The medical community is currently experiencing a wave of enthusiasm for clinical trials in which adult stem/progenitor cells are used to repair tissues. The enthusiasm is based on promising results in animal models for a variety of diseases and the encouraging reports from some initial clinical trials.1-6  It is also driven by the prospect that stem/progenitor cells may offer new hope for patients with end-stage diseases for which there are no therapies. In the wave of enthusiasm, however, several essential precautions are not being fully addressed. Therefore, there is a great danger that potentially important new therapies will be discarded prematurely because of poorly designed clinical trials.

In theory, adult stem/progenitor cells may provide a therapy for an almost unlimited number of serious and currently untreatable diseases. Their potential derives from their normal role as cells that repair injured tissues.1,7  It is now known that essentially every tissue and organ in the body contains such cells for tissue repair. After the stem/progenitor cells in a tissue are exhausted by severe or chronic injury, they can be supplemented by similar cells that flow through the blood stream from the bone marrow. Both the stem/progenitor cells found in most tissues and the similar cells from bone marrow can differentiate into most cellular phenotypes and thereby replace damaged cells. It was recently made known, however, that the cells can repair injured tissues by a variety of other mechanisms, some of which are still poorly defined. The cells are a rich source of chemokines and cytokines, as is well known from the use of confluent layers of the stem/progenitor cells referred to as marrow stromal cells as feeder layers for culture of hematopoietic cells. The chemokines and cytokines can stimulate regeneration of cells by inhibiting apoptosis, suppressing immune reactions, and increasing angiogenesis. The cells can also enhance proliferation and differentiation of tissue-endogenous stem/progenitors cells as indicated by recent experiments in which human stem/progenitor cells were infused into the hippocampus of immunodeficient mice.8  In addition, they may rescue cells with nonfunctioning mitochondria by transfer of either mitochondria or mitochondrial DNA, as was recently observed in coculture experiments.9  To some extent, they may also repair tissues by cell fusion.1,10  Recent observations, in fact, suggest that we may have unnecessarily confused ourselves by referring to them as adult stem cells. They can more properly be referred to as reparative cells, or some catchier name.

Despite the great promise, it is clear that development of new therapies with cells that repair tissues will not be a linear sequence of events. As with most dramatically new therapies, the data from basic studies and from animal models are never as conclusive as one would like. The best one can say is that the data are encouraging enough to justify carefully controlled trials in patients in whom the risks can be fully justified. The molecular events of tissue repair remain a mysterious and complex process, perhaps one of the most complex processes in all of biology and medicine. Therefore, as researchers proceed, the current clinical trials must be examined carefully and used as a basis for further research to improve the therapies. The situation is analogous to the development of bone marrow transplantation in which the first long-term successes11  were not achieved until nearly a decade after the first trials in patients with end-stage hematologic malignancies.12 

The first clinical trials with adult stem/progenitor cells to repair nonhematopoietic tissues were carried out with the plastic adherent cells from bone marrow referred to in the hematologic literature as marrow stromal cells, but first defined as fibroblastoid colony-forming units, then as mesenchymal stem cells, or most recently as multipotent mesenchymal stromal cells (MSCs).1,13  The cells can readily be isolated from a small sample of marrow and rapidly expanded so as to generate large numbers of cells for autologous therapies. The initial clinical trials with MSCs were in patients with severe osteogenesis imperfecta2  and then in patients with mucopolysaccharidoses.3  Subsequently, trials were initiated for graft-versus-host disease that capitalize on the ability of the cells to suppress immune reactions.4,5 

Currently, the largest number of clinical trials is in patients with heart disease. Here, a confusing variety of cells and strategies for different syndromes have been tested (Table 1) 14-43  One approach was to mobilize bone marrow cells by subcutaneous administration of G-CSF. Another was to isolate unfractionated mononuclear cells from autologous bone marrow and infuse the cells either into a coronary artery or into the border region of myocardial infarcts. Still another approach was to isolate CD34+ or CD133+ cells from marrow or CD34+-enriched cells from peripheral blood after mobilization and then to infuse the cells into a coronary artery or the borderline of infarcted areas. Still other approaches were to use the same routes of infusion with either isolated endothelial progenitor cells or MSCs. To date, only a limited number of adverse effects have been attributed to any of the different therapies. In contrast, an earlier trial in which skeletal myoblasts were infused into the myocardium produced a high incidence of arrhythmias. Most of the trials using bone marrow cells have reported improvements in cardiac function. However, the number of patients enrolled in well-controlled trials is still limited.

Table 1.

Summary of published clinical trials treating myocardial infarction with cellular therapies

Name of study or authorsCell typeDelivery methodCell isolation/purificationDiagnosisNo. of patients (exp/control)Safety and adverse eventsOther observationsLength of study
Zohlnhofer et al14  G-CSF to mobilize bone marrow SC NA Acute MI 56/58 Safe No significant effects 4-6 mo 
STEMMI; Ripa et al15  G-CSF to mobilize bone marrow SC NA Acute ST-elevation MI 36/36 Safe No significant effects 6 mo 
Huttmann et al16  G-CSF to mobilize bone marrow SC NA Chronic heart disease 9 ICM/8 ICM controls ICM may risk increased angina and arrhythmia 4 DCM and 5 ICM NYHA improvement and increased 6-min walking distance 6 mo 
Valgimigli et al17  G-CSF to mobilize bone marrow SC NA Acute MI 7/7 Safe LVEF up, EDV down 3, 6 mo and follow-up 
REPAIR-AMI; Schachinger et al18  BMCs or PBSCs ICI Ficoll density gradient sedimentation Acute MI 103/101 Safe LVEF up, ESV down, improved contractility at 4 mo; lower mortality, recurrence, and procedures at 1 y 4 mo, 1 y 
TOPCARE-AMI; Schachinger et al19  BMCs or PBSCs ICI Ficoll density gradient sedimentation Acute MI 30 PBSC and 29 BMC Safe LVEF up, ESV down, reduced infarct size 1 y 
MAGIC; Kang et al20  G-CSF mobilized PBSCs ICI COBE Spectra Apheresis System Reperfused MI 10 PBSC, 10 G-CSF only/7 control G-CSF alone caused complications LVEF up, better perfusion and exercise time 6 mo 
Archundia et al21  G-CSF mobilized PBSCs IMI in old infarct Baxter closed circuit apheresis Old MI 5/10 Safe Improved contractility 28-52 wk 
Yaoita et al22  BMCs or G-CSF mobilized PBSCs IMI BMCs: Not specified/PBSCs: apheresis Ischemic heart disease 10 Safe Increased perfusion Up to 32 mo 
Assmus et al23  BMCs or PBSCs ICI Ficoll density gradient sedimentation Healed MI 24 PBSC, 28 BMC/23 control with crossover Safe With BMCs or crossover, LVEF up, improved contractility and NYHA; with PBSCs, no significant improvements 3 mo, 3 mo crossover 
Lunde et al24  BMCs ICI Ficoll density gradient sedimentation Acute MI 47/50 Safe No significant effects on global left ventricular function 3 wk, 6 mo 
BOOST; Meyer et al25  BMCs ICI Gelatin-polysuccinate density gradient sedimentation Acute MI 30/30 LVEF normal at 18 mo LVEF up at 6 months 6-18 mo 
Janssens et al26  BMCs ICI Ficoll density gradient sedimentation Acute ST-elevation MI 33/34 Safe Smaller infarcts, improved recovery of systolic functions 4 mo 
Fernandez-Aviles et al27  BMCs ICI Ficoll density gradient sedimentation Reperfused MI 20/13 Safe LVEF up, ESV down, wall thickening 6 mo 
IACT; Strauer et al28  BMCs ICI Ficoll density gradient sedimentation Chronic coronary artery disease 18/18 Safe LVEF up, O2 consumption up, viability up, increased WMV, smaller infarct 3 mo 
Dohmann et al29  BMCs IMI Ficoll density gradient sedimentation Ischemic heart failure 14/7 Safe LVEF up, ESV down, smaller infarct, NYHA score improvement 6 mo 
Ruan et al30  BMCs ICI Not specified Acute MI 9/11 Safe LVEF up, EDV up, ESV down 3 mo 
Strauer et al31  BMCs ICI Ficoll density gradient sedimentation Acute MI 10/10 Safe LVEF up, WMV up, ESV down increased perfusion 3 mo 
Perin et al32  BMCs IMI Ficoll density gradient sedimentation Ischemic cardiomyopathy 11/9 Safe NYHA and CCS angina scores improved, exercise capacity up, perfusion up 6, 12 mo 
Hamano et al33  BMCs IMI COBE Spectra Apheresis System Ischemic heart disease Safe Perfusion up in 3/5 1 y 
Silva et al34  BMCs IMI Ficoll density gradient sedimentation Patients listed for heart transplantation Safe O2 consumption up, perfusion up, exercise improved, 4/5 no longer needed heart transplant 6 mo 
Tse et al35  BMCs IMI Ficoll density gradient sedimentation Ischemic myocardium Safe Improved perfusion, WMV, and function at infarct 3 mo 
Fuchs et al36  BMCs IMI Ficoll density gradient sedimentation Advanced coronary artery disease 10 Safe CCS angina score improved, stress-induced ischemia improved 3 mo 
Bartunek et al37  CD133+ BMCs ICI Ficoll and anti-CD133 MACs Recent MI 19/16 Various coronary complications LVEF up, ESP/ESV ratio up, perfusion up, viability up, LVEDV down 4 mo 
Stamm et al38  CD133+ BMCs IMI Ficoll and anti-CD133 MACs Patients undergoing LAVD Safe Improved LVEF in 4/6 and perfusion in 5/6 3-9 mo 
Chen et al39  MSCs ICI Percoll density gradient sedimentation Acute MI 34/35 Safe LVEF up, LVEDV and ESV down, WMV up, perfusion up, better electromechanics 3 mo 
Katritsis et al40  MSCs + EPCs ICI Ficoll and plastic adherence Infarcted myocardium 11/11 Safe Improved contractility, lower wall motion score, increased viability 4 mo 
Menasche et al41  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Postinfarct left ventricle dysfunction 10 Arrhythmia LVEF up, scar thickening, NYHA score improvement 10.9 mo 
Pagani et al42  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Ischemia-damaged myocardium Arrhythmia More blood vessels 68, 91, 144, and 191 d 
Herreros et al43  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Nonacute MI 12 Safe LVEF up, viability up, contractility improved 3 mo 
Name of study or authorsCell typeDelivery methodCell isolation/purificationDiagnosisNo. of patients (exp/control)Safety and adverse eventsOther observationsLength of study
Zohlnhofer et al14  G-CSF to mobilize bone marrow SC NA Acute MI 56/58 Safe No significant effects 4-6 mo 
STEMMI; Ripa et al15  G-CSF to mobilize bone marrow SC NA Acute ST-elevation MI 36/36 Safe No significant effects 6 mo 
Huttmann et al16  G-CSF to mobilize bone marrow SC NA Chronic heart disease 9 ICM/8 ICM controls ICM may risk increased angina and arrhythmia 4 DCM and 5 ICM NYHA improvement and increased 6-min walking distance 6 mo 
Valgimigli et al17  G-CSF to mobilize bone marrow SC NA Acute MI 7/7 Safe LVEF up, EDV down 3, 6 mo and follow-up 
REPAIR-AMI; Schachinger et al18  BMCs or PBSCs ICI Ficoll density gradient sedimentation Acute MI 103/101 Safe LVEF up, ESV down, improved contractility at 4 mo; lower mortality, recurrence, and procedures at 1 y 4 mo, 1 y 
TOPCARE-AMI; Schachinger et al19  BMCs or PBSCs ICI Ficoll density gradient sedimentation Acute MI 30 PBSC and 29 BMC Safe LVEF up, ESV down, reduced infarct size 1 y 
MAGIC; Kang et al20  G-CSF mobilized PBSCs ICI COBE Spectra Apheresis System Reperfused MI 10 PBSC, 10 G-CSF only/7 control G-CSF alone caused complications LVEF up, better perfusion and exercise time 6 mo 
Archundia et al21  G-CSF mobilized PBSCs IMI in old infarct Baxter closed circuit apheresis Old MI 5/10 Safe Improved contractility 28-52 wk 
Yaoita et al22  BMCs or G-CSF mobilized PBSCs IMI BMCs: Not specified/PBSCs: apheresis Ischemic heart disease 10 Safe Increased perfusion Up to 32 mo 
Assmus et al23  BMCs or PBSCs ICI Ficoll density gradient sedimentation Healed MI 24 PBSC, 28 BMC/23 control with crossover Safe With BMCs or crossover, LVEF up, improved contractility and NYHA; with PBSCs, no significant improvements 3 mo, 3 mo crossover 
Lunde et al24  BMCs ICI Ficoll density gradient sedimentation Acute MI 47/50 Safe No significant effects on global left ventricular function 3 wk, 6 mo 
BOOST; Meyer et al25  BMCs ICI Gelatin-polysuccinate density gradient sedimentation Acute MI 30/30 LVEF normal at 18 mo LVEF up at 6 months 6-18 mo 
Janssens et al26  BMCs ICI Ficoll density gradient sedimentation Acute ST-elevation MI 33/34 Safe Smaller infarcts, improved recovery of systolic functions 4 mo 
Fernandez-Aviles et al27  BMCs ICI Ficoll density gradient sedimentation Reperfused MI 20/13 Safe LVEF up, ESV down, wall thickening 6 mo 
IACT; Strauer et al28  BMCs ICI Ficoll density gradient sedimentation Chronic coronary artery disease 18/18 Safe LVEF up, O2 consumption up, viability up, increased WMV, smaller infarct 3 mo 
Dohmann et al29  BMCs IMI Ficoll density gradient sedimentation Ischemic heart failure 14/7 Safe LVEF up, ESV down, smaller infarct, NYHA score improvement 6 mo 
Ruan et al30  BMCs ICI Not specified Acute MI 9/11 Safe LVEF up, EDV up, ESV down 3 mo 
Strauer et al31  BMCs ICI Ficoll density gradient sedimentation Acute MI 10/10 Safe LVEF up, WMV up, ESV down increased perfusion 3 mo 
Perin et al32  BMCs IMI Ficoll density gradient sedimentation Ischemic cardiomyopathy 11/9 Safe NYHA and CCS angina scores improved, exercise capacity up, perfusion up 6, 12 mo 
Hamano et al33  BMCs IMI COBE Spectra Apheresis System Ischemic heart disease Safe Perfusion up in 3/5 1 y 
Silva et al34  BMCs IMI Ficoll density gradient sedimentation Patients listed for heart transplantation Safe O2 consumption up, perfusion up, exercise improved, 4/5 no longer needed heart transplant 6 mo 
Tse et al35  BMCs IMI Ficoll density gradient sedimentation Ischemic myocardium Safe Improved perfusion, WMV, and function at infarct 3 mo 
Fuchs et al36  BMCs IMI Ficoll density gradient sedimentation Advanced coronary artery disease 10 Safe CCS angina score improved, stress-induced ischemia improved 3 mo 
Bartunek et al37  CD133+ BMCs ICI Ficoll and anti-CD133 MACs Recent MI 19/16 Various coronary complications LVEF up, ESP/ESV ratio up, perfusion up, viability up, LVEDV down 4 mo 
Stamm et al38  CD133+ BMCs IMI Ficoll and anti-CD133 MACs Patients undergoing LAVD Safe Improved LVEF in 4/6 and perfusion in 5/6 3-9 mo 
Chen et al39  MSCs ICI Percoll density gradient sedimentation Acute MI 34/35 Safe LVEF up, LVEDV and ESV down, WMV up, perfusion up, better electromechanics 3 mo 
Katritsis et al40  MSCs + EPCs ICI Ficoll and plastic adherence Infarcted myocardium 11/11 Safe Improved contractility, lower wall motion score, increased viability 4 mo 
Menasche et al41  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Postinfarct left ventricle dysfunction 10 Arrhythmia LVEF up, scar thickening, NYHA score improvement 10.9 mo 
Pagani et al42  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Ischemia-damaged myocardium Arrhythmia More blood vessels 68, 91, 144, and 191 d 
Herreros et al43  Skeletal myoblasts IMI Biopsy dissociation and plastic culture Nonacute MI 12 Safe LVEF up, viability up, contractility improved 3 mo 

G-CSF indicates granulocyte colony-stimulating factor; SC, subcutaneous; NA, not applicable; MI, myocardial infarcttion; ICM, ischemic cardiomyopathy; DCM, dilated cardiomyopathy; NYH, New York Heart Association; LVEF, left ventricular ejection fraction; EDV, end-diastolic volume; BMCs, bone marrow mononuclear cells; PBSCs, peripheral blood stem cells; ICI, intracoronary injection; ESV, end-systolic volume; IMI, intramyocardial injection; WMV, wall movement velocity; CCS, Canadian Cardiovascular Society; MACs, magnetic-assisted cell sorting; LAVD, left ventricular assist device; MSCs, mesenchymal stem cells or multipotent stromal cells; EPCs, endothelial progenitor cells.

As these trials proceed, it seems imperative that we address some of the potential dangers that have frequently been ignored.

One potential danger is that the clinical trials will be performed without appropriate controls or without well-defined end points. The danger seems particularly apparent in trials such as those in acute myocardial infarction in which there is great variability in the size and location of the lesions, the outcomes are difficult to predict, and different parameters have been used to assess heart function (Table 1).

Ironically, a second potential risk arises from the striking ability of stem/progenitors cells to enhance repair of tissues and to suppress immune reactions: Several reports demonstrated that MSCs stimulate the growth of cancers in mice.44,45  The cells apparently enhance growth of the cancer by decreasing immune reactions or by responding to the cancer as “a wound that never heals.” Therefore, there is a risk that administering MSCs or similar cells will enhance the growth of a previously undetected cancer in a patient. The risk may be small, but it probably should not be overlooked by the physician, by the patient, or in the consent form. By alerting everyone to the possibility, researchers may be able to avoid repeating the sad episode in the history of viral gene therapy in which a shadow was cast over the whole field by a trial in which 9 of 10 patients with severe combined immunodeficiency disease were cured but 2 patients subsequently developed leukemia because of an unanticipated insertional mutation from a retrovirus.46 

A related risk that is more difficult to define is that stem/progenitor cells that are extensively expanded in culture may themselves generate tumors in patients. Expansion of cells in culture is an attractive strategy because it makes it possible to administer more stem/progenitor cells than the patient can generate on his or her own. MSCs and related stem/progenitor cells can be expanded in culture as rapidly as or even more rapidly than embryonic stem cells. One important distinction between adult stem/progenitor cells and embryonic stem cells is that the embryonic stem cells are immortal in culture and have a great propensity to generate tumors in mice. In contrast, MSCs senesce after expansion through 40 to 50 population doublings, and early passage cells have not produced tumors. However, researchers have known for a long time that if fibroblasts from mouse embryos are cultured for prolonged periods, they undergo senescence followed by a “crisis” phase in which many of the cells die.47  The few cells that survive the crisis first become immortal in culture and then, after further expansion, can become tumorogenic. A similar sequence of events was observed with human MSCs that were cultured under stressful conditions for many weeks after which they became immortal, developed unstable chromosomes, and generated tumors in mice.48  We know of no instance in which culture-expanded cells have generated tumors in patients, but there is clearly some risk in administering stem/progenitor cells that have been extensively expanded in culture. DNA replication is an accurate but imperfect process. Therefore, every cell division has a small chance of introducing deleterious mutations, most of which cannot be detected by karyotyping. The risk of mutations is probably higher with cells that, like embryonic stem cells, are immortal in culture. The risk is probably lower with cells that undergo a limited number of population doublings in culture, retain a normal karyotype, and are not immortal in culture. However, despite our best efforts, stem/progenitor cells are still black boxes. Further research is certainly necessary to understand all their mysterious features and to develop better assays for potentially deleterious changes in culture.

A further danger is posed by cells that are injected in high concentrations into tissues. Concentrated cells injected into tissues can form aggregates, particularly if sheared by passage through small needles under pressure. Also, aggregates of cells with the potential to differentiate can generate their own microenvironment to form nodules of bone or other undesirable structures. Cells such as MSCs rapidly form cell-to-cell adhesions as they are expanded in culture. The adherence junctions must be cut with trypsin or other proteases to lift the cells from culture plates and disperse them. However, the cells in suspension will quickly regenerate the adhesion junctions and aggregate. Therefore, if they are not handled with extreme care, they can produce pulmonary emboli or infarctions after infusion into patients.

Finally, researchers currently face the danger of generating a great deal of confusion by clinical trials in which the cells used are not adequately characterized. The hematopoietic stem cells used in some clinical trials (Table 1) have been well characterized, but the ability of hematopoietic stem cells to repair nonhematopoietic tissues has not been reproducibly demonstrated in animal studies.49  The use of unfractionated mononucleated cells from bone marrow has little support from animal studies and raises a series of questions about the mechanisms involved. The use of MSCs or related cells also presents problems in that cultures of the cells are heterogeneous, even when generated as single-cell–derived colonies.1  As a result, there is considerable variability in the properties of different preparations of MSCs used in clinical trials. Unfortunately, there currently are no adequate markers to identify most of the stem/progenitor cells being used. Accordingly, there is a great need to standardize protocols for preparing the cells and to develop more definitive markers.

As research goes forward, there will be a continuing need for careful reanalysis of both the risks and potential benefits to patients. Certainly, researchers will all be sorry if clinical trials with adult stem/progenitor cells do not incorporate some of the simple and essential precautions that can prematurely close down new therapies, in this case, therapies that show great promise of helping millions of patients for whom we can now offer little or no hope.

Contribution: D.J.P. wrote the paper, and S.D.O. prepared the table.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Darwin J. Prockop, Center for Gene Therapy, Tulane University Health Sciences Center, New Orleans, LA 70112; e-mail: [email protected].

This work was supported by the National Institutes of Health (grants HL 073755, HL073252, and P01 HL 075161) and by the Louisiana Gene Therapy Research Consortium.

1
Prockop DJ, Gregory CA, Spees JL. One strategy for cell and gene therapy: harnessing the power of adult stem cells to repair tissues.
Proc Natl Acad Sci U S A
2003
;
100
:suppl 1,
11917
–11923.
2
Horwitz EM, Prockop DJ, Gordon PL, et al. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta.
Blood
2001
;
97
:
1227
–1231.
3
Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH).
Bone Marrow Transplant
2002
;
30
:
215
–222.
4
LeBlanc K and Ringden O. Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant
2005
;
11
:
321
–334.
5
Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients.
Biol Blood Marrow Transplant
2005
;
11
:
389
–398.
6
Fazel S, Tang GH, Angoulvant D, et al. Current status of cellular therapy for ischemic heart disease.
Ann Thorac Surg
2005
;
79
:
S2238
–S2247.
7
Ye L, Haider HK, Sim EKW. Adult stem cells for cardiac repair: a choice between skeletal myoblasts and bone marrow stem cells.
Exp Biol Med (Maywood)
2006
;
231
:
8
–19.
8
Weiss DJ, Berberich MA, Borok Z, et al. Adult stem cells, lung biology and lung disease.
Proc Am Thorac Soc
2006
;
3
:
193
–207.
9
Munoz JR, Stoutenger BR, Robinson AP, Spees JL, Prockop DJ. Human stem/progenitor cells from bone marrow promote neurogenesis of endogenous neural stem cells in the hippocampus of mice.
Proc Natl Acad Sci U S A
2005
;
102
:
18171
–18176.
10
Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration.
Proc Natl Acad Sci U S A
2006
;
103
:
1283
–1288.
11
Ogle BM, Casalho M, Platt JL. Biological implications of cell fusion.
Nat Rev Mol Cell Biol
2005
;
6
:
567
–575.
12
Mathe G, Amiel JL, Schwarzenberg L, et al. Successful allogenic bone marrow transplantation in man: chimerism, induced specific tolerance and possible anti-leukemic effects.
Blood
1965
;
25
:
179
–196.
13
Thomas ED, Lochte HL Jr, Lu WC, Ferrebee JW. Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy.
N Engl J Med
1957
;
257
:
491
–496.
14
Zohlnhofer D, Ott I, Mehilli J, et al. Stem cell mobilization by granulocyte colony-stimulating factor in patients with acute myocardial infarction: a randomized controlled trial.
JAMA
2006
;
295
:
1003
–1010.
15
Ripa R, Jorgensen E, Yongzhong W, et al. Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-controlled stem cells in myocardial infarction (STEMMI) trial.
Circulation
2006
;
113
:
1983
–1992.
16
Huttmann A, Duhrsen U, Stypmann J, et al. Granulocyte colony-stimulating factor-induced blood stem cell mobilization in patients with chronic heart failure—feasibility, safety and effects on exercise tolerance and cardiac function.
Basic Res Cardiol
2006
;
101
:
78
–86.
17
Valgimigli M, Rigolin GM, Cittanti C, et al. Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile.
Eur Heart J
2005
;
26
:
1838
–1845.
18
Schachinger V, Erbs S, Elsasser A, et al. Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction.
N Engl J Med
2006
;
355
:
1210
–1221.
19
Schachinger V, Assmus B, Britten M, et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction: final one-year results of the TOPCARE-AMI Trial.
J Am Coll Cardiol
2004
;
44
:
1690
–1699.
20
Kang H, Kim H, Zhang S, et al. Effects of intracoronary infusion of peripheral blood stem-cells mobilized 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.
21
Archundia A, Aceves JL, Lopez-Hernandez M, et al. Direct cardiac injection of G-CSF mobilized bone-marrow stem-cells improves ventricular function in old myocardial infarction.
Life Sci
2005
;
78
:
279
–283.
22
Yaoita H, Takase S, Maruyama Y, et al. Scintigraphic assessment of the effects of bone marrow-derived mononuclear cell transplantation combined with off-pump coronary artery bypass surgery in patients with ischemic heart disease.
J Nucl Med
2005
;
46
:
1610
–1617.
23
Assmus B, Honold J, Schachinger V, et al. Transcoronary transplantation of progenitor cells after myocardial infarction.
N Engl J Med
2006
;
355
:
1222
–1232.
24
Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction.
N Engl J Med
2006
;
355
:
1199
–1209.
25
Meyer G, Wollert K, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial.
Circulation
2006
;
113
:
1287
–1294.
26
Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind randomized controlled trial.
Lancet
2006
;
367
:
113
–121.
27
Fernandez-Aviles F, San Roman JA, Garcia-Frade J, et al. Experimental and clinical regenerative capability of human bone marrow cells after myocardial infarction.
Circ Res
2004
;
95
:
742
–748.
28
Strauer BE, Brehm M, Zeus T, et al. Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow cell transplantation in chronic coronary artery disease: the IACT Study.
J Am Coll Cardiol
2005
;
46
:
1651
–1658.
29
Dohmann HF, Perin EC, Takiya CM, et al. Transendocardial autologous bone marrow mononuclear cell injection in ischemic heart failure: postmortem anatomicopathologic and immunohistochemical findings.
Circulation
2005
;
112
:
521
–526.
30
Ruan W, Pan CZ, Huang GQ, et al. Assessment of left ventricular segmental function after autologous bone marrow stem cells transplantation in patients with acute myocardial infarction by tissue tracking and strain imaging.
Chin Med J (Engl)
2005
;
118
:
1175
–1181 [Erratum in Chin Med J (Engl). 2005;118:1906.].
31
Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans.
Circulation
2002
;
106
:
1913
–1918.
32
Perin EC, Dohmann HF, Borojevic R, 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
:
II213
–II218.
33
Hamano K, Masahiko N, Hirata 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 J
2001
;
65
:
845
–847.
34
Silva GV, Perin EC, Dohmann HF, et al. Catheter-based transendocardial delivery of autologous bone-marrow-derived mononuclear cells in patients listed for heart transplantation.
Tex Heart Inst J
2004
;
31
:
214
–219.
35
Tse HF, Kwong YL, Chan JK, et al. Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation.
Lancet
2003
;
361
:
47
–49.
36
Fuchs S, Satler L, Kornowski R, et al. 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.
37
Bartunek J, Vanderheyden M, Vanderkerckhove B, et al. Intracoronary injection of CD133-positive enriched bone marrow progenitor cells promotes cardiac recovery after recent myocardial infarction: feasibility and safety.
Circulation
2005
;
112
:
I178
–183.
38
Stamm C, Westphal B, Kleine HD, et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration.
Lancet
2003
;
361
:
45
–46.
39
Chen SL, Fang WW, Ye F, et al. 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.
40
Katritsis DG, Sotiropoulou PA, Karvouni E, et al. Transcoronary transplantation of autologous mesenchymal stem cells and endothelial progenitors into infarcted human myocardium.
Catheter Cardiovasc Interv
2005
;
65
:
321
–329.
41
Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction.
J Am Coll Cardiol
2003
;
41
:
1078
–1083.
42
Pagani FD, DerSimonian H, Zawadzka A, et al. Autologous skeletal myoblasts transplanted to ischemia-damaged myocardium in humans. Histological analysis of cell survival and differentiation.
J Am Coll Cardiol
2003
;
41
:
879
–888.
43
Herreros J, Prosper F, Perez A, 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.
44
Studeny M, Marini FC, Champlin RE, Zompetta C, Fidler IJ, Andreeff M. Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors.
Cancer Res
2002
;
62
:
3603
–3608.
45
Djouad F, Plence P, Bony C, et al. Immunosuppressive effect of mesenchymal stem cells favors tumor growth in allogeneic animals.
Blood
2003
;
102
:
3837
–3844.
46
Hacein-Bey-Abina S, Von Kalle C, Schmidt M, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1.
Science
2003
;
302
:
415
–419.
47
Rubin H. Multistage carcinogenesis in cell culture.
Dev Biol (Basel)
2001
;
106
:
143
–160.
48
Rubio D, Garcia-Castro J, Martin MC, et al. Spontaneous human adult stem cell transformation.
Cancer Res
2005
;
65
:
3035
–3039 [Erratum in Cancer Res. 2005;65:4969.].
49
Orlic D. BM stem cells and cardiac repair: where do we stand in 2004?
Cytotherapy
2005
;
7
:
3
–15.
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