhancing effects have been reported [136,137]. Finally, discrepancies between in vitro and in vivo work have also been described. An example is a study by Tian and colleagues in which the effect of MSC on a lung cancer cell line (A549) was investigated. The in vitro results showed inhibition of proliferation and invasion, and promotion of apoptosis of tumor cells by MSC. Surprisingly, when MSC were injected into mice, increased tumor growth and vessel formation was observed [138]. Further research to unravel the potential dual role of (subsets of) MSC is needed before safely applying MSC therapy to patients with malignancies.

8. MSC migration towards other organs Besides the aforementioned organs, MSC migration to liver, kidney, brain, lung and skin has also been described. In an acute kidney injury model in mice very low MSC migration rates were observed after intravenous injection. Overexpression of chemokine receptors CXCR4 or CXCR7 on MSC did not improve migration of MSC towards injured kidneys. Besides poor engraftment, MSC were unable to ameliorate kidney injury [139]. In contrast, in a rat model of acute kidney injury, intravenously injected MSC homed to the injured kidneys and induced a reduction of histological damage [140]. Interestingly, in a recent study, labeled MSC-derived EVs were injected into mice with kidney failure and were recruited towards the damaged kidneys [141]. Whether EVs improved kidney function was not described in this study, though there is supporting evidence that MSC-derived EVs can ameliorate kidney injury [142–144]. In a study from Li and colleagues it was shown that MSC exhibited a greater homing capability to the injured liver than HSC in mice. Also fibrosis and inflammation were more effectively modulated by MSC compared to HSC [145]. However, besides hepatocellular differentiation, MSC can also cause liver fibrosis by transdifferentiation into myofibroblasts that contributed to scar formation in injured livers [146–148]. To further improve MSC homing to fibrotic livers in mice, pretreatment of MSC with IL-6 resulted in increased homing and reduced fibrosis and apoptosis compared to the control situation without pre-treatment [149]. In a mouse model of chronic asthma MSC were intravenously administered. One week after administration a significant amount MSC were observed in the lungs of asthmatic mice whereas low numbers were detected in healthy control mice. Two weeks after infusion histopathological changes associated with asthma were ameliorated compared to asthmatic mice without MSC treatment [150]. Finally, MSC migration to skin and brain has also been investigated, which has been extensively reviewed elsewhere [151,152].

9. Conclusions/discussion Due to their immunomodulatory and multilineage differentiation potential, MSC are considered as promising cells for cellular therapies and tissue engineering. The mechanisms underlying these processes are not yet fully understood. MSC are present in virtually all post-natal organs and tissues [2]. One could argue that recruitment of MSC via the bloodstream is unnecessary because of the regenerative and immunomodulatory effects of local MSC which may explain low migration rates [33]. When comparing different studies using exogenously delivered MSC, there is a tendency that the efficiency of MSC migration increases in the case of tissue damage or inflammatory conditions [44,99]. However, others claim that MSC do not migrate towards injured areas but act from a distance and are short lived after infusion [69]. Differences observed in migration might be explained by different levels of tissue damage and/or inflammation. Without injury or inflammation MSC are less likely to migrate to specific organs as MSC strongly respond to inflammatory and chemotactic stimuli released from injured or inflamed areas [114,153]. Contradictory, a very recent study showed that the degree of inflammation was not correlated with the persistence and survival of MSC in a mouse model of arthritis [154]. After reviewing many studies we were unable to find a correlation between MSC that actually migrated towards their destination and a favorable clinical outcome. A lot of studies reported clinical improvement despite no or very low long-term engraftment of MSC [25,146]. Whether MSC, their paracrine factors or their EVs are the main players in tissue repair and homeostasis is still unknown. Increasing evidence is appearing suggesting a paracrine or EV-mediated effect of MSC [155,156]. Even if the effect is mainly paracrine or EV-mediated, migration of MSC itself may still play an important role. Paracrine factors or EV released in close proximity of injured areas or inflammation might be more likely to become involved in tissue repair and homeostasis.

More than a decade ago it was already shown that MSC lose their migratory capacity and chemokine receptors upon culturing [16,157]. However culturing is still necessary to obtain sufficient cell numbers for transplantation. Pre-treatment of MSC with cytokines can result in enhanced expression of homing receptors and genes known to be involved in migration [153,158]. This eventually can result in lower transplantation doses of MSC and therefore shorter expansion times. To improve homing, many studies with genetically modified MSC were performed to enhance migration. Some of them were successful [66] whereas others fail to increase migration [139]. To identify the molecular signature of migratory MSC, we previously performed a microarray analysis on migrated and nonmigrated MSC from fetal BM. Only a small set of genes was differentially expressed including NR4A1/Nur77 and NR4A2/Nurr1 (nuclear orphan receptors) [159]. Inducing Nur77 and Nurr1 expression could lead to increased migration. Besides focusing on chemokine receptors, one should also consider the inner migration machinery of MSC. Recent findings suggest that lamins might play a role in directional migration [160]. It was shown that nuclear lamin A/C deficiency results in impaired migration [161,162]. Also absence of lamin B1 results in spinning of cells rather than directed migration [163], a phenomenon that we also observed using live-imaging of MSC. Studying and manipulating lamin levels in MSC might give an indication of their migratory capacities and possibilities of improvement thereof. In conclusion, culture-expanded MSC are able to migrate towards target organs but migratory capacities are limited. The type of organ and degree of inflammation might play an important role. Also the contribution of engrafted MSC or systemic effects or MSC (paracrine factors, extracellular vesicles) are unclear. We anticipate that further unravelling and improving the organ and/or target directed migratory capacity of MSC will have far reaching implications for the application of MSC in clinical practice

Acknowledgements

ASC, CV and MAN are all supported by the Landsteiner Foundation for Blood Transfusion Research (LSBR Fellowships #1101 and #1014, respectively). For this review we were limited in the number of words and references we could use and given the breadth of the topics we discussed, we were obliged to make a selection of the papers that we would refer to. Hence, we apologize to those authors whom relevant work we did not refer to in this review.

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Table

Receptor

Ligand

Source of MSC

Migration towards?

Reference

CCR1

CCL5 CCL5 CCL7 CCL3 CCL5 CCL2 CCL5 CCL3 CCL17 CCL5 + CCL22 CCL5 CCL19 CCL19 + CCL21 CCL21 CCL19 + CCL21 CCL19 CCL25 CCL25 CCL28 CXCL8 CXCL8 CXCL8 CXCL1 + CXCL2 CXCL12 CXCR12

Human bone marrow Human bone marrow Mouse MSC Human bone marrow Human bone marrow Human bone marrow Human bone marrow Rat MSC Human bone marrow Human bone marrow Human bone marrow Human bone marrow Human bone marrow Mouse MSC Human bone marrow Rat MSC Human bone marrow Mouse MSC Human bone marrow Human umbilical cord Human bone marrow Human bone marrow Mouse MSC Human bone marrow Human bone marrow, human adipose tissue, fetal bone marrow, fetal lung Mouse MSC Human bone marrow Mouse MSC Human bone marrow Rat MSC Human bone marrow + Cord Blood Rat MSC Human bone marrow

In vitro migration assay In vitro migration assay Myocardium In vitro migration assay In vitro migration assay Injured heart In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay Secondary lymphoid organs In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay towards liver-injury mouse serum In vitro migration assay In vitro migration assay towards glioma cells In vitro migration assay In vitro migration assay Myocardium In vitro migration assay In vitro migration assay

[157] [77] [164] [81] [153] [165] [153] [166] [77] [153] [153] [157] [77] [82] [81] [167] [157] [60] [77] [168] [169] [169] [164] [157] [23]

In vitro migration assay + In vivo bone marow In vitro migration assay towards pancreatic island supernatants Bone fracture In vitro migration assay In vitro migration assay In vitro migration assay Pancreas In vitro migration assay

[45] [81] [170] [171] [166] [172] [173] [43]

CCR2 CCR3 CCR4 CCR5 CCR7

CCR9 CCR10 CXCR1 CXCR2 CXCR4

CXCR12 CXCL12 CXCL12 CXCL12 CXCL12 CXCL12 CXCL12 CXCL12

CXCR5 CXCR6

CX3CR1

CXCL12 CXCL12 CXCL12 CXCL13 CXCL13 CXCL16 CXCL16 CXCL16 CX3CL1

Mouse MSC Human bone marrow Human bone marrow + placenta Human bone marrow Human bone marrow Human bone marrow Human bone marrow Human MSC + mouse MSC Human bone marrow

In vitro migration assay towards liver-injury mouse serum Transwell In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay In vitro migration assay Prostate tumours In vitro migration assay towards pancreatic island supernatants

[60] [153] [80] [157] [77] [157] [81] [174] [81]

Figure

Figure 1

Bone Marrow

Adipose Tissue

Cord Blood

MSCs

Bone Marrow

Bone

Spleen & LNs

Heart

Irradiation Chemotherapy Inflammation

Intestine

Tumor

Other organs