Vol. 27, No. 3, 2007
Issue release date: May 2007
Am J Nephrol 2007;27:301–307
Kidney and beyond – Review Article
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Prepare Cells to Repair the Heart: Mesenchymal Stem Cells for the Treatment of Heart Failure

Ohnishi S. · Nagaya N.
Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Osaka, Japan
email Corresponding Author


 goto top of outline Key Words

  • Mesenchymal stem cell
  • Heart failure
  • Neovascularization
  • Tissue regeneration
  • Translational research
  • Gene expression
  • Paracrine effect

 goto top of outline Abstract

Heart failure is one of the most important cardiovascular diseases, with high mortality, and invasive treatment such as mechanical circulatory support and cardiac transplantation is sometimes required for severe heart failure. Therefore, the development of less invasive and more effective therapeutic strategies is desired. Cell therapy is attracting growing interest as a new approach for the treatment of heart failure. As a cell source, various kinds of stem/progenitor cells such as bone marrow cells, endothelial progenitor cells, mesenchymal stem cells (MSC) and cardiac stem cells have been investigated for their efficacy and safety. Especially, bone marrow-derived MSC possess multipotency and can be easily expanded in culture, and are thus an attractive therapeutic tool for heart failure. Recent studies have revealed the underlying mechanisms of MSC in cardiac repair: MSC not only differentiate into specific cell types such as cardiomyocytes and vascular endothelial cells, but also secrete a variety of paracrine angiogenic and cytoprotective factors. It has also been suggested that endogenous MSC as well as exogenously transplanted MSC migrate and participate in cardiac repair. Based on these findings, several clinical trials have just been started to evaluate the safety and efficacy of MSC for the treatment of heart failure.

Copyright © 2007 S. Karger AG, Basel

goto top of outline Introduction

Heart failure is a major cardiovascular health problem worldwide. About 5.2 million patients in the US have heart failure, and the lifetime risk of developing chronic heart failure for both men and women is 1 in 5 [1]. Coronary artery disease is the most common cause of heart failure, followed by idiopathic dilated cardiomyopathy and valvular heart disease [2, 3]. Myocardial infarction causes necrosis of the myocardium, followed by infiltration of inflammatory cells. Then a scar forms, leading to the loss of cardiac function, ventricular remodeling and progressive dysfunction, and, finally, congestive heart failure [4,5,6]. Drugs commonly used for the treatment of chronic heart failure include loop diuretics, angiotensin-converting enzyme inhibitors, β-adrenergic receptor blockers, aldosterone antagonists, angiotensin II receptor blockers and digitoxin; however, patients with severe heart failure require invasive treatment such as mechanical circulatory support, continuous inotropic infusion, or cardiac transplantation [7,8,9]. Therefore, there is a need to develop more effective, less invasive therapeutic strategies for heart failure.

Cell therapy for heart failure has the potential to restore cardiac function by inducing neovascularization, and regenerating and protecting cardiomyocytes [4]. Bone marrow-derived mononuclear cells (MNC) and endothelial progenitor cells (EPC) have been applied for ischemic cardiovascular disease in human studies [10,11,12]. Recently, mesenchymal stem cells (MSC), a subpopulation of MNC, have emerged as a new therapeutic cell source because they possess multipotency and can be easily expanded in culture [13]. This article reviews cell therapy for heart failure, and focuses on the therapeutic potential of MSC for heart failure.


goto top of outline Cell Sources for Cardiac Repair

Several kinds of cells have the potential to be applied for cardiac repair; embryonic stem (ES) cells and somatic stem or progenitor cells (skeletal myoblasts, MNC, MSC, EPC, cardiac stem cells) (table 1). Because ethical problems may limit the immediate application of ES cells, we herein describe the features and characteristics of somatic cells.

Table 1. Characteristics of cells used for the treatment of heart failure

Skeletal myoblasts, which are derived from cultured satellite cells, were the first to be tested in clinical trials. Satellite cells are muscle progenitor cells which normally mediate the regeneration of skeletal muscle [14]. They can be easily expanded in culture in an undifferentiated state, and are highly resistant to tissue ischemia. In vivo studies have demonstrated that the administration of myoblasts improved cardiac function [15,16,17,18]. However, in early clinical studies, myoblast transplantation was associated with sustained ventricular tachycardia [19], which requires defibrillator implantation and/or amiodarone therapy.

Bone marrow cells include several types of stem/progenitor cells such as hematopoietic stem cells and MSC, although the vast majority of bone marrow cells are hematopoietic cells [20, 21]. Because of the extensive clinical experience in bone marrow transplantation for hematological diseases over the past decades and the fact that large numbers of bone marrow cells can be easily obtained, the study of bone marrow cell transplantation for treating heart failure has moved quickly from small animals to human studies. Direct or intracoronary injection of bone marrow cells appears to be safe and beneficial for the treatment of acute myocardial infarction and chronic ischemic heart disease [11,22,23,24,25]. However, it is not clear whether the optimal bone marrow cell population for transplantation is hematopoietic stem cells, MSC, or abundant committed cells. The major goal of studies using bone marrow cells will be to identify the most effective cell population from these complex mixtures.

EPC, a rare subpopulation of bone marrow cells with a similar phenotype and function to those of fetal angioblasts, have been demonstrated to be involved in neovascularization after myocardial infarction [26]. In addition, there was a significant reduction in collagen deposition and apoptosis of cardiomyocytes and an improvement in cardiac function. It has been demonstrated that granulocyte colony-stimulating factor (G-CSF) and stem cell factor can mobilize EPC [27, 28]. Clinical trials studying the ability of G-CSF to mobilize stem/progenitor cells in patients with coronary artery disease did not reach a conclusion on efficacy, while concerns have been raised on safety in relation to arterial restenosis and plaque destabilization. HMG-CoA reductase inhibitors [29], estrogens [30], exercise [31], and nonsmoking [32] are more practical than growth factor or chemokine administration to enhance the number of circulating EPC in patients. Currently, clinical trials of EPC therapy for neovascularization and myocardial regeneration using CD34-positive cells from BM are in progress.

In the past few years, the search for stem or progenitor cells in the heart has intensified. These would be comparable to the satellite cells in skeletal muscle. Evidence is accumulating that cardiac stem cells reside at specific locations in the adult heart. Beltrami et al. [ 33] described the isolation of lineage-negative, c-kit-positive cells from the adult rat heart and showed that these cells were able to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells. In addition, Sca-1-positive cells were isolated from the adult mouse heart [34]. This Sca-1-positive subpopulation differentiated in vitro into cardiomyocytes in response to 5-azacytidine, and expressed several cardiac specific markers. In addition, Sca-1-positive cells differentiated into cardiomyocytes after intravenous injection. Messina et al. [ 35] identified a subpopulation of cardiosphere-forming cells after culturing human atrial or ventricular biopsies and embryonic, fetal or postnatal mouse hearts. The mouse cardiospheres started to beat spontaneously, whereas human cardiospheres only started to beat after co-culture with rat neonatal cardiomyocytes. Furthermore, cardiospheres expressed endothelial markers and were positive for Sca-1 and c-kit. Recently, another subpopulation of cardiac stem cells has been described [36]. These cardiac stem cells were Isl1-positive and were identified in rat, mouse and human adult hearts. Isl1-positive cardiac stem cells were positive for cardiac transcriptional factors Nkx2.5 and GATA4, while transcriptional factors associated with mature cardiomyocytes were absent. However, Sca-1 and c-kit were not expressed on these cells. When co-cultured with neonatal rat cardiomyocytes, 30% of the Isl1-positive cardiac stem cells differentiated into cardiomyocytes.


goto top of outline MSC: Distribution and Behavior

MSC reside not only in bone marrow [37] and adipose tissue [38], but also in other tissues such as synovium [39], periosteum [40], muscle [41], dental pulp [42], periodontal ligament [43], placenta [44] and umbilical cord blood [45]. A recent study suggests that MSC reside in virtually all postnatal organs and tissues, and may be localized to vessel walls [46]. MSC can differentiate not only into osteoblasts, chondrocytes and adipocytes, but also into cardiomyocytes and vascular endothelial cells [13, 47]. Bone marrow-derived MSC, which are most investigated, are a rare subpopulation of bone marrow cells (approximately 0.001–0.01%) [13]. It has been demonstrated that bone marrow MSC can be mobilized and differentiate into cardiomyocytes in a murine model of myocardial infarction, suggesting the importance of bone marrow MSC in cardiac regeneration [48]. Moreover, when cultured MSC were intravenously administered to rats with myocardial infarction, they were preferentially engrafted into the infarcted, but not the noninfarcted, myocardium, and a small fraction of the transplanted MSC differentiated into cardiomyocytes and vascular endothelial cells [49].


goto top of outline Differentiation of MSC into Myocardial Lineage

In vitro studies have demonstrated that MSC can differentiate not only into adipocytes and osteocytes, but also into cardiomyocytes and vascular endothelial cells [13, 47,50,51,52,53]. The differentiation of MSC into cardiomyocytes in vitro has been induced in cultures containing either MSC alone treated with 5-azacytidine or a cocktail of growth factors, and in co-culture with cardiomyocytes, and has been demonstrated by evidence of spontaneous beating or cardiomyocyte specific markers [50,51,52,54,55,56,57,58,59,60,61], although there is a lack of a clear definition of which markers are evidence for full differentiation into functional cells [62]. After direct injection of MSC into infarcted myocardium in a pig model, engrafted MSC differentiated toward a myogenic lineage, expressing muscle specific proteins, and attenuated cardiac function and pathologic thinning [63]. Furthermore, we and others have demonstrated that directly or intravenously injected MSC differentiated into endothelial cells, and were involved in angiogenesis as well as myogenesis in animal models of myocardial infarction [49, 64, 65].


goto top of outline Paracrine Effects Produced by MSC

MSC exert their effect on cardiac regeneration not only by differentiation into specific cell types, but also through paracrine actions. In vitro studies have demonstrated that MSC can secrete a variety of angiogenic, anti-apoptotic and mitogenic factors such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), adrenomedullin (AM) and insulin-like growth factor-1 (IGF-1) [66, 67]. Interestingly, administration of conditioned medium obtained from MSC culture exerted cytoprotective effects on the myocardium in an animal model of myocardial infarction [68]. We have recently demonstrated that cultured cardiomyocytes were injured in response to monocyte chemoattractant protein-1 (MCP-1), which plays an important role in myocarditis, whereas this effect was significantly attenuated by conditioned medium derived from MSC culture [69]. These results suggest a cardioprotective effect of MSC acting in a paracrine manner, demonstrating the importance of secreted factors in cardiac repair.


goto top of outline Gene Expression in MSC

MNC have been shown to induce therapeutic neovascularization in critical limb ischemia and myocardial infarction in human studies [10, 11]. Similarly, many studies have demonstrated the therapeutic potential of MSC; however, the underlying mechanisms contributing to cardiovascular protection might be different between MSC and MNC. The gene expression profiles under normoxia and hypoxia are largely different between MSC and MNC [70]. MNC express a number of genes involved in inflammatory response and chemotaxis. On the other hand, MSC express a number of genes involved in development (e.g. transgelin, actin-γ1), morphogenesis (e.g. bone morphological protein-2, transforming growth factor-β3), cell adhesion (e.g. neural cell adhesion molecule-1, cadherin-11) and proliferation (e.g. connective tissue growth factor, platelet-derived growth factor-A) under normoxia. Furthermore, focusing on genes encoding secretory proteins in response to hypoxia, the upregulated genes in MSC include several molecules involved in cell proliferation and survival such as VEGF-D, placenta growth factor (PGF), pre-B cell colony-enhancing factor 1 (PBEF1), heparin-binding epidermal growth factor-like growth factor (HB-EGF) and matrix metalloproteinase-9 (MMP-9), while the upregulated genes in MNC under hypoxia include proinflammatory cytokines such as chemokine (CXC motif) ligand 2 (CXCL2) and interleukin-1α (IL-1α) [70]. These results suggest that transplanted MSC may act to promote cell proliferation, including angiogenesis, and cell survival in response to hypoxia, while MNC may induce an inflammatory response, followed by angiogenesis. In fact, implantation of MNC into ischemic limbs has been reported to lead to local inflammatory reactions [71].

It is postulated that not only exogenously administered MSC, but also endogenous MSC migrate and participate in wound repair. In healthy animals, intravenous administration of MSC preferentially engraft in the bone marrow cavity; however, when rats were subjected to ischemia/reperfusion, a significant number of xenogeneic MSC could be identified in the circulation, and subsequently in the infarcted region of the heart [72]. Taking these findings together, MSC are considered to exert cardiac repair by a variety of mechanisms.


goto top of outline MSC for Treatment of Heart Failure

Myocardial injection of MSC improved cardiac function in a rat model of dilated cardiomyopathy, a myocardial disease characterized by a loss of cardiomyocytes and an increase in fibroblasts [73, 74], possibly through induction of angiogenesis and myogenesis, as well as by inhibition of myocardial fibrosis [67]. In this study, MSC transplantation significantly increased capillary density and decreased the collagen volume fraction in the myocardium. In addition, intravenous administration of MSC improved inflammatory changes and cardiac function in rats with acute myocarditis, suggesting an anti-inflammatory effect of MSC [69]. Recently, we have demonstrated that adipose tissue-derived monolayered MSC, generated by cell sheet technology using temperature-responsive culture dishes, repair scarred myocardium after myocardial infarction in rats [75]. Interestingly, the engrafted MSC sheet gradually grew after transplantation to form a thick stratum that included undifferentiated MSC as well as newly formed vessels, which were composed of graft-derived cells, host-derived cells or both. Unlike a fibroblast cell sheet, the monolayered MSC reversed wall thinning in the scar area, contributing to a reduction in left ventricle wall stress and improvement of cardiac function. Therefore, this new technology may overcome problems associated with needle injection of bone marrow cells into the scar area, i.e. difficulty to reconstruct sufficient cardiac mass.

There are few reports describing the results of clinical studies on the treatment of heart failure, but several studies are on going. It has been reported that intracoronary administration of autologous bone marrow-derived MSC improved cardiac function in patients with acute myocardial infarction [76] and chronic ischemic cardiomyopathy [77]. Katritsis and co-workers reported that intracoronary transplantation of bone marrow-derived MSC may contribute to regional regeneration of myocardial tissue following myocardial infarction [78], and intracoronary transplantation of these cells did not appear to be arrhythmogenic [79]. The National Institute of Health in the United States provides information on current clinical trials using MSC (www.clinicaltrials.gov). In December 2005, the Rigshospitalet in Denmark started a phase I/II safety and efficacy study (NCT00260338) to evaluate the clinical effect of autologous bone marrow-derived MSC therapy in patients with severe chronic myocardial ischemia. In October 2006, Helsinki University started a prospective double-blind trial (NCT00418418) of intraoperative transmyocardial autologous bone marrow-derived MSC transplantation versus placebo in patients with heart failure scheduled to undergo coronary bypass operation. In October 2006, the National Heart, Lung, and Blood Institute in the United States started a phase II study (NCT00383630) to evaluate the effect of injected autologous bone marrow cells to improve heart function in individuals with a left ventricular assist device (LVAD) awaiting heart transplantation. This study is enrolling individuals undergoing surgery to receive an LVAD, and patients are randomly assigned to one of the following three groups: group 1 patients receive injected MSC while undergoing LVAD implantation; group 2 patients receive injected immunoselected CD34-positive hematopoietic stem cells while undergoing LVAD implantation; group 3 patients undergo LVAD implantation. We have also started a pilot study of intramyocardial injection of autologous bone marrow-derived MSC in patients with end-stage heart failure. In this study, 20 ml of bone marrow cells are aspirated from the ilium, and MSC are cultured and expanded with medium containing autologous serum for 3 weeks. A large number of MSC are directly injected into the myocardium at 40 sites, using a catheter.


goto top of outline Conclusions

MSC have emerged as a new therapeutic tool for cell therapy in heart failure, and exert their effects by differentiating into specific cell types as well as through paracrine actions such as angiogenic, cytoprotective, anti-inflammatory and anti-fibrotic effects. Whether autologous MSC have significant value in the treatment of heart failure is currently being explored in clinical trials.

 goto top of outline References
  1. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y: Heart disease and stroke statistics – 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171.
  2. Fox KF, Cowie MR, Wood DA, Coats AJ, Gibbs JS, Underwood SR, Turner RM, Poole-Wilson PA, Davies SW, Sutton GC: Coronary artery disease as the cause of incident heart failure in the population. Eur Heart J 2001;22:228–236.
  3. He J, Ogden LG, Bazzano LA, Vupputuri S, Loria C, Whelton PK: Risk factors for congestive heart failure in US men and women: NHANES I epidemiologic follow-up study. Arch Intern Med 2001;161:996–1002.
  4. Fraser JK, Schreiber RE, Zuk PA, Hedrick MH: Adult stem cell therapy for the heart. Int J Biochem Cell Biol 2004;36:658–666.
  5. Tiyyagura SR, Pinney SP: Left ventricular remodeling after myocardial infarction: past, present, and future. Mt Sinai J Med 2006;73:840–851.
  6. Sharpe N: Cardiac remodeling in coronary artery disease. Am J Cardiol 2004;93:17B–20B.

    External Resources

  7. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005;112:e154–e235.
  8. Bukharovich IF, Kukin M: Optimal medical therapy for heart failure. Prog Cardiovasc Dis 2006;48:372–385.
  9. Adorisio R, De Luca L, Rossi J, Gheorghiade M: Pharmacological treatment of chronic heart failure. Heart Fail Rev 2006;11:109–123.
  10. Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H, Amano K, Kishimoto Y, Yoshimoto K, Akashi H, Shimada K, Iwasaka T, Imaizumi T: Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet 2002;360:427–435.
  11. Tse HF, Kwong YL, Chan JK, Lo G, Ho CL, Lau CP: Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003;361:47–49.
  12. Iwami Y, Masuda H, Asahara T: Endothelial progenitor cells: past, state of the art, and future. J Cell Mol Med 2004;8:488–497.
  13. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–147.
  14. Siminiak T, Kalmucki P, Kurpisz M: Autologous skeletal myoblasts for myocardial regeneration. J Interv Cardiol 2004;17:357–365.
  15. Murry CE, Wiseman RW, Schwartz SM, Hauschka SD: Skeletal myoblast transplantation for repair of myocardial necrosis. J Clin Invest 1996;98:2512–2523.
  16. Taylor DA, Atkins BZ, Hungspreugs P, Jones TR, Reedy MC, Hutcheson KA, Glower DD, Kraus WE: Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998;4:929–933.
  17. Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP: Myoblast transplantation for heart failure. Lancet 2001;357:279–280.
  18. Hagege AA, Carrion C, Menasche P, Vilquin JT, Duboc D, Marolleau JP, Desnos M, Bruneval P: Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 2003;361:491–492.
  19. Siminiak T, Kalawski R, Fiszer D, Jerzykowska O, Rzezniczak J, Rozwadowska N, Kurpisz M: Autologous skeletal myoblast transplantation for the treatment of postinfarction myocardial injury: phase I clinical study with 12 months of follow-up. Am Heart J 2004;148:531–537.
  20. Abkowitz JL, Catlin SN, McCallie MT, Guttorp P: Evidence that the number of hematopoietic stem cells per animal is conserved in mammals. Blood 2002;100:2665–2667.
  21. Pittenger MF, Martin BJ: Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res 2004;95:9–20.
  22. Fuchs S, Satler LF, Kornowski R, Okubagzi P, Weisz G, Baffour R, Waksman R, Weissman NJ, Cerqueira M, Leon MB, Epstein SE: Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study. J Am Coll Cardiol 2003;41:1721–1724.
  23. Perin EC, Dohmann HF, Borojevic R, Silva SA, Sousa AL, Mesquita CT, Rossi MI, Carvalho AC, Dutra HS, Dohmann HJ, Silva GV, Belem L, Vivacqua R, Rangel FO, Esporcatte R, Geng YJ, Vaughn WK, Assad JA, Mesquita ET, Willerson JT: Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 2003;107:2294–2302.
  24. Fernandez-Aviles F, San Roman JA, Garcia-Frade J, Fernandez ME, Penarrubia MJ, de la Fuente L, Gomez-Bueno M, Cantalapiedra A, Fernandez J, Gutierrez O, Sanchez PL, Hernandez C, Sanz R, Garcia-Sancho J, Sanchez A: Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction. Circ Res 2004;95:742–748.
  25. Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H: Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141–148.
  26. Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S: Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med 2001;7:430–436.
  27. Kang HJ, Kim HS, Zhang SY, Park KW, Cho HJ, Koo BK, Kim YJ, Soo Lee D, Sohn DW, Han KS, Oh BH, Lee MM, Park YB: Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 2004;363:751–756.
  28. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J, McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P: Bone marrow cells regenerate infarcted myocardium. Nature 2001;410:701–705.
  29. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M, Rutten H, Fichtlscherer S, Martin H, Zeiher AM: HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest 2001;108:391–397.
  30. Iwakura A, Luedemann C, Shastry S, Hanley A, Kearney M, Aikawa R, Isner JM, Asahara T, Losordo DW: Estrogen-mediated, endothelial nitric oxide synthase-dependent mobilization of bone marrow-derived endothelial progenitor cells contributes to reendothelialization after arterial injury. Circulation 2003;108:3115–3121.
  31. Laufs U, Werner N, Link A, Endres M, Wassmann S, Jurgens K, Miche E, Bohm M, Nickenig G: Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation 2004;109:220–226.
  32. Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K, Iino S, Inden Y, Murohara T: Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol 2004;24:1442–1447.
  33. Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P: Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003;114:763–776.
  34. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD: Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 2003;100:12313–12318.
  35. Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A: Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 2004;95:911–921.
  36. Laugwitz KL, Moretti A, Lam J, Gruber P, Chen Y, Woodard S, Lin LZ, Cai CL, Lu MM, Reth M, Platoshyn O, Yuan JX, Evans S, Chien KR: Postnatal isl1+ cardioblasts enter fully differentiated cardiomyocyte lineages. Nature 2005;433:647–653.
  37. Friedenstein AJ, Gorskaja JF, Kulagina NN: Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976;4:267–274.
  38. Gimble J, Guilak F: Adipose-derived adult stem cells: isolation, characterization, and differentiation potential. Cytotherapy 2003;5:362–369.
  39. De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP: Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001;44:1928–1942.
  40. Nakahara H, Bruder SP, Goldberg VM, Caplan AI: In vivo osteochondrogenic potential of cultured cells derived from the periosteum. Clin Orthop Relat Res 1990:223–232.
  41. Asakura A, Komaki M, Rudnicki M: Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 2001;68:245–253.
  42. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S: Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci USA 2000;97:13625–13630.
  43. Seo BM, Miura M, Gronthos S, Bartold PM, Batouli S, Brahim J, Young M, Robey PG, Wang CY, Shi S: Investigation of multipotent postnatal stem cells from human periodontal ligament. Lancet 2004;364:149–155.
  44. Fukuchi Y, Nakajima H, Sugiyama D, Hirose I, Kitamura T, Tsuji K: Human placenta-derived cells have mesenchymal stem/progenitor cell potential. Stem Cells 2004;22:649–658.
  45. Erices A, Conget P, Minguell JJ: Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol 2000;109:235–242.
  46. da Silva Meirelles L, Chagastelles PC, Nardi NB: Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J Cell Sci 2006;119:2204–2213.
  47. Prockop DJ: Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 1997;276:71–74.
  48. Kawada H, Fujita J, Kinjo K, Matsuzaki Y, Tsuma M, Miyatake H, Muguruma Y, Tsuboi K, Itabashi Y, Ikeda Y, Ogawa S, Okano H, Hotta T, Ando K, Fukuda K: Nonhematopoietic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction. Blood 2004;104:3581–3587.
  49. Nagaya N, Fujii T, Iwase T, Ohgushi H, Itoh T, Uematsu M, Yamagishi M, Mori H, Kangawa K, Kitamura S: Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol 2004;287:H2670–H2676.
  50. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S: Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999;103:697–705.
  51. Wakitani S, Saito T, Caplan AI: Myogenic cells derived from rat bone marrow mesenchymal stem cells exposed to 5-azacytidine. Muscle Nerve 1995;18:1417–1426.
  52. Xu W, Zhang X, Qian H, Zhu W, Sun X, Hu J, Zhou H, Chen Y: Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med (Maywood) 2004;229:623–631.
  53. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, Verfaillie CM: Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002;109:337–346.
  54. Fukuhara S, Tomita S, Yamashiro S, Morisaki T, Yutani C, Kitamura S, Nakatani T: Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg 2003;125:1470–1480.
  55. Rangappa S, Entwistle JW, Wechsler AS, Kresh JY: Cardiomyocyte-mediated contact programs human mesenchymal stem cells to express cardiogenic phenotype. J Thorac Cardiovasc Surg 2003;126:124–132.
  56. Xaymardan M, Tang L, Zagreda L, Pallante B, Zheng J, Chazen JL, Chin A, Duignan I, Nahirney P, Rafii S, Mikawa T, Edelberg JM: Platelet-derived growth factor-AB promotes the generation of adult bone marrow-derived cardiac myocytes. Circ Res 2004;94:E39–E45.

    External Resources

  57. Shim WS, Jiang S, Wong P, Tan J, Chua YL, Tan YS, Sin YK, Lim CH, Chua T, Teh M, Liu TC, Sim E: Ex vivo differentiation of human adult bone marrow stem cells into cardiomyocyte-like cells. Biochem Biophys Res Commun 2004;324:481–488.
  58. Yoon YS, Wecker A, Heyd L, Park JS, Tkebuchava T, Kusano K, Hanley A, Scadova H, Qin G, Cha DH, Johnson KL, Aikawa R, Asahara T, Losordo DW: Clonally expanded novel multipotent stem cells from human bone marrow regenerate myocardium after myocardial infarction. J Clin Invest 2005;115:326–338.
  59. Wang T, Xu Z, Jiang W, Ma A: Cell-to-cell contact induces mesenchymal stem cell to differentiate into cardiomyocyte and smooth muscle cell. Int J Cardiol 2006;109:74–81.
  60. Kadivar M, Khatami S, Mortazavi Y, Shokrgozar MA, Taghikhani M, Soleimani M: In vitro cardiomyogenic potential of human umbilical vein-derived mesenchymal stem cells. Biochem Biophys Res Commun 2006;340:639–647.
  61. Li H, Yu B, Zhang Y, Pan Z, Xu W, Li H: Jagged1 protein enhances the differentiation of mesenchymal stem cells into cardiomyocytes. Biochem Biophys Res Commun 2006;341:320–325.
  62. Belema Bedada F, Technau A, Ebelt H, Schulze M, Braun T: Activation of myogenic differentiation pathways in adult bone marrow-derived stem cells. Mol Cell Biol 2005;25:9509–9519.
  63. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, Martin BJ: Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 2002;73:1919–1925; discussion 1926.
  64. Liu J, Hu Q, Wang Z, Xu C, Wang X, Gong G, Mansoor A, Lee J, Hou M, Zeng L, Zhang JR, Jerosch-Herold M, Guo T, Bache RJ, Zhang J: Autologous stem cell transplantation for myocardial repair. Am J Physiol 2004;287:H501–H511.

    External Resources

  65. Davani S, Marandin A, Mersin N, Royer B, Kantelip B, Herve P, Etievent JP, Kantelip JP: Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 2003;108(suppl 1):II253–II258.
  66. Kinnaird T, Stabile E, Burnett MS, Lee CW, Barr S, Fuchs S, Epstein SE: Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res 2004;94:678–685.
  67. Nagaya N, Kangawa K, Itoh T, Iwase T, Murakami S, Miyahara Y, Fujii T, Uematsu M, Ohgushi H, Yamagishi M, Tokudome T, Mori H, Miyatake K, Kitamura S: Transplantation of mesenchymal stem cells improves cardiac function in a rat model of dilated cardiomyopathy. Circulation 2005;112:1128–1135.
  68. Gnecchi M, He H, Liang OD, Melo LG, Morello F, Mu H, Noiseux N, Zhang L, Pratt RE, Ingwall JS, Dzau VJ: Paracrine action accounts for marked protection of ischemic heart by Akt-modified mesenchymal stem cells. Nat Med 2005;11:367–368.
  69. Ohnishi S, Yanagawa B, Tanaka K, Miyahara Y, Obata H, Kataoka M, Kodama M, Ishibashi-Ueda H, Kangawa K, Kitamura S, Nagaya N: Transplantation of mesenchymal stem cells attenuates myocardial injury and dysfunction in a rat model of acute myocarditis. J Mol Cell Cardiol 2007;42:88–97.
  70. Ohnishi S, Yasuda T, Kitamura S, Nagaya N: Effect of hypoxia on gene expression of bone marrow-derived mesenchymal stem cells and mononuclear cells. Stem Cells 2007, in press.
  71. Tateno K, Minamino T, Toko H, Akazawa H, Shimizu N, Takeda S, Kunieda T, Miyauchi H, Oyama T, Matsuura K, Nishi J, Kobayashi Y, Nagai T, Kuwabara Y, Iwakura Y, Nomura F, Saito Y, Komuro I: Critical roles of muscle-secreted angiogenic factors in therapeutic neovascularization. Circ Res 2006;98:1194–1202.
  72. Saito T, Kuang JQ, Bittira B, Al-Khaldi A, Chiu RC: Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg 2002;74:19–24; discussion 24.
  73. Cooper LT Jr, Gersh BJ: Viral infection, inflammation, and the risk of idiopathic dilated cardiomyopathy: can the fire be extinguished? Am J Cardiol 2002;90:751–754.
  74. Hein S, Schaper J: Pathogenesis of dilated cardiomyopathy and heart failure: insights from cell morphology and biology. Curr Opin Cardiol 1996;11:293–301.
  75. Miyahara Y, Nagaya N, Kataoka M, Yanagawa B, Tanaka K, Hao H, Ishino K, Ishida H, Shimizu T, Kangawa K, Sano S, Okano T, Kitamura S, Mori H: Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006;12:459–465.
  76. Chen SL, Fang WW, Ye F, Liu YH, Qian J, Shan SJ, Zhang JJ, Chunhua RZ, Liao LM, Lin S, Sun JP: Effect on left ventricular function of intracoronary transplantation of autologous bone marrow mesenchymal stem cell in patients with acute myocardial infarction. Am J Cardiol 2004;94:92–95.
  77. Chen S, Liu Z, Tian N, Zhang J, Yei F, Duan B, Zhu Z, Lin S, Kwan TW: Intracoronary transplantation of autologous bone marrow mesenchymal stem cells for ischemic cardiomyopathy due to isolated chronic occluded left anterior descending artery. J Invasive Cardiol 2006;18:552–556.

    External Resources

  78. Katritsis DG, Sotiropoulou PA, Karvouni E, Karabinos I, Korovesis S, Perez SA, Voridis EM, Papamichail M: Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium. Catheter Cardiovasc Interv 2005;65:321–329.
  79. Katritsis DG, Sotiropoulou P, Giazitzoglou E, Karvouni E, Papamichail M: Electrophysiological effects of intracoronary transplantation of autologous mesenchymal and endothelial progenitor cells. Europace 2007;9:167–171.

 goto top of outline Author Contacts

Noritoshi Nagaya, MD, PhD
Fujishirodai 5-7-1, Suita
Osaka 565-8565 (Japan)
Tel. +81 6 6833 5012, Fax +81 6 6833 9865
E-Mail nnagaya@ri.ncvc.go.jp

 goto top of outline Article Information

Received: March 7, 2007
Accepted: March 19, 2007
Published online: April 25, 2007
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 1, Number of References : 79

 goto top of outline Publication Details

American Journal of Nephrology

Vol. 27, No. 3, Year 2007 (Cover Date: May 2007)

Journal Editor: Bakris, G. (Chicago, Ill.)
ISSN: 0250–8095 (print), 1421–9670 (Online)

For additional information: http://www.karger.com/AJN

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