Stem Cell Cardiology – 175 clinical studies – abbreviated references

Neocardiogenesis Foundation
Abbreviated references ©2009 W.W. Keesee Editor

Neocardiogenesis Definition and Scope

The term neocardiogenesis comes from cardiogenesis, which refers to the development of the heart in the embryo; neocardiogenesis, in turn, means the development of the heart in adults. The heart has mechanisms already in place that are responsible for small scale repair. However, these repair mechanisms are not sufficient for large scale repair, made necessary by events such as myocardial infarctions. Neocardiogenesis replaces dead cardiac muscle cells with living cells so that both the structure and function of the heart are maintained. This improves myocardial pumping of fluid around the body. [2] Background The human heart has been thought of as a postmitotic organ. Cardiomyocytes (muscle cells of the heart) were thought to be terminally differentiated cells that were irreplaceable and thus required to maintain cardiac function throughout life. However it is now known that the heart is able to regenerate new small vessels needed to repair an ischemic (lacking blood) myocardium. The belief that humans are born with a fixed number of cardiomyocytes, and that the growth of these cells was directly responsible for the growth of the heart, has also been disproven.[3] Reports of the heart's ability to repair itself have started to appear in peer reviewed journals [4] and papers have been published that have shown the potential of bone marrow cells to regenerate myocardium (myogenesis).[5] Other studies into the regeneration of myocardium have highlighted evidence of angiogenesis.[6] It has been reported that improvement in heart contractility has occurred as a result of the induction of angiogenesis.[7] The results of these studies suggest that there is a possibility that, during neocardiogenesis, angiogenesis and myogenesis are interlinked and operate simultaneously in the process of cardiac regeneration.
Bone Marrow-Derived Stem Cells for Myocardial Regeneration:
A rare subset of the homogenous bone marrow cellular mix, the mesenchymal stem/progenitor has been under intense investigation as a possible immuno – compatible, allogenic, universally usable biologic therapeutic.
1. Anaversa P. Nadal-Ginard B. Myocyte renewal and ventricular remodeling. Nature. 2002; 415; 240-3.
2. Scorsin M. Hagege A. Vilquin JT, Fiszman M. Marotte F, Samuel JL., Rappaport L., Schwartz K. Menasche P. Comparison of the effects of fetal cardiomyocytes and skeletal myoblast transplantation on postinfarction left ventricular function. J. Thorac Cardiovasc. Surg. 2000; 119; 1169-75.
3. Kao RL, Chiu RC. Cellular Cardiomyoplasty: Myocardial Repair with Cell Implantation. Austin Texas: Landes Bioscience; 1997.
4. Murray CE, Wiseman RW, Schwartz SM, Hauschka SD. Skeletal myoblast transplantation for repair of myocardial necrosis. J. Clin Invest. 1996; 98:2512-23.
5. Taylor DA et al; Regenerating functional myocardium; improved performance after skeletal myoblast transplantation. Nat Med. 1998; 4:929-33.
6. Orlic et al; Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98; 10344-9.
7. Toma C. Pittenger MF, et al; Human Mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002; 105; 93-8.
8. Tomita S. et al; Autologous transplantation of bone marrow cells improves damaged heart function. Circulation. 1999; 100; 11247-56.
9. Fukuda K. Development of regenerative cardiomyocytes from mesenchymal stem cells cardiovascular tissue engineering. Artif Organs, 2001; 25; 187-93.
10. Ferarrari G. et al. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998; 279; 1528-30.
11. Perin EC, et al. Transendocardial, autologous bone marrow transplantation for severe, chronic ischemic heart failure. Circulation. 2003; 107:2294-302.
12. Strauer BE, et al. Repair of infracted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation. 2002; 106; 1913-8.
13. Mosca JD et al. Mesenchymal stem cells as vehicles for gene delivery. Clin Orthop: 2000:S71-90.
14. Pittenger MF, et al. Multilineage potential of adult human mesenchymal stem cells. Science, 1999; 284; 143-7.
15. Menasche P. et al. Autologous skeletal myoblast transplantation for severe post infarction left ventricular dysfunction. J.Am Coll Cardiol. 2003; 41;; 1078-83.
16. Gronthos et al. Mononuclear and cellular characterization of highly purified stromal stem cells derived from bone marrow. J Cell Sci.2003; 116; 1827-35.
17. Mc Intosh et al. Stromal cell modulation of the immune system: A potential role for mesenchymal stem cells. Graft. 2000; 3; 324-328.
18. Tse et al. T-cell proliferation by human marrow stromal cells; Implications in transplantation. Transplantation. 2003; 389-97.
19. Di Nicola et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99; 3838-43.
20. Saito T. et al. Xenotransplant cardiac chimera: immune tolerance of adult stem cells. Ann Thorac Surg. 2002; 74; 19-24.
21. Mangi AA et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infracted hearts. Nat Med. 2003; 10; 10.
22. Orlic D. et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410; 701-5.
23. Stamm C. et al. Autologous bone-marrow stem cell transplantation for myocardial regeneration. Lancet. 2003; 361; 45-6.
24. Barbash IM et al. Systemic delivery of bone-marrow derived mesenchymal stem cells to infarcted myocardium; feasibility, cell migration, and body distribution. Circulation. 2003; 108; 863-8.
25. Kraithman DL et al. In vivo magnetic resonance imaging of mesenchymal stem cells in myocardial infraction. Circulation. 2003; 107; 2290-3.
26. Hill JM et al. Serial Cardiac Magnetic Resonance Imaging of injected Mesenchymal Stem Cells. Circulation. 2003; 11; 11.
27. Asahara T et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999; 85; 221-8.
28. Kalka C. et al. Transplantation of ex-vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA. 2000; 97; 3422-7.
29. Kawamoto A. et al. Therapuetic potential of ex-vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation. 2001; 103; 634-7.
30. Kocher AA. Et al. Neovascularization of ischemic myocardium by human bone marrow derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. Nat Med. 2001; 7; 430-6.
31. Al-Khaldi A et al. Therapeutic angiogenesis using autologous bone marrow stromal cells: Improved blood flow in chronic limb ischemia model. Ann Thorac Surg. 2003; 75; 204-9.
32. Jackson KA et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest. 2001; 107; 1395-401.
33. Price MJ et al. Intravenous allogenic mesenchymal stem cells home to myocardial injury and reduce left ventricular remodeling in a porcine balloon occlusion-reperfusion model of myocardial infraction. J. Am. Coll. Card. 2003; 41; 269A.
34. Silva GV, et al. Mesenchymal stem cells differentiate into an endothelial phenotype, enhance vascular density and improve heart function in a chronic myocardial ischemic model. Circulation 2005. 111 ;( 2); 150-156.
35. Duan HF, et al. Treatment of myocardial ischemia with bone marrow-derived mesenchymal stem cells over expressing hepatocyte growth factor. Mol Ther2003; 3; 467-474.

There is now considerable experimental evidence that transplantation of bone marrow cells into the heart induces angiogenesis and improves contractility. The use of the patient’s own cells for the regeneration of cardiac muscle has the advantages that it is ethically acceptable and immunosupression is unnecessary. The studies reviewed herein suggest that transplantation of unmanipulated autologous bone marrow may provide a novel and promising means of reversing post-infarction left ventricular dysfunction caused by
scarred tissue, and may have important clinical implications for improving the long-term prognosis of these patients and possibly the prevention of the occurrence of heart failure.

1. Li RK. Et al. Autologous porcine heart cell transplantation improved heart function after myocardial infraction. J. Thorac Cardiovasc Surg.119; 62-68; 2000.
2. Kamihata H. et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances perfusion and regional function via side supply of angioblasts, angiogenic legands, cytokines. Circulation. 104; 1046-1052; 2001.
3. Tomita, S. et al. Improved heart function with myogenesis and angiogenesis after autologous porcine bone marrow stromal cell transplantation. J Thorac Cardiovasc Surg. 123; 1132-1140; 2002.
4. Balsam, LB. et al. Haematopoietic stem cells adopt mature hematopoietic fates in ischaemic myocardium. Nature. 429; 668-673; 2004.
5. Galinanes, M. et al. Autotransplantation of unmanipulated bone marrow into scarred myocardium is safe and enhances cardiac function in humans. Cell Transpl.13-7-13; 2004.
6. Krause, DS. et al. Multi-organ, multi-linage engraftment by single bone marrow –derived stem cell. Cell.105; 369-337; 2001.
7. Fuchs, S. et al. Catheter based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease. J Am Coll Cardiol. 41; 1721-1724; 2003.
8. Beltrami, AP.et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell.114; 763-776; 2003.
9. Oh.H. et al. Cardiac progenitor cells from adult myocardium; homing, differentiation, and fusion after infarction. PNAS. 100; 12313-12318; 2003.
10. Kinnaird, T. et al. 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. 94; 678-685; 2004.
11. Mathur, A. et al. Stem cells and the repair of the heart. Lancet. 364; 183-192; 2004.
12. Kinnaird T, et al. Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. Circulation 2004; 109; 1543-1549.
13. Anversa P, et al. Molecular genetic advances in cardiovascular medicine focus on the myocyte. Circulation 2004; 109; 2832-2838.
14. Urbanek K, et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 2003; 100; 10; 440-445.

Ischemic heart disease accounts for approximately 50% of all cardiovascular deaths and is the leading cause of congestive heart failure. Myocardial necrosis is due to myocardial infaraction and is, by nature, an irreversible injury. After 15 to 20 minutes of coronary artery occlusion the cardiomyocytes are destroyed irreversibly. Many of the therapies, available to clinicians today, can significantly improve the prognosis of patients with acute myocardial infraction. However , the post infarcted heart remains a major challenge, resulting from ventricular remodeling processes, characterized by progressive expansion of the infract area and dilatation of the left ventricular(LV) cavity.
The major goal to reverse LV remodeling would be the enhancement of regeneration of cardiac myocytes as well as the stimulation of neovascularization within the infarcted area, by repopulation of the injured myocardium with healthy autologous cells, or by the induced proliferation of endogenous resident cardiac stem cells.

1. Ryan TJ. Et al. ACC/AHA guidelines for the management of patients with acute myocardial infraction. A report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 1999; 34; 890-911.
2. Graf T. et al. Differentiation plasticity of hematopoietic cells. Blood 2002; 99; 3089-3101.
3. Reyes M. et al. Purification and ex-vivo expansion of postnatal human mesodermal progenitor cells. Blood. 2001; 98; 2615-2625.
4. Grounds MD, et al. The role of stem cells in skeletal and cardiac muscle repair. J Histochem Cytochem 2002; 50; 589-610.
5. Beltrami AP, et al. Evidence that human cardio myocytes divide after myocardial infraction. N Engl J Med 2001; 344; 1750-1757.
6. Laflamme MA. Et al. Evidence for cardiomyocyte repopulation by extra cardiac progenitors in transplanted human hearts. Circ Res. 2002; 90; 634-640.
7. Strauer BE, et al. Intracoronary, human autologous stem cell transplantation for myocardial regeneration following myocardial infraction. Dtsch Med Wochenschr 2001; 126; 932-938.
8. Tse HF, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet 2003; 361; 47-49.
9. Menasche P. et al. Myoblast transplantation for heart failure. Lancet 2001; 357; 279-280.
10. Hamano K. et al. Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: Clinical trial and preliminary results. Jpn Circ J2001; 65; 845-847.
11. Garot JJ. Et al. Magnetic resonance imaging of targeted catheter based implantation of myogenic precursor cells into infarcted left ventricular myocardium. J Am Coll Cardiol 2003; 41; 1841-1846.
12. Lederman RJ.et al. Catheter based endomyocardial injection with real time magnetic resonance imaging. Circulation 2002; 105; 1282-1284.
13. Hagege AA, et al. Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 2003; 361; 491-492.
14. Muller P, et al. Cardiomyocytes of noncardiac origin in myocardial biopsies of human transplanted hearts. Circulation 2002. 106; 31-35.
15. Lee M, et al. Stem cell transplantation in myocardial infraction. Rev Cardiovasc Med. 2004; 5(2); 82-98.
16. Pittenger MF et al. Mesenchymal stem cells and their potential as cardiac therapeutics. Circulation Res. 2004; 95:9-20.

Intra- coronary Bone-Marrow Cell Transfer After Myocardial Infraction: Timing and Method for Transplantation.
Different routes of stem cell delivery have been used to repair infracted myocardium after acute myocardial infraction. Of these, intracoronary administration of hematopoietic progenitors represents the best tried method for stem cell therapy in patients with acute myocardial infraction. The procedures described herein, are based upon experience, which have been empirically designed. It is clear that that the procedures proposed will partially or fully change in the future as new experimental and clinical evidence emerges. Stem cells can be obtained from bone marrow. In that case bone marrow is aspirated from the iliac crest under local anesthesia with an aspiration needle. At this time, the cells can be injected, or cultivated overnight before being infused into the coronary artery. It is not known yet whether all mononuclear cells or a specific sub-population of cells previously described should be given. Therefore, not only hematopoietic and mesenchymal stem cells, but also other mononuclear cells are infused to the necrotic area. Circulating progenitor cells can also serve as a source for stem cells. In that case, peripheral venous blood (250ml) is collected, mononuclear cells are purified and ex-vivo cultured for 3 days and then reinfused. For intracoronary delivery of cells, an over-the-wire angioplasty balloon is used. Then the guide wire is withdrawn and the central lumen of the balloon is used to infuse the cells. Intracoronary infusion of the cell suspension is carried out, manually or with a pump, alternating periods of occlusion –infusion and reperfusion until the entire dose is given.

1. Tosh D. et al. How cells change their phenotype. Nat Rev Mol Cell Biol 2002; 3; 187-194.
2. Beltrami AP, et al. Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 2003; 114; 763-776.
3. Beltrani AP et al. Evidence that human cardiac myocytes divide after myocardial infraction. N Engl J Med 2001; 334; 1750-1757.
4. Thiele J, et al. Regeneration of heart muscle tissue: quantification of chimeric cardiomyocytes and endothelial cells following transplantation. Histol Histopatathol 2004; 19; 201-209.
5. Deb A, ET al. Bone marrow derived cardiomyocytes are present in adult human heart: A study of gender- mismatched bone marrow transplantation patients. Circulation 2003. 107; 1247-9.
6. Kang HJ. Et al. Effects of intracoronary infusion of peripheral blood stem cells with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomized clinical trial. Lancet 2004; 363; 751-756.
7. Menasche P, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol. 2003; 41; 1078-83.
8. Herreros J, et al. Autologous intramyocardial injection of cultured skeletal muscle-derived stem cells in patients with non-acute myocardial infarction. Eur Heart J 2003; 24; 2012-2020.
9. Pagani FD, et al. Autologous skeletal myoblasts transplanted to ischemic-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003; 41; 879-888.
10. Galinanes M, et al. Autotransplantation of unmanipulated bone marrow is safe and enhances cardiac function in humans. Cell Transplant 2004; 13; 7-13.
11. Smits PC, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow up. J Am Coll Cardiol 2003; 42; 2063-2069.
12. Assmus B, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction. (TOPCARE-AMI). Circulation 2002; 106; 3009-3017.
13. Fernandez-Aviles F, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infraction. Cir Res. 2004; 95; 742-748.
14. Wollert KC, et al. Intracoronary bone –marrow cell transfer after myocardial infraction: the BOOST randomized controlled clinical trial. Lancet 2004; 364; 141-148.
15. Chen SL, et al. Effect on left ventricular function of intracoronary transplantation of autologous bone-marrow mesenchymal stem cell in patients with acute myocardial infraction. Am J Cardiol 2004; 94; 92-5.
Epicardial local delivery has shown to be an easy and reliable method for gene and cell therapy. Although epicardial transplantation has been the most common route of delivery for cell transplant, an endoventricular approach has several advantages, including that the procedure can be used in high risk patients and repeated with minimal risk to the patient. In addition, it is associated with lower morbidity rate than surgery, and is effectively used to treat areas normally inaccessible by surgery, such as the septum. At present, several endoventricular devices are under evaluation. They may be divided into two categories: the three -dimensional (3-D) guidance catheter delivery system and the two-dimensional (2-D) fluoroscopy guidance systems.

Endoventricular delivery is a more safe, accurate and reproducible delivery of cells, which ideally incorporates the visually, dynamic internal architecture of the ventricle, in real time. The catheter maneuverability and orientation of the catheter tip in three dimensional spaces, has the exacting ability to penetrate and inject into the thin, scarred myocardium. Endoventricular injection catheters have an exemplary safety record, with few reports of myocardial rupture leading to cardiac tamponade from overly aggressive catheter manipulation or injection.
While catheter injection of cells is a relatively new innovation, the ability to access the heart without having to perform a medium sternotomy, is quietly revolutionizing the future of interventional cardiology .The procedure is likely to have application in a majority of patients with previous myocardial infarctions and congestive heart failure. The use of real time, 3-D guidance appears to be key in targeting areas that need to be treated. Cardiologists can pre-map, the heart for study and identify the afflicted parts of the heart; marking 25, to 75, target/injection points, pre-programmed into the imaging computer. Each one of these 77 target points actually express specific electrical output measurements, which immediately show if the scarred myocardium is completely dead or there is some evidence of viability. Before and after color photo images allows physicians
to compare and contrast the efficacy over time. The complete procedure routinely takes 45 minutes.

1. Perin EC, et al. Transendocardial, autologous bone marrow transplantation for severe, chronic ischemic heart failure. Circulation. 2003; 107:2294-302.
2. Pagani FD, et al. Autologous skeletal myoblasts transplanted to ischemic-damaged myocardium in humans. Histological analysis of cell survival and differentiation. J Am Coll Cardiol 2003; 41; 879-888.
3. Smits PC, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow up. J Am Coll Cardiol 2003; 42; 2063-2069.
4. Fuchs, S. et al. Catheter based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease. J Am Coll Cardiol. 41; 1721-1724; 2003.
5. Menasche P, et al. Autologous skeletal myoblast transplantation for severe post infarction left ventricular dysfunction. J Am Coll Cardiol. 2003; 41; 1078-83.
6. Fortuin FD, Losordo DW, et al. One-year follow up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotmy in no-option patients. J.Am. Coll. Cardiol.92, 436-9.
7. Dib N, et al. Safety and feasibility of autologous myoblast transplantation in patients with ischemic cardiomyopathy: Interim results from the United States experience. Circulation. 106,II-463. 2002
8. Vale PR, Losordo DW, et al. Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation. 103, 2138-43, 2001.
9. Dib N, et al. Feasibility and safety of autologous myoblast transplantation in patients with ischemic cardiomyopathy. Cell Transplantation. 14. 2003.
10. Fuchs S, et al. A randomized double blind placebo controlled multi-center pilot study of the safety and feasibility of AdGVVEGF121.10 via an
intramyocardial injection catheter in patients with advanced coronary artery disease. J Am Coll Cardiol. 41, 21A, 2003.
11. Ince H, et al. Transcatheter transplantation of autologous skeletal myoblasts in post infarction patients with severe left ventricular dysfunction. J.Endovas.Ther.6; 695-704. 2004.
12. Dib N, et al. Endoventricular transplantation of allogenic skeletal myoblasts in a porcine model of myocardial infraction. J. Endovas. Ther. 9, 313-9. 2002.
13. Yoon PD, et al. Myocardial regeneration. Transplanting satellite cells into damaged myocardium. Texas Heart Inst. J. 1995; 22; 119-125.
14. Kornowski R, et al. Preliminary animal and clinical experiences using an electromechanical mapping procedure to distinguish infarcted from healthy myocardium. Circulation. 1998; 98; 1116-1124.
15. Deutsch E, et al. Autologous skeletal muscle transplantation in the swine heart: feasibility and viability endocardial delivery. Circulation. 1999; 100; 1-164.
16. Hennebry TA, et al. No-Option Patients: a nightmare today, a future with hope. J Inv Cardiol 2004; 17; 93-4.
17. Perin E, Willerson JT, et al. Adult stem cell therapy in perspective. Circulation. 2003; 107; 935-938.
18. Kornowski R, et al. Evaluation of the acute and chronic safety of the biosense injection catheter system in porcine hearts. Cathet Cardiovas Intervent 1999; 48; 447-453.
19. Sarmento-Leite R, Silva GV, et al. Comparison of left ventricular electromechanical mapping and left ventricular angiography: Defining practical standards for analysis of NOGA maps. Texas Heart Inst J. 2003; 30; 9-6.
20. Forrester JS, et al. Stem cell repair of infarcted myocardium: An overview for clinicians. Circulation 2003. 108; 1139-1145.
21. Perin EC, et al. Assessing myocardial viability and infract transmurality with left ventricular electromechanical mapping inpatients with stable coronary artery disease: Validation by delayed-enhancements magnetic resonance imaging. Circulation.2002;106;957-961.
22. Perin EC, Dohmann HF, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004; 110(supp II); 213-218.
23. Dohmann HF, et al. Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: Postmortem anautomicopathologic and immunohistochemical findings. Circulation 2005. 112; 521-526.
24. Assmus B. et al. Transcoronary transplantation of progenitor cells and recovery of left ventricular function in patients with chronic heart disease: Results of randomized, controlled, clinical trial. Circulation 2004; 110(supp III) ;238.

Whole Bone Marrow Transplantation
Emerson C. Perin, MD, PhD, and Guilherme V. Silva, MD;Texas Heart Institute.
Treating ischemic heart failure remains one of the most challenging tasks in current cardiology practice. Despite recent technological advances, many heart failure patients are not ideal candidates for percutaneous or surgical revasculation. This so-called “no-option” patient group usually comprises those individuals who have undergone multiple revascularization procedures and have significant residual myocardial ischemia. The hallmark of the so-called “no-option” group of patients is that the current treatment approach yields unsatisfactory results and they continue to have unmanageable symptoms of refractory angina or heart failure. New insights6 into the mechanisms of cardiac repair have provided evidence that the heart can undergo a repair process in adulthood. Currently, several types of stem cells are under investigation for the use in cardiac stem cell therapy. Bone marrow-derived stem cells were among the first to be studied in clinical trials, and are the most widely used cell source for cardiac cell therapy.

Bone Marrow Cells and Vascular Growth
Takayuki Asahara, MD, PhD.
Tissue regeneration by somatic stem/progenitor cells has been recognized as a system for maintenance of homeostasis in many organs. The isolation and investigation of these somatic stem/progenitor cells describes how these cells contribute to post-natal organogenesis. On the basis of their regenerative potency, these somatic stem/progenitor cells are considered a key therapeutic strategy for damaged organs.
Recently, endothelial progenitor cells (EPC’s) have been isolated from peripheral blood. EPC’s share common stem/progenitor cells with hematopoietic stem cells (HSC’s), both being derived from bone marrow (BM) and able to incorporate into foci of physiological or pathological neovascularization. The findings that EPC’s home to sites of neovascularization and differentiate into endothelial cells (EC’s) in situ is consistent with vasculogenesis- a critical paradigm… This discovery has drastically changed our understanding of adult blood vessel formation.

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4. Asahara T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 1999; 85; 221-228.
5. Tamaki T, et al. Identification of myogenic-endothelial progenitor cells in the interstitial spaces of skeletal muscle. J Cell Biol 2002; 157; 571-577.
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11. Murohara T. et al. Transplanted cord-blood derived endothelial precursors cells augment post natal neovasculazition. J Clin Invest 2000; 105; 1527-1536.
12. Crosby JR, et al. Endothelial cells of hematopoietic origin make a significant contribution to adult blood vessel formation. Circ Res 2000; 87; 728-730.
13. Murayama T, et al. Determination of bone marrow-derived endothelial progenitor cell significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hermatol 2002; 30; 967-972.
14. Reyes M, et al. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 2002; 109; 337-346.
15. Boyer M, et al. Isolation of endothelial cells and their progenitor cells from human peripheral blood. J Vasc Surg 2000; 31; 181-189.
16. Kalka C, et al. Transplantation of ex vivo expanded endothelial progenitor cells for therapeutic neovascularization. Proc Natl Acad Sci USA 2000; 97; 3422-3427.
17. Quirici N, et al. Differentiation and expansion of endothelial cells from human bone marrow CD34 (+) cells. Br J Haematol 2001; 115; 186-194.
18. Takahashi T, et al. Ischemia and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med 1999; 5; 434-438.
19. Asahara T, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. EMBO J 1999; 18; 3964-3972.
20. Dimmeler S, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI3-kinase/Akt pathway. J Clin invest 2001; 108; 391-397.
21. Vasa M. et al. Increase in circulating endothelial progenitor cells by statin therapy in patients with stable coronary artery disease. Circulation 2001; 103; 2885-2890.
22. Urbich C, et al. Double- edged role of statins in angiogenesis signaling. Circ Res 2002; 90; 737-744.
23. Murayama T, et al. Aging impairs therapeutic contributions of human endothelial progenitor cells postnatal neovascularization. (Abstract) Circulation 2001; 104; 11-68.
24. Vasa M, et al Number and migratory activity activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res 2001; 89; E1-E7.
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27. Kawamoto A, et al. Therapeutic potential of ex-vivo expanded endothelial progenitor cells for myocardial ischemia. Circulation 2001; 103; 634-637.
28. Kocher AA, et al. 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.
29. Iwasaki H, et al. Dose dependent contribution of CD34 positive cell transplantation to concurrent vasculogenesis and cardiomyogenesis for functional regenerative recovery post myocardial infarction. Circulation 2006; 113; 1311-1325.
30. Iwaguro H, et al. Endothelial progenitor cell vascular endothelial growth factor gene transfer for vascular regeneration. Circulation 2002; 105; 732-738.
31. Shintani S., et al. Augmentation of postnatal neovascularization with autologous bone marrow transplant. Circulation 2001; 103; 897-903.
32. Hamano K et al. The induction of angiogenesisby the implantation of bone marrow cells a novel and simple therapeutic method. Surgery 2001; 130; 44-54.
33. Kamihata H, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001; 104; 1046-1052.
34. Bhattacharya V, et al. Enhanced endothelialization and microvessel formation in polyester grafts seeded with CD34+ bone marrow cells. Blood 2000; 95; 581-585.
35. Shimizu T, et al. Fabrication of pulsatile cardiac tissue grafts using 3-dimensional cell sheet manipulation technique and temperature-responsive cell culture surfaces. Circ Res 2002; 90; e40.
36. Shimizu T, et al. Electrically communicating three-dimensional cardiac tissue mimic fabricated by layered cultured cardiomyocyte sheets. J Biomed Mater Res 2002; 60; 110-117.
Cardiac stem cells: A new view of cardiac biology.
Annarosa Leri, MD, Alessandro Boni, PhD, Robert Siggins, PhD, Angelo Nasciembene, MD,& Toru Hosoda , MD.
The heart has been found to be a self-renewing organ characterized by resident cardiac stem cells (CSC’s) and early committed cells (ECC’s) stored in niches. This novel view of the heart raises the possibility that defects in myocardial homeostasis and ventricular dysfunction occur because of a progressive increase in the number of CSC’s-(minus) ECC’s permanently withdrawn from the cell cycle. The heart is composed of myocytes that constitute a population of highly specialized cells. In self renewing organs, cell number depends on the stem cell pool. Although stem cell antigens have been unequivocally detected in CSC’s. There is no one marker capable of providing an absolute identification of stem cells in vivo. This is why the search for the “true” stem cell removed from its microenvironment has been elusive. Acknowledgment: This work was supported by NIH grants.
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2. Leri A, et al. Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 2005; 85; 1373-1416.
3. Chien KR, et al. Stem cells: Lost in translation. Nature 2004; 428; 607-608.
4. Urbanek K, et al. Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci USA 2003; 100; 10440-10445.
5. Chimenti C, et al. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 2003; 93; 604-613.
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7. Palmer TD, et al. Vascular niche for adult hippocampal neurogenesis. J Comp Neurol 2000; 425; 479-494.
8. Leri A, et al. Symmetric and asymmetric division of cardiac stem cells in the mouse heart. Circulation 2003; 108; iv-33.
9. Oh H, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infraction. Proc Natl Acad Sci USA 2003; 100; 12313-12318.
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11. Rosenblatt-Velin N, et al. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes. J Chin Invest 2005; 115; 1724-1733.
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13. Leri A, MD, Piero Anversa MD & William FrishmanMD. Cardiovascular Regeneration and stem cell therapy. Professor’s medicine/chairman; vice-chairman; Cardiovascular Research Institute; New York Medical College.
Bone-marrow-derived cells in myocardial repair and regeneration
Raj Kishore, PhD, & Douglas Lorordo, MD.
In 1960, McColloch and Till introduced the concept of the adult stem cell by identifying the bone marrow(BM) as a repository of cells having the capacity of reconstituting the entire hematopoietic system following lethal irradiation. Over 30 years later Asahara et al extended this concept, revealing that BM-derived cells were also capable of vasculogenesis, a process previously considered to be restricted to embryonic life. Evidence has also continued to accumulate, indicating the remarkable ability of adult stem cells to produce differentiated cells from embryologically unrelated tissues.
Three available lines of evidence converge in favor of this interpretation: (1) the recent observations that cardiac endogenous cells are present in the normal myocardium and are involved in the maintenance of cellular homeostasis , with the ability to expand and regenerate myocytes and microvasculative in the infarcted myocardium; (2)the evidence that in humans cardiomyocyte repopulation by BM-derived progenitors of hematopoietic origin can take place, (3) the demonstration that it is possible to increase the efficiency of the intrinsic cardiac regenerative capacity. It is therefore reasonable to propose that BM-derived cells are part of an endogenous repair/regeneration process.
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5. Orlic D, et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc Natl Acad Sci USA 2001; 98(18) :10344-10349.
6. Badorff C, et al. Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003; 107 ;( 7):1024-1032.
7. Dimmeler S, et al. Unchain my heart: the scientific foundation of cardiac repair. J Clin Invest 2005; 115(3):572-583.
8. Ma N, et al. Human cord blood cells induce angiogenesis following myocardial infraction in NOD/SCID-mice. Cardiovas Res 2005; 66(1):45-54.
9. Zhang S, et al. Both cell fusion and transdifferentiation account for the transformation of human peripheral blood CD34-positive cells into cardiomyocytes in vivo. Circulation 2004; 110(25):3803-3807.
10. Yeh ET, et al. Transdifferentiation of human peripheral blood CD34+ enriched cell population into cardiomyocytes, endothelial cells, and smooth muscle cells in vivo. Circulation 2003; 108(17): 2070-2073.
11. Gibson CM, et al. Relationship of TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention to long term outcomes after thrombolytic administration in acute myocardial infraction. Circulation 2002; 105(16): 1909-1913.
12. Balsam LB, et al. Haematopoietic stem cells adopt mature haematopoietic fates in the ischaemic myocardium. Nature 2004; 428(6983):668-673.
13. Askari AT, et al. Effect of stromal-cell-derived factor I on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003: 362(9385): 697-703.
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15. Ying GL, et al. Changing potency by spontaneous fusion. Nature 2002; 416(6880); 545-548.
16. Losordo DW. Et al. Phase ½ placebo –controlled, double blind, dose escalating trial of myocardial vascular growth 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 2002; 105; 2012-2018.
17. Britten MB, et al. Infract remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infraction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003; 109(18): 2212-2218.
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Conclusions –future directions
Piero Anaversa MD, Edmund H. Sonnenblick, MD, & William H. Frishman. MD.
In April 2001, the recognition that hematopoietic stem cells (HSC’s) can acquire the cardiac cell lineages and regenerate the infarcted heart in mice started a scientific revolution that has dominated and continues to dominate the cardiovascular field biologically and clinically. This possibility, however, has generated profound enthusiasm and strong skepticism in the scientific and clinical community. The basis for this controversy is multifactorial and involves not only scientific reasons but also emotional beliefs. Under the ingrained conviction that HSC’s cannot disobey lineage specification, the detractors of HSC plasticity immediately claimed that they were unable to reproduce published results , and reaffirmed their negative view regarding the therapeutic efficacy of bone marrow cells for human disease. In spite of the fact that the experimental design and methodological analysis of the myocardium used in these negative studies were strikingly different from those employed in the original report; these data
fomented the debate and repurposed the use of skeletal myoblasts as the only safe and promising cells to be implemented in patients with chronic heart failure.
It is rather instructive that the disbelievers of HSC transdifferentiation are similarly against the possibility of cardiomyocyte regeneration by activation of endogenous stem cells. Their conviction is that we are born with a determined number of cardiomyocytes that can live for 100 years or more. Sense the majority of the cardiomyocytes are present at the death of the organ and organisms, according to this paradigm, these cells should be essentially immortal. (Editors note; here the authors cite studies and counter-studies that refute this historical view of the heart)
So far, experimental studies and clinical trials have employed rather heterogeneous bone marrow cell preparations, and this treatment has resulted in a consistent improvement in function of the infarcted heart. However, the search for the most effective HSC for cardio repair continues.
An unusual, unexpected behavior has emerged with the explosion of stem cell biology. The scientific community is divided in several sectors, which tend to promote one cell type versus another. Embryonic stem cells (ESC’s) are totipotent cells…problems related to rejection and tumor formations exist with this cell population… (Editors note: the FDA has recently approved the first human clinical study)
Mesenchymal stem cells have been defined as the nonhematopoietic progenitor cell compartment of the bone marrow. Marrow stromal cells are highly proliferative and clonogenic …Cells beat spontaneously and synchronously; Importantly, MSC’s lead to myocardium regeneration in vivo.
Circulating bone-marrow-derived cells include a subset of the endothelial progenitor cells (EPC’s), which promotes neovasculation in vivo. Evidence suggests that EPC’s generate new vessels..Additionally, the ability of EPC’s to acquire myocyte lineage has been documented in vitro and in vivo. The clinical importance of these findings is enormous.

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