Several types of major surgeries are impacted by ischemia–reperfusion injury (IRI). Particularly during organ transplantation, it is an unavoidable event that contributes to early graft dysfunction and enhanced graft immunogenicity. Better comprehension of the fundamental molecular and immunological mechanisms underlying this complex type of injury could help to find innovative starting points for therapeutic interventions.
Preventive therapies might include ischemic conditioning involving short, nonlethal episodes of ischemia , several metabolic intervention options [2,3], therapeutic gas application , modulation of nucleotide signaling [5,6▪▪] or microRNA application . Targeting innate and adaptive immune activation by inhibiting Toll-like receptor (TLR) signaling , complement activation  or inducing the recruitment of regulatory T cells  might promote the therapeutic effects against IRI. Moreover, therapeutic concepts for the treatment of transplant recipients include induction of vasodilation, inhibition of the inflammatory cascade and of course, allograft suppression [11▪].
On the basis of the published in-vitro data on immunosuppressive and immunomodulatory functions of mesenchymal stromal cells (MSCs) as well as their potential to support tissue repair by proangiogenic and antifibrotic action [12▪], the application of MSCs for IRI treatment was investigated. In particular, the tissue repair functions of MSCs could act to dampen the inflammation process and promote vascular supply during ischemia and reperfusion. A large number of experimental data describe the protective efficacy of these cells in the models of acute kidney injury (AKI) by reducing apoptosis and increasing proliferation of tubular cells [13▪▪,14,15]. Tendencies toward protection against prolonged cold ischemia after kidney transplantation were established as well [16▪]. MSCs were also successfully tested in other organ systems such as liver [17,18], lungs  heart  and intestines .
In this review, we will outline the key mechanisms of IRI and its impact on graft failure. Moreover, we will summarize the recently published preclinical and clinical results investigating the treatment of IRI with MSCs or MSC-derived products.
ISCHEMIA–REPERFUSION INJURY IN TRANSPLANTATION
The challenges of IRI are inseparable from organ transplantation. The disruption of the blood supply to the organ during harvesting causes an imbalanced metabolic supply and microvascular dysfunction known as the initial ischemic phase. When the blood supply is subsequently restored, the sudden perfusion and oxygenation paradoxically increases the organ damage by triggering innate and adaptive immune responses [6▪▪].
Key mechanisms of ischemia–reperfusion injury
Despite the differences described between warm and cold ischemic damage , consistent pathophysiological features of IRI could be specified as impairment of the endothelial barrier and metabolic disturbances [decreases in cAMP and adenosine triphosphate (ATP)]; induction of cell death programs; transcriptional reprogramming; the no-reflow phenomenon; induction of autoimmune processes and the innate and adaptive immune mechanisms [6▪▪,11▪,23▪]. The ‘sterile inflammation’, that is especially predominant within the reperfusion phase, is mainly characterized by the release of intracellular (e.g. HGMB-1 or ATP) and extracellular (e.g. adenosine) danger-associated molecular pattern (DAMP) molecules and enhanced accumulation of inflammatory cells (monocytes, dendritic cells and granulocytes), but also involves activation of the complement system [24–26]. DAMPs are then able to activate innate immune responses via TLRs [27,28]. Reactive oxygen species (ROS) and the acidotic milieu cause phospholipolysis, endothelial membrane injury and formation of thrombin-mediated fibrin deposits [11▪,29▪]. ROS in combination with excessive nitric oxide are able to induce DNA damage and activate poly ADP-ribose polymerase (PARP) and various types of cell death pathways [29▪].
The innate immune mechanisms described are closely linked to adaptive responses by activation of naive T cells via the presentation of antigens by dendritic cells. Whether antigen-nonspecific T-cell activation is also involved and whether regulatory T cells influence the balance of immune reactions is not yet clear [30,31]. In addition, tissue injuries after IRI might be worsened by intense platelet aggregation via integrin-meditated endothelial interactions  or transport across epithelia  causing thrombotic occlusions. Platelets might also contribute to the injury by releasing proinflammatory factors [34,35]. Ischemia–reperfusion damage might be especially critical in lung transplantation, as there is a dual blood supply system and available oxygen from alveolar ventilation [36▪].
Impact of ischemia–reperfusion injury on acute graft failure
It is well accepted that IRI of the transplanted organ strongly influences graft function and survival as a nonallogeneic factor . Acute graft failure causes early mortality and morbidity.
Ischemic damage of the transplanted organ especially by extended cold ischemic time was shown to enhance graft immunogenicity by increased expression of adhesion molecules, heat shock proteins, chemokines and immunoproteasomes . In a rat model, it was recently shown that upregulation of the heat shock protein Hsp70 directly correlated to an upregulation of MHC class I and ICAM-1 [39▪▪]. Consequently, the survival of kidney transplant patients immediately receiving organs from living donors is better than from brain-dead or deceased donors where cold storage and transport are often required . There is clear experimental evidence that brain-death donated kidneys might locally upregulate C3 factor as well as TLR4 and its ligands thereby triggering enhanced organ injury [41▪].
In kidney transplantation, AKI often progresses to a clinical diagnosis of delayed graft function (DGF), characterized by an increase in creatinine levels within 48 h of an inciting event [42,43]. Ischemic damage of the transplanted organ and the reperfusion injury upon transplantation into the recipient both contribute to DGF development [11▪]. As a long-term effect of IRI and DGF, typical signs of chronic transplant dysfunction might develop [44,45]. Interestingly, transplanted livers from cadavers in which the primary cause of death was heart failure suffer from a higher degree of ischemic damage and lead to increased renal pathogenesis as well . Similar processes are known from lung transplants in which the symptoms of acute graft failure occur within 72 h after transplantation and include pulmonary edema, increased pulmonary artery pressure, decreased lung compliance and impaired gas exchange .
MESENCHYMAL STROMAL CELLS FOR THE TREATMENT OF ISCHEMIA–REPERFUSION INJURY
Because of their anti-inflammatory, tissue repair and immunomodulatory features, MSCs were tested in various experimental animal models of IRI and also in initial clinical trials. The following paragraphs present a short overview of potential MSCs modes of action and their application against IRI in kidney, heart and lung.
Hypothetical modes of action by mesenchymal stromal cells in ischemia–reperfusion injury
Intravenously administrated MSCs were shown to home to ischemic tubular sites and could be detected within the first hour after cell infusion [48,49]. Cell recruitment is thought to be caused by migration toward an SDF-1 gradient and adhesion to different molecules generated and expressed by the injured and hypoxic tissue [49,50,51▪]. Cell-fate and cell-tracking studies revealed that exogenously administrated MSCs are transiently present at the injury site before clearance from the circulation [52▪]. Very recent data by Eggenhofer et al. demonstrated that MSCs applied by intravenous injection in a liver IRI model are shortlived and do not migrate into the target organ. Therefore, the exact process of MSC migration and recruitment is still under debate [54▪]. Liu et al.[51▪] could show that hypoxia preconditioning of MSCs enhances their recruitment into the injured organ via an SDF-1/CXCR4- and CXCR7-dependent pathway. Recently, it was also indicated that MSCs are able to actively transmigrate into inflamed tissue across TNF-α-activated endothelium and become partially integrated in the endothelial layer [55▪▪]. Engraftment rates of intravenously administrated MSCs vary depending on the organ examined. At least in AKI or acute myocardial infarction, direct replacement of damaged tissue by transdifferentiated MSC-derived cells seems to be a rather limited phenomenon. Consequently, MSCs were shown to physically participate only at low frequency in regeneration of the target tissue [50,56–58]. These observations suggest that MSC-associated beneficial effects in IRI are mediated mostly through paracrine and endocrine modes of action.
MSCs act at different levels of the IRI process and thereby support repair processes required for regeneration of damaged tissue (Fig. 1). By releasing growth factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), hepatocyte growth factor (HGF), keratinocyte growth factor (KGF), monocyte chemoattractant protein-1 (MCP-1), stromal cell-derived factor-1 (SDF-1) and fibroblast growth factor (FGF), MSCs stimulate endogenous cellular repair programs, including stimulation of proliferation and angiogenesis [59–64]. In an inflammatory environment, MSCs were reported to be ‘licensed’ to further modulate or alter inflammatory responses. Furthermore, MSCs may release mediators such as IL-10, IL-6, TGF-β, prostaglandin E2 (PGE2), NO and IDO and thereby locally generate an anti-inflammatory proreparative cellular state [65,66]. In addition to various other immunomodulatory actions , MSCs have been reported to induce regulatory T-cell expansion [68,69] which could influence allograft rejection and might provide additional support against IRI damage. Recently, it was shown that MSC treatment promotes macrophages to shift toward the anti-inflammatory M2 phenotype, characterized by the expression of a mannose receptor (CD206) and distinct cytokine profile consisting of high levels of IL-10 and IL-6, and low levels of IL-12 and TNF-α [70,71,72▪].
Furthermore, MSC-derived microvesicles (MSC-MVs) are reported to contribute to the observed regenerative effects of MSCs in IRI by transferring RNA and providing ATP through mitochondrial transfer to ischemic tissue [73,74▪,75▪▪,76]. As restoration of ATP supply in damaged cells represents an essential step in the repair process of ischemic tissues, energy transfer mediated by MSC-MVs could explain the beneficial effects of MSCs measured in the early phase of IRI (Fig. 1). Moreover, Bruno et al.[74▪] could demonstrate that MSC-MVs induce prosurvival genes (Bcl-xL, Bcl2 and BIRC8) and downregulate proapoptotic genes like Casp1, Casp8 and LTA.
Effects in preclinical models of ischemia-induced acute injuries
Several animal models of IRI demonstrate beneficial effects following MSC administration or administration of MSC derivatives such as microvesicles or conditioned media. Here, we review the current data from selected preclinical studies using MSCs for the treatment of IRI in kidney, heart and lung (Table 1).
Mesenchymal stromal cells application: Infusion of exogenous MSCs to treat acute renal injury was reported some years ago to result in accelerated tubular repair and improved kidney function. Clamping of the renal pedicles in a rat model and subsequent intra-aortic treatment with MSCs could ameliorate organ function and resulted in fewer apoptotic events compared to vehicle-treated controls . Recently, MSCs were also shown to stimulate tubular cell proliferation, reduce acute tubular necrosis and suppress oxidative stress and proinflammatory responses [77,79,82] or hinder the progression of fibrosis [15,88]. Renal protective efficacy could be further enhanced by human cord-derived MSCs expressing HGF in a rat IRI model  or BMP-7-trancduced MSCs in a rabbit model , and other groups have attempted to enhance MSCs by other means [51▪,81,84,85]. Surprisingly, no protective effects were seen after MSCs application in a porcine AKI model [78▪]. Initial promising results using MSCs in rat kidney transplantation studies were able to demonstrate reduced signs of inflammation induced by prolonged cold ischemia in the early phase of acute allograft rejection [16▪] or even long-term beneficial effects in a model of chronic allograft nephropathy . However, positive effects on graft survival and function in a rat acute kidney allograft rejection model were missing .
Various preclinical studies of ischemic heart disease are accumulating evidence for MSC therapeutic effects including reduced infarct size, improved cardiac function and increased angiogenesis [63,64,90,97]. Further studies using genetically manipulated or preconditioned MSCs were able to improve the cytoprotective effect [89,92–94,98].
In models of endotoxin-induced acute lung injury, infusion of MSCs resulted in significantly decreased levels of proinflammatory cytokines, increased levels of anti-inflammatory cytokines and improved survival rates [95,99–102]. The use of MSCs for the delivery of viral IL-10 in a rat model of lung IRI was shown to reduce the signs of injury with lowered proportions of apoptotic cells and immune cell infiltration [103▪].
Application of mesenchymal stromal cell derivatives: Recent studies have shown that conditioned media, containing factors and microvesicles released by MSCs, was protective in rat models of AKI . Intravenous treatment with MSC-conditioned media (CM) after myocardial infarction increased capillary density and supported cardiac function . Data obtained from the studies in pigs with intracoronary injection of concentrated MSC-CM could demonstrate early protection of ischemic myocardium, reduced infarct size and improved cardiac repair [104▪,105]. Other studies using MSC-MVs in a model of renal IRI could show significant inhibition of apoptosis coupled with the stimulation of tubular epithelial cell proliferation . In an acute lung injury model, administration of MSC-MVs was reported to protect injured cells through mitochondrial transfer, though perhaps other mechanisms are possible [75▪▪].
Mesenchymal stromal cells in clinical trials against ischemia–reperfusion injury
Clinical trials using allogeneic or autologous MSC-based approaches for the regeneration of IRI and associated tissue damage have been initiated. Moreover, the first phase I and II trials involving MSCs, mainly from bone marrow but also from other tissues, have been completed (www.clinicaltrials.gov). So far, no major adverse effects have been reported using MSC-based cell therapies in these clinical trials. Ongoing studies are addressing essential questions concerning the delivery technique, the cell number and frequency of MSC administration required for well tolerated and effective use in future clinical applications. In this section, we present selected recent clinical trials testing the impact of MSC-based therapies for the regeneration of ischemic kidney, heart and lung diseases (Table 2).
An increasing number of clinical studies are entering clinical trial phase I–III in order to explore the therapeutic effects of MSCs in diverse clinical conditions. For ischemic cardiovascular and renal diseases, different delivery routes are currently under investigation (#NCT00733876, #NCT01429038, #NCT01291329 and #NCT00587990). Various dose-escalating studies will further apply therapeutically relevant MSC amounts (#NCT00733876 and #NCT00893360) against IRI.
Regarding the field of solid-organ transplantation, one phase II clinical trial has been finished (#NCT00658073) which tested whether patients undergoing renal transplantation could be treated with an autologous MSC-based cell therapy instead of the traditional anti-IL-2 receptor antibody induction therapy. The MSC treatment resulted in lower incidences of acute rejection and decreased risk of opportunistic infection compared to antibody induction therapy . A phase I randomized dose-escalation study testing allogeneic MSCs for the treatment of myocardial infarction (#NCT00114452) ameliorated pulmonary and left ventricular function and improved regularity of cardiac rhythm without causing adverse effects . Recently, a phase II clinical trial investigating human Wharton's jelly-derived MSCs on cardiac regeneration (#NCT01291329) was concluded. This study tested whether intracoronary injection of MSCs efficiently improved cardiac regeneration in patients with acute myocardial infarction. Other combined phase I/II clinical trials using intra-myocardial administration of autologous bone marrow MSCs to treat patients with either severe chronic myocardial ischemia or with chronic ischemic ventricular dysfunction secondary to myocardial infarction (#NCT00587990 and #NCT00260338) have also been completed. More insight into the therapeutic potential of MSCs should be obtained once the complete results of these trials are published.
Several experimental animal models of IRI in kidney, heart and lung indicate the benefits of MSCs against warm or cold ischemia for both acute and chronic damage at different phases of IRI. MSC effects appear mainly mediated by the paracrine and endocrine factors acting on inflammation and apoptosis to improve organ function, but may also involve immunomodulation. Protection against IRI damage with MSC treatment might reduce graft immunogenicity, thereby supporting improved graft function and survival. Better characterization of the specific mechanisms involved could help to improve the treatment regimens in clinical studies and indicate useful biomarkers to monitor MSC treatment efficacy.
Conflicts of interest
There are no conflicts of interest.
N.S. receives a scholarship from the Berlin-Brandenburg School for Regenerative Therapies (BSRT) funded by the German Research Foundation.
Disclosure: The authors have nothing to declare.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 115).
1. Eckle T, Kohler D, Lehmann R, et al. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 2008; 118:166–175.
2. Bernard A, Meier C, Ward M, et al. Packed red blood cells suppress T-cell proliferation through a process involving cell–cell contact. J Trauma 2010; 69:320–329.
3. Najjar SS, Rao SV, Melloni C, et al. Intravenous erythropoietin in patients with ST-segment elevation myocardial infarction: REVEAL: a randomized controlled trial. JAMA 2011; 305:1863–1872.
4. Siriussawakul A, Chen LI, Lang JD. Medical gases: a novel strategy for attenuating ischemia
injury in organ transplantation? J Transplant 2012; 2012:819382.
5. Eltzschig HK. Adenosine: an old drug newly discovered. Anesthesiology 2009; 111:904–915.
6▪▪. Eltzschig HK, Eckle T. Ischemia
– from mechanism to translation. Nat Med 2011; 17:1391–1401.
This excellent review clearly describes the key mechanisms of ischemia–reperfusion injury and derived therapeutic approaches to enhance ischemic tolerance.
7. Qian L, Van Laake LW, Huang Y, et al. miR-24 inhibits apoptosis and represses Bim in mouse cardiomyocytes. J Exp Med 2011; 208:549–560.
8. Kanzler H, Barrat FJ, Hessel EM, et al. Therapeutic targeting of innate immunity with Toll-like receptor agonists and antagonists. Nat Med 2007; 13:552–559.
9. Diepenhorst GM, van Gulik TM, Hack CE. Complement-mediated ischemia
injury: lessons learned from animal and clinical studies. Ann Surg 2009; 249:889–899.
10. Liesz A, Suri-Payer E, Veltkamp C, et al. Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 2009; 15:192–199.
11▪. Siedlecki A, Irish W, Brennan DC. Delayed graft function in the kidney transplant. Am J Transplant 2011; 11:2279–2296.
This review highlights the pathologic contributions from both donors and recipients in the development of delayed graft function in kidney transplants.
12▪. Singer NG, Caplan AI. Mesenchymal stem cells: mechanisms of inflammation
. Annu Rev Pathol 2011; 6:457–478.
The authors provide a comprehensive overview on mesenchymal stem cells in this review, including their immunomodulatory and tissue repair functions as well as a summary of ongoing clinical trials.
13▪▪. Togel FE, Westenfelder C. Mesenchymal stem cells: a new therapeutic tool for AKI. Nat Rev Nephrol 2010; 6:179–183.
In this study, preclinical and clinical data are discussed which indicate the potential of mesenchymal stem cells as a new therapeutic tool for acute kidney injury.
14. Morigi M, Rota C, Montemurro T, et al. Life-sparing effect of human cord blood–mesenchymal stem cells in experimental acute kidney injury. Stem Cells 2010; 28:513–522.
15. Donizetti-Oliveira C, Semedo P, Burgos-Silva MT, et al. Adipose tissue-derived stem cell treatment prevents renal disease progression. Cell Transplant 2012; 21:1727–1741.
16▪. Hara Y, Stolk M, Ringe J, et al. In vivo effect of bone marrow-derived mesenchymal stem cells in a rat kidney transplantation model with prolonged cold ischemia
. Transpl Int 2011; 24:1112–1123.
In this rat kidney transplantation model, the beneficial effects of MSCs on prolonged cold ischemia are described for the first time.
17. Kanazawa H, Fujimoto Y, Teratani T, et al. Bone marrow-derived mesenchymal stem cells ameliorate hepatic ischemia reperfusion
injury in a rat model. PLoS One 2011; 6:e19195.
18. Sun CK, Chang CL, Lin YC, et al. Systemic administration of autologous adipose-derived mesenchymal stem cells alleviates hepatic ischemia
injury in rats. Crit Care Med 2012; 40:1279–1290.
19. Chen S, Chen L, Wu X, et al. Ischemia
postconditioning and mesenchymal stem cells engraftment synergistically attenuate ischemia reperfusion
-induced lung injury in rats. J Surg Res 2012; 178:81–91.
20. Fang J, Chen L, Fan L, et al. Enhanced therapeutic effects of mesenchymal stem cells on myocardial infarction by ischemic postconditioning through paracrine mechanisms in rats. J Mol Cell Cardiol 2011; 51:839–847.
21. Yandza T, Tauc M, Saint-Paul MC, et al.
The pig as a preclinical model for intestinal ischemia
and transplantation studies. J Surg Res 2012 [Epub ahead of print]. doi:10.1016/j.ss.2012.07.025
22. Zhai Y, Busuttil RW, Kupiec-Weglinski JW. Liver ischemia
injury: new insights into mechanisms of innate-adaptive immune-mediated tissue inflammation
. Am J Transplant 2011; 11:1563–1569.
23▪. Frank A, Bonney M, Bonney S, et al. Myocardial ischemia reperfusion
injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 2012; 16:123–132.
The review describes the most recent experimental results for the treatment of myocardial ischemia–reperfusion injury.
24. Rock KL, Latz E, Ontiveros F, et al. The sterile inflammatory response. Annu Rev Immunol 2010; 28:321–342.
25. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010; 11:785–797.
26. Atkinson C, He S, Morris K, et al. Targeted complement inhibitors protect against posttransplant cardiac ischemia
injury and reveal an important role for the alternative pathway of complement activation. J Immunol 2010; 185:7007–7013.
27. McKay DB. The role of innate immunity in donor organ procurement. Semin Immunopathol 2011; 33:169–184.
28. Leventhal JS, Schroppel B. Toll-like receptors in transplantation: sensing and reacting to injury. Kidney Int 2012; 81:826–832.
29▪. De Vries DK, Schaapherder AF, Reinders ME. Mesenchymal stromal cells
in renal ischemia
injury. Front Immunol 2012; 3:162.
This review highlights the application of mesenchymal stem cells in renal ischemia–reperfusion injury, including possible challenges with this approach.
30. Satpute SR, Park JM, Jang HR, et al. The role for T cell repertoire/antigen-specific interactions in experimental kidney ischemia reperfusion
injury. J Immunol 2009; 183:984–992.
31. Nadig SN, Wieckiewicz J, Wu DC, et al. In vivo prevention of transplant arteriosclerosis by ex vivo-expanded human regulatory T cells. Nat Med 2010; 16:809–813.
32. Moser M, Nieswandt B, Ussar S, et al. Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med 2008; 14:325–330.
33. Weissmuller T, Campbell EL, Rosenberger P, et al. PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases. J Clin Invest 2008; 118:3682–3692.
34. Muller F, Mutch NJ, Schenk WA, et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139:1143–1156.
35. Lisman T, Porte RJ. The role of platelets in liver inflammation
and regeneration. Semin Thromb Hemost 2010; 36:170–174.
36▪. Den Hengst WA, Gielis JF, Lin JY, et al. Lung ischemia
injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol Heart Circ Physiol 2010; 299:H1283–H1299.
The authors present a clinical view on the pathophysiological process of ischemia–reperfusion injury in the lung in a clear and comprehensive style.
37. Martins PN, Chandraker A, Tullius SG. Modifying graft immunogenicity and immune response prior to transplantation: potential clinical applications of donor and graft treatment. Transpl Int 2006; 19:351–359.
38. Kotsch K, Martins PN, Klemz R, et al. Heme oxygenase-1 ameliorates ischemia
injury by targeting dendritic cell maturation and migration. Antioxid Redox Signal 2007; 9:2049–2063.
39▪▪. Bidmon B, Kratochwill K, Rusai K, et al. Increased immunogenicity is an integral part of the heat shock response following renal ischemia
. Cell Stress Chaperones 2012; 17:385–397.
In this study, it was shown by in-vitro and in-vivo experiments in a rat model that the upregulation of renal immunogenicity is an integral part of the heat shock response.
40. Terasaki PI, Cecka JM, Gjertson DW, et al. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med 1995; 333:333–336.
41▪. Damman J, Daha MR, van Son WJ, et al. Crosstalk between complement and Toll-like receptor activation in relation to donor brain death and renal ischemia
injury. Am J Transplant 2011; 11:660–669.
In this mini-review, the authors discuss the recent findings on the crosstalk between complement and TLR signaling pathways, and their roles in renal graft outcome.
42. Perico N, Cattaneo D, Sayegh MH, et al. Delayed graft function in kidney transplantation. Lancet 2004; 364:1814–1827.
43. Yarlagadda SG, Coca SG, Formica RN Jr, et al. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 2009; 24:1039–1047.
44. Zheng Q, Liu S, Song Z. Mechanism of arterial remodeling in chronic allograft vasculopathy. Front Med 2011; 5:248–253.
45. Nankivell BJ, Kuypers DR. Diagnosis and prevention of chronic kidney allograft loss. Lancet 2011; 378:1428–1437.
46. Leithead JA, Tariciotti L, Gunson B, et al. Donation after cardiac death liver transplant recipients have an increased frequency of acute kidney injury. Am J Transplant 2012; 12:965–975.
47. Van der Kaaij NP, Kluin J, Haitsma JJ, et al. Surfactant pretreatment decreases long-term damage after ischemia
injury of the lung. Eur J Cardiothorac Surg 2009; 35:304–312.
48. Burst VR, Gillis M, Putsch F, et al. Poor cell survival limits the beneficial impact of mesenchymal stem cell transplantation on acute kidney injury. Nephron Exp Nephrol 2010; 114:e107–e116.
49. Togel F, Hu Z, Weiss K, et al. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol 2005; 289:F31–F42.
50. Herrera MB, Bussolati B, Bruno S, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int 2007; 72:430–441.
51▪. Liu H, Liu S, Li Y, et al. The role of SDF-1-CXCR4/CXCR7 axis in the therapeutic effects of hypoxia-preconditioned mesenchymal stem cells for renal ischemia
injury. PLoS One 2012; 7:e34608.
The authors indicate a target pathway (SDF-1-CXCR4/CXCR7) for improving the beneficial effects of MSC-based therapies for renal ischemia/reperfusion injury.
52▪. Togel FE, Westenfelder C. Kidney protection and regeneration following acute injury: progress through stem cell therapy
. Am J Kidney Dis 2012 [Epub ahead of print]. doi: 10.1053/j.ajkd.2012.08.034
This review emphasizes the important mechanisms by which MSCs may contribute to the regeneration of AKI.
53. Eggenhofer E, Benseler V, Kroemer A, et al. Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion. Front Immunol 2012; 3:297.
54▪. Ankrum J, Karp JM. Mesenchymal stem cell therapy
: two steps forward, one step back. Trends Mol Med 2010; 16:203–209.
This critical review highlights the clinical status of MSC therapies and discusses the importance of clarifying the mechanism of MSC-homing or MSC-migration for future effective MSC treatment.
55▪▪. Teo GS, Ankrum JA, Martinelli R, et al. Mesenchymal stem cells transmigrate between and directly through TNF-alpha-activated endothelial cells. Stem Cells 2012; 30:2472–2486.
In this research article, the authors describe different mechanisms of MSC transmigration toward inflamed tissue.
56. Freyman T, Polin G, Osman H, et al. A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. Eur Heart J 2006; 27:1114–1122.
57. Togel F, Weiss K, Yang Y, et al. Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury. Am J Physiol Renal Physiol 2007; 292:F1626–F1635.
58. Assis AC, Carvalho JL, Jacoby BA, et al. Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infarcted heart. Cell Transplant 2010; 19:219–230.
59. Togel F, Zhang P, Hu Z, et al. VEGF is a mediator of the renoprotective effects of multipotent marrow stromal cells in acute kidney injury. J Cell Mol Med 2009; 13:2109–2114.
60. Lee JW, Gupta N, Serikov V, et al. Potential application of mesenchymal stem cells in acute lung injury. Expert Opin Biol Ther 2009; 9:1259–1270.
61. Birukova AA, Zagranichnaya T, Fu P, et al. Prostaglandins PGE(2) and PGI(2) promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation. Exp Cell Res 2007; 313:2504–2520.
62. Fang X, Neyrinck AP, Matthay MA, et al. Allogeneic human mesenchymal stem cells restore epithelial protein permeability in cultured human alveolar type II cells by secretion of angiopoietin-1. J Biol Chem 2010; 285:26211–26222.
63. Poynter JA, Herrmann JL, Manukyan MC, et al. Intracoronary mesenchymal stem cells promote postischemic myocardial functional recovery, decrease inflammation
, and reduce apoptosis via a signal transducer and activator of transcription 3 mechanism. J Am Coll Surg 2011; 213:253–260.
64. Sato T, Iso Y, Uyama T, et al. Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization. Lab Invest 2011; 91:553–564.
65. Jarvinen L, Badri L, Wettlaufer S, et al. Lung resident mesenchymal stem cells isolated from human lung allografts inhibit T cell proliferation via a soluble mediator. J Immunol 2008; 181:4389–4396.
66. Imberti B, Morigi M, Tomasoni S, et al. Insulin-like growth factor-1 sustains stem cell mediated renal repair. J Am Soc Nephrol 2007; 18:2921–2928.
67. Roemeling-van Rhijn M, Weimar W, Hoogduijn MJ. Mesenchymal stem cells: application for solid-organ transplantation. Curr Opin Organ Transplant 2012; 17:55–62.
68. Casiraghi F, Azzollini N, Cassis P, et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 2008; 181:3933–3946.
69. Ge W, Jiang J, Baroja ML, et al. Infusion of mesenchymal stem cells and rapamycin synergize to attenuate alloimmune responses and promote cardiac allograft tolerance. Am J Transplant 2009; 9:1760–1772.
70. Kim J, Hematti P. Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. Exp Hematol 2009; 37:1445–1453.
71. Maggini J, Mirkin G, Bognanni I, et al. Mouse bone marrow-derived mesenchymal stromal cells
turn activated macrophages into a regulatory-like profile. PLoS One 2010; 5:e9252.
72▪. Wise AF, Ricardo SD. Mesenchymal stem cells in kidney inflammation
and repair. Nephrology (Carlton) 2012; 17:1–10.
This review provides important insights on how MSCs act in renal inflammation and promote cellular repair.
73. Collino F, Deregibus MC, Bruno S, et al. Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One 2010; 5:e11803.
74▪. Bruno S, Grange C, Collino F, et al. Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One 2012; 7:e33115.
In this article, the authors show that single or multiple injection of MSC-MVs to a different extent accelerate the functional recovery and improve the survival after induced AKI.
75▪▪. Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med 2012; 18:759–765.
This report provides the first evidence that MSCs are able to protect against ALI through mitochondrial transfer.
76. Bruno S, Grange C, Deregibus MC, et al. Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol 2009; 20:1053–1067.
77. Cao H, Qian H, Xu W, et al. Mesenchymal stem cells derived from human umbilical cord ameliorate ischemia
-induced acute renal failure in rats. Biotechnol Lett 2010; 32:725–732.
78▪. Brunswig-Spickenheier B, Boche J, Westenfelder C, et al. Limited immune-modulating activity of porcine mesenchymal stromal cells
abolishes their protective efficacy in acute kidney injury. Stem Cells Dev 2010; 19:719–729.
In this article, the authors show that porcine MSCs fail to protect renal function and are unable to efficiently stimulate kidney repair after ischemic AKI in pigs.
79. Chen YT, Sun CK, Lin YC, et al. Adipose-derived mesenchymal stem cell protects kidneys against ischemia
injury through suppressing oxidative stress and inflammatory reaction. J Transl Med 2011; 9:51.
80. Gatti S, Bruno S, Deregibus MC, et al. Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia–reperfusion
-induced acute and chronic kidney injury. Nephrol Dial Transplant 2011; 26:1474–1483.
81. La Manna G, Bianchi F, Cappuccilli M, et al. Mesenchymal stem cells in renal function recovery after acute kidney injury: use of a differentiating agent in a rat model. Cell Transplant 2011; 20:1193–1208.
82. Furuichi K, Shintani H, Sakai Y, et al. Effects of adipose-derived mesenchymal cells on ischemia
injury in kidney. Clin Exp Nephrol 2012; 16:679–689.
83. Zhen-Qiang F, Bing-Wei Y, Yong-Liang L, et al. Localized expression of human BMP-7 by BM-MSCs enhances renal repair in an in vivo model of ischemia
injury. Genes Cells 2012; 17:53–64.
84. Tian H, Lu Y, Shah SP, et al. 14S,21R-dihydroxy-docosahexaenoic acid treatment enhances mesenchymal stem cell amelioration of renal ischemia
injury. Stem Cells Dev 2012; 21:1187–1199.
85. Altun B, Yilmaz R, Aki T, et al. Use of mesenchymal stem cells and darbepoetin improve ischemia
-induced acute kidney injury outcomes. Am J Nephrol 2012; 35:531–539.
86. Seifert M, Stolk M, Polenz D, et al. Detrimental effects of rat mesenchymal stromal cell pretreatment in a model of acute kidney rejection. Front Immunol 2012; 3:202.
87. Franquesa M, Herrero E, Torras J, et al.
Mesenchymal stem cell therapy
prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev 2012; 21:3125–3135.
88. Alfarano C, Roubeix C, Chaaya R, et al.
Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia
in cyclosporine-immunosuppressed rats. Cell Transplant 2012. doi: 10.3727/096368912X640448.
89. Herrmann JL, Wang Y, Abarbanell AM, et al. Preconditioning mesenchymal stem cells with transforming growth factor-alpha improves mesenchymal stem cell-mediated cardioprotection. Shock 2010; 33:24–30.
90. Kelly ML, Wang M, Crisostomo PR, et al. TNF receptor 2, not TNF receptor 1, enhances mesenchymal stem cell-mediated cardiac protection following acute ischemia
. Shock 2010; 33:602–607.
91. Lai RC, Arslan F, Lee MM, et al. Exosome secreted by MSC reduces myocardial ischemia
injury. Stem Cell Res 2010; 4:214–222.
92. Li H, Zuo S, Pasha Z, et al. GATA-4 promotes myocardial transdifferentiation of mesenchymal stromal cells
via up-regulating IGFBP-4. Cytotherapy 2011; 13:1057–1065.
93. Kim YS, Ahn Y, Kwon JS, et al. Priming of mesenchymal stem cells with oxytocin enhances the cardiac repair in ischemia
injury. Cells Tissues Organs 2012; 195:428–442.
94. Zuo S, Jones WK, Li H, et al. Paracrine effect of Wnt11-overexpressing mesenchymal stem cells on ischemic injury. Stem Cells Dev 2012; 21:598–608.
95. Song L, Xu J, Qu J, et al. A therapeutic role for mesenchymal stem cells in acute lung injury independent of hypoxia-induced mitogenic factor. J Cell Mol Med 2012; 16:376–385.
96. Chen Y, Qian H, Zhu W, et al. Hepatocyte growth factor modification promotes the amelioration effects of human umbilical cord mesenchymal stem cells on rat acute kidney injury. Stem Cells Dev 2011; 20:103–113.
97. Noiseux N, Gnecchi M, Lopez-Ilasaca M, et al. Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 2006; 14:840–850.
98. Gnecchi M, He H, Melo LG, et al. Early beneficial effects of bone marrow-derived mesenchymal stem cells overexpressing Akt on cardiac metabolism after myocardial infarction. Stem Cells 2009; 27:971–979.
99. Xu J, Woods CR, Mora AL, et al. Prevention of endotoxin-induced systemic response by bone marrow-derived mesenchymal stem cells in mice. Am J Physiol Lung Cell Mol Physiol 2007; 293:L131–L141.
100. Gupta N, Su X, Popov B, et al. Intrapulmonary delivery of bone marrow-derived mesenchymal stem cells improves survival and attenuates endotoxin-induced acute lung injury in mice. J Immunol 2007; 179:1855–1863.
101. Li J, Li D, Liu X, et al. Human umbilical cord mesenchymal stem cells reduce systemic inflammation
and attenuate LPS-induced acute lung injury in rats. J Inflamm (Lond) 2012; 9:33.
102. Matthay MA, Thompson BT, Read EJ, et al. Therapeutic potential of mesenchymal stem cells for severe acute lung injury. Chest 2010; 138:965–972.
103▪. Manning E, Pham S, Li S, et al. Interleukin-10 delivery via mesenchymal stem cells: a novel gene therapy approach to prevent lung ischemia
injury. Hum Gene Ther 2010; 21:713–727.
The authors present a promising therapeutic strategy using IL-10-engineered MSCs to prevent ischemia–reperfusion injury in lung transplantation.
104▪. Timmers L, Lim SK, Hoefer IE, et al. Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction. Stem Cell Res 2011; 6:206–214.
In this trial, improved angiogenesis and ameliorated cardiac function are measured after MSC-CM treatment of myocardial infarction in a porcine model.
105. Nguyen BK, Maltais S, Perrault LP, et al. Improved function and myocardial repair of infarcted heart by intracoronary injection of mesenchymal stem cell-derived growth factors. J Cardiovasc Transl Res 2010; 3:547–558.
106. Tan J, Wu W, Xu X, et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307:1169–1177.
107. Hare JM, Traverse JH, Henry TD, et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009; 54:2277–2286.