ognizant Communication Corporation

CELL TRANSPLANTATION
The Regenerative Medicine Journal

ABSTRACTS
VOLUME 16, NUMBER 8, 2007

Cell Transplantation, Vol. 16, pp. 879-886, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

SDF-1 Recruits Cardiac Stem Cell-Like Cells That Depolarize In Vivo

Samuel Unzek,1* Ming Zhang,2* Niladri Mal,2 William R. Mills,3 Kenneth R. Laurita,3 and Marc S. Penn1,2,4

1Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA
2Department of Cell Biology, Cleveland Clinic Foundation, Cleveland, OH, USA
3Heart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA
4Department of Biomedical Engineering, Cleveland Clinic Foundation, Cleveland, OH, USA

Prolongation or reestablishment of stem cell homing through the expression of SDF-1 in the myocardium has been shown to lead to homing of endothelial progenitor cells to the infarct zone with a subsequent increase in vascular density and cardiac function. While the increase in vascular density is important, there could clearly be other mechanisms involved. In a recent study we demonstrated that the infusion of mesenchymal stem cells (MSC) and MSC that were engineered to overexpress SDF-1 led to significant decreases in cardiac myocyte apoptosis and increases in vascular density and cardiac function compared to control. In that study there was no evidence of cardiac regeneration from either endogenous stem cells or the infused mesenchymal stem cells. In this study we performed further detailed immunohistochemistry on these tissues and demonstrate that the overexpression of SDF-1 in the newly infracted myocardium led to recruitment of small cardiac myosin-expressing cells that had proliferated within 2 weeks of acute MI. These cells did not differentiate into mature cardiac myocytes, at least by 5 weeks after acute MI. However, based on optical mapping studies, these cells appear capable of depolarizing. We observed greater optical action potential amplitude in the infarct border in those animals that received SDF-1 overexpressing MSC than observed in noninfarcted animals and those that received control MSC. Further immunohistochemistry revealed that these proliferated cardiac myosin-positive cells did not express connexin 43, but did express connexin 45. In summary, our study suggests that the prolongation of SDF-1 expression at the time of acute MI leads to the recruitment of endogenous cardiac myosin stem cells that may represent cardiac stem cells. These cells are capable of depolarizing and thus may contribute to increased contractile function even in the absence of maturation into a mature cardiac myocyte.

Key words: SDF-1 expression; Cardiac stem cells; Depolarization; Cardiac myocytes

Address correspondence to Marc S. Penn, M.D., Ph.D., Director, Skirball Laboratory for Cardiovascular Cellular Therapeutics, NE3 Departments of Cardiovascular Medicine and Cell Biology, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel: +1-216-444-7122; Fax: +1-216-444-9404; E-mail: pennm@ccf.org

*These two authors contributed equally to this work.




Cell Transplantation, Vol. 16, pp. 887-898, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Acute Myocardial Infarction in Swine Rapidly and Selectively Releases Highly Proliferative Endothelial Colony Forming Cells (ECFCs) Into Circulation

Lan Huang,1,2,4 Dongming Hou,3,5 Meredith A. Thompson,1,2 Sarah E. Baysden,1,2 W. Christopher Shelley,1,2 David A. Ingram,1,2,4,5 Keith L. March,1,2,4,5 and Mervin C. Yoder1,2,4,5

1Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA
2Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, USA
3Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
4Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
5Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN, USA

We have recently identified endothelial colony forming cells (ECFCs) in human blood and blood vessels, and ECFC are elevated in patients with coronary artery disease. Because pigs are a favored model for studying myocardial ischemia, we questioned whether ECFCs also exist in swine and whether myocardial ischemia would alter the number of ECFC in circulation. ECFCs were present in circulating blood and aortic endothelium of healthy pigs. In pigs with an acute myocardial infarction (AMI) (n = 9), the number of circulating ECFC was markedly increased compared to sham control pigs (15 ± 6 vs. 1 ± 1 colonies/100 cc blood, p < 0.05). Moreover, the percentage of circulating high proliferative potential ECFCs (HPP-ECFCs) was significantly increased following AMI induction compared to sham control (38.4 ± 5.8% vs. 0.4 ± 0.4%, p < 0.05) and to baseline (38.4 ± 5.8% vs. 2.4 ± 2.4%, p < 0.05) blood samples. This is the first study to report that ECFCs are present in blood and aorta in healthy pigs and that the number and distribution of circulating ECFCs is altered following AMI. Because circulating ECFC are also altered in human subjects with severe coronary artery disease, the pig model of AMI may be an excellent preclinical model to test the role of ECFC in the pathophysiology of AMI.

Key words: Angiogenesis; Endothelium; Endothelial colony forming cell (ECFC); Myocardial infarction

Address correspondence to Mervin C Yoder, M.D., Richard and Pauline Klingler Professor of Pediatrics, and Professor of Biochemistry and Molecular Biology, Herman B Wells Center for Pediatrics Research, Indiana University School of Medicine, 1044 West Walnut Street, R4-402E, Indianapolis, IN 46202, USA. Tel: 317-274-4738; Fax: 317-274 8928; E-mail: myoder@iupui.edu or Keith L. March, M.D., Ph.D., Professor of Medicine, Cellular & Integrative Physiology, and Biomedical Engineering, Director, Indiana Center for Vascular Biology & Medicine, 975 West Walnut Street, IB 441, Indianapolis, IN 46202, USA. Tel: 317-278-0130; Fax: 317-278-0089; E-mail: kmarch@iupui.edu




Cell Transplantation, Vol. 16, pp. 899-906, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Improved Cell Survival in Infarcted Myocardium Using a Novel Combination Transmyocardial Laser and Cell Delivery System

Amit N. Patel,1 Cristiano Spadaccio,1 Michael Kuzman,1 Eulsoon Park,1 David W. Fischer,1 Steven L. Stice,2 Chandra Mullangi,1 and Catalin Toma1

1Center for Cardiac Cell Therapy-Heart Lung Esophageal Surgical Institute and Cardiovascular Institute, University of Pittsburgh/UPMC/McGowan Institute of Regenerative Medicine, Pittsburgh, PA, USA
2Regenerative Bioscience Center, University of Georgia, Athens, GA, USA

Stem cell therapy has been used to treat ischemic cardiac disease with promising early results. However, there has been limited success using cell therapy in infarcted tissue. The cells have an inadequate microvascular environment in order to survive once implanted into scar tissue. The goal of this study was to create a microvascular environment into infarcted myocardial tissue using transmyocardial laser revascularization (TMR) as a pretreatment before cell implantation and evaluate cell survival afterwards. Balloon occlusion catheter-based myocardial infarct of the circumflex artery was created in a porcine model. The infarct was allowed to mature for 2 weeks. Three groups consisting of TMR alone (TMR), TMR + fluorescent-labeled allogeneic mesenchymal stem cells (MSCs) (TMR + Cells), and MSCs alone (Cells) were injected into the infarcted tissue using a combination TMR and cell delivery system (PhoenixTM, Cardiogenesis). The hearts were explanted at 1 week after treatment for cell and tissue evaluation. The myocardial infarcts were verified in all animals using both ultrasound and direct visual imaging. All arms of the study were successful with a mean of 2.0 ± 106 MSCs injected per site into the scar tissue. All animals survived to explant at 1 week. On histological examination, 300 high-power fields were evaluated demonstrating that the TMR + Cells group had 25 ± 5 cells and the Cells group 5 ± 2 cells compared to baseline TMR alone by fluorescence. The use of TMR as a pretreatment for MSC injection increases early cell survival in infarcted tissue without increased adverse events. Further long-term functional and differentiation analysis will be required to evaluate the efficacy for future clinical translation.

Key words: Cell therapy; Transmyocardial laser; Heart; Porcine; Mesenchymal stem cell

Address correspondence to Amit N. Patel, M.D., M.S,, Director of Cardiac Cell Therapy, The Heart, Lung and Esophageal Surgery Institute, UPMC Presbyterian, McGowan Institute of Regenerative Medicine, 200 Lothrop Street, Suite C 700, Pittsburgh, PA 15213, USA. Tel: 412-648-6411; E-mail: patelan@upmc.edu




Cell Transplantation, Vol. 16, pp. 907-917, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
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Human Cord Blood Cells and Myocardial Infarction: Effect of Dose and Route of Administration on Infarct Size

Robert J. Henning,1 Jose D. Burgos,1 Mark Vasko,1 Felipe Alvarado,1 Cyndy D. Sanberg,4 Paul R. Sanberg,2 and Michael B. Morgan3

1Department of Medicine of the James A. Haley VA Hospital, University of South Florida College of Medicine, Tampa, FL, USA
2Department of Neurosurgery, Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, FL, USA
3Department of Pathology of the James A. Haley VA Hospital, University of South Florida College of Medicine, Tampa, FL, USA
4Saneron CCEL Therapeutics, Inc., Tampa, FL, USA

There is no consensus regarding the optimal dose of stem cells or the optimal route of administration for the treatment of acute myocardial infarction. Bone marrow cells, containing hematopoietic and mesenchymal stem cells, in doses of 0.5 x 106 to >30 x 106 have been directly injected into the myocardium or into coronary arteries or infused intravenously in subjects with myocardial infarctions to reduce infarct size and improve heart function. Therefore, we determined the specific effects of different doses of human umbilical cord blood mononuclear cells (HUCBC), which contain hematopoietic and mesenchymal stem cells, on infarct size. In order to determine the optimal technique for stem cell administration, HUCBC were injected directly into the myocardium (IM), or into the LV cavity with the ascending aorta transiently clamped to facilitate coronary artery perfusion (IA), or injected intravenously (IV) in rats 1-2 h after the left anterior coronary artery was permanently ligated. Immune suppressive therapy was not given to any rat. One month later, the infarct size in control rat hearts treated with only Isolyte averaged 23.7 ± 1.7% of the LV muscle area. Intramyocardial injection of HUCBC reduced the infarct size by 71% with 0.5 x 106 HUCBC and by 93% with 4 x 106 HUCBC in comparison with the controls (p < 0.001). Intracoronary injection reduced the infarction size by 47% with 0.5 x 106 HUCBC and by 80% with 4 x 106 HUCBC (p < 0.001), and IV HUCBC reduced infarct size by 51% with 0.5 x 106 and by 75-77% with 16-32 million HUCBC (p < 0.001) in comparison with control hearts. With 4 x 106 HUCBC, infarction size was 65% smaller with IM HUCBC than with IA HUCBC and 78% smaller than with IV HUCBC (p < 0.05). Nevertheless, IM, IA, and IV HUCBC all produced significant reductions in infarct size in comparison with Isolyte-treated infarcted hearts without requirements for host immune suppression. The present experiments demonstrate that the optimal dose of HUCBC for reduction of infarct size in the rat is 4 x 106 IM, 4 x 106 IA, and 16 x 106 IV, and that the IM injection of HUCBC is the most effective technique for reduction in infarct size.

Key words: Stem cells; Cell therapy; Myocardial infarction; Coronary artery disease

Address correspondence to Robert J. Henning, M.D., James A. Haley Medical Center, 13000 Bruce B. Downs, Tampa, FL 33612, USA. Tel: 813-973-5873; Fax: 813-978-5874; E-mail Robert.Henning@va.gov




Cell Transplantation, Vol. 16, pp. 919-926, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Time-Dependent Effects on Coronary Remodeling and Epicardial Conductance After Intracoronary Injection of Enriched Hematopoietic Bone Marrow Stem Cells in Patients With Previous Myocardial Infarction

Marc Vanderheyden,1,2 Steven Vercauteren,1 Samer Mansour,1 Leen Delrue,2 Bart Vandekerckhove,3,4 Guy R. Heyndrickx,1 Inge Van Haute,3 Bernard De Bruyne,1 Frank Timmermans,4 William Wijns,1 and Jozef Bartunek1,2

1Cardiovascular Center, OLV Ziekenhuis, Aalst, Belgium
2Molecular Cardiology Unit, OLV Ziekenhuis, Aalst, Belgium
3Cell Therapy Unit, Flemish Red Cross, Gent, Belgium
4University of Gent, Belgium

Bone marrow (BM) cells may interact with coronary endothelium and modulate coronary atherosclerosis. We investigated the time course of coronary luminal loss and changes in conductance after intracoronary injection of enriched hematopoietic BM stem cells in patients with previous myocardial infarction (MI). Among 24 patients with acute MI, 13 were randomized to early (<7 days) and 11 to late (4 months) intracoronary injection of CD133+ cells after the infarction. Segmental quantitative coronary angiography and fractional flow reserve (FFR) measurements of the infarct-related (IR) artery (A) and contralateral artery (control) were performed. In the early group, at 4 months, cumulative luminal loss (LL) of the minimal luminal diameter (MLD) of the IRA distal to the stented segment was -0.39 (-0.51-0.10) mm (p < 0.05 vs. control). There was no further change in LL between 4 and 8 months [-0.09 (-0.26-0.15) mm]. In parallel, FFR decreased at 4 months [-0.16 (-0.26-0.001), p < 0.05 vs. control] but slightly increased from 4 to 8 months follow-up [+0.05 (-0.10-0.09)]. In the late group, LL of the MLD of the IRA distal to the stented segments was -0.12 (-0.47-0.07) mm (NS vs. control) at 4 months and further -0.07 (-0.25-0.05) mm (NS) between 4 and 8 months. At 8 months, the total LL of the MLD in the early and late group was only slightly higher compared to control [-0.34 (-0.48-?0.16), -0.36 (-0.69-?0.09), and -0.12 (-0.39-0.05) mm, respectively, NS]. Early intracoronary administration of hematopoietic BM stem cells in patients with previous MI is associated with accelerated luminal loss and reduced conductance of the infarct-related artery.

Key words: Myocardial infarction; Coronary artery diseases; Bone marrow stem cells; Atherosclerosis

Address correspondence to Jozef Bartunek, M.D., Ph.D., or Marc Vanderheyden, M.D., Cardiovascular Center Aalst, OLV Ziekenhuis, Moorselbaan 164, 9300 Aalst, Belgium. Tel: 32 53 72 4447; Fax: 32 53 72 4550; E-mail: Jozef.Bartunek@olvz-aalst.be or Marc.Vanderheyden@olvz-aalst.be




Cell Transplantation, Vol. 16, pp. 927-934, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One Year Follow-Up

Juan C. Chachques,1 Jorge C. Trainini,2 Noemi Lago,2 Osvaldo H. Masoli,2 Jose L. Barisani,2 Miguel Cortes-Morichetti,1 Olivier Schussler,1 and Alain Carpentier1

1Department of Cardiovascular Surgery, Pompidou Hospital, Paris, France
2Avellaneda Hospital, Buenos Aires, Argentina

Cell transplantation for the regeneration of ischemic myocardium is limited by poor graft viability and low cell retention. In ischemic cardiomyopathy the extracellular matrix is deeply altered; therefore, it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated intrainfarct cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles. In 15 patients (aged 54.2 ± 3.8 years) presenting LV postischemic myocardial scars and with indication for a single OP-CABG, autologous mononuclear bone marrow cells (BMC) were implanted during surgery in the scar. A 3D collagen type I matrix seeded with the same number of BMC was added on top of the scarred area. There was no mortality and no related adverse events (follow-up 15 ± 4.2 months). NYHA FC improved from 2.3 ± 0.5 to 1.4 ± 0.3 (p = 0.005). LV end-diastolic volume evolved from 142 ± 24 to 117 ± 21 ml (p = 0.03), and LV filling deceleration time improved from 162 ± 7 to 196 ± 8 ms (p = 0.01). Scar area thickness progressed from 6 ± 1.4 to 9 ± 1.5 mm (p = 0.005). EF improved from 25 ± 7% to 33 ± 5% (p = 0.04). Simultaneous intramyocardial injection of mononuclear bone marrow cells and fixation of a BMC-seeded matrix onto the epicardium is feasible and safe. The cell-seeded collagen matrix seems to increase the thickness of the infarct scar with viable tissues and helps to normalize cardiac wall stress in injured regions, thus limiting ventricular remodeling and improving diastolic function. Patients' improvements cannot be conclusively related to the cells and matrix due to the association of CABG. Cardiac tissue engineering seems to extend the indications and benefits of stem cell therapy in cardiology, becoming a promising way for the creation of a "bioartificial myocardium." Efficacy and safety of this approach should be evaluated in a large randomized controlled trial.

Key words: Stem cell therapy; Myocardial regeneration; Tissue engineering; Heart failure; Ischemic heart disease; Bioartificial myocardium; Cellular cardiomyoplast

Address correspondence to Juan C. Chachques, M.D., Ph.D., Department of Cardiovascular Surgery, Pompidou Hospital, 20 rue Leblanc, 75015 Paris, France. Tel: ++33613144398; Fax: ++33140728608; E-mail: j.chachques@brs.aphp.fr




Cell Transplantation, Vol. 16, pp. 935-940, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

Safety of Intramyocardial Stem Cell Therapy for the Ischemic Myocardium: Results of the Rostock Trial After 5-Year Follow-Up

Can Yerebakan, Alexander Kaminski, Andreas Liebold, and Gustav Steinhoff

Department of Cardiac Surgery, University of Rostock, Rostock, Germany

Stem cell treatment for acute or chronic ischemic myocardium has gained major attention in the last decade. Experimental and clinical studies have shown evidence for functional improvement after cell-based treatments in acute or chronically ischemic jeopardized myocardium. Since 2001 we have performed bone marrow-derived CD133+ stem cell transplantations with concomitant coronary artery bypass surgery. Although our focus is mainly on the functional results of the stem cell treatment, possible long-term side effects of the new therapeutic strategy should also be addressed. Here we present for the first time the long-term follow-up safety results of the Rostock trial after direct intramyocardial stem cell treatment in 32 patients.

Key words: Stem cells; Myocardial regeneration; Myocardial ischemia; Cardiac surgery; Heart failure

Address correspondence to Gustav Steinhoff, M.D., Department of Cardiac Surgery, University of Rostock, Schillingallee 35, D-18057, Rostock, Germany. Tel: 0049 381 494 6101; Fax: 0049 381 494 6102; E-mail: gustav.steinhoff@med.uni-rostock.de




Cell Transplantation, Vol. 16, pp. 941-950, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
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Intramyocardial Delivery of Bone Marrow Mononuclear Cells and Mechanical Assist Device Implantation in Patients With End-Stage Cardiomyopathy

Boris A. Nasseri,1 Marian Kukucka,2 Michael Dandel,1 Christoph Knosalla,1 Evgenij Potapov,1 Hans B. Lehmkuhl,1 Rudolph Meyer,1 Wolfram Ebell,3 Christof Stamm,1,4 and Roland Hetzer1,4

1Department of Cardiothoracic and Vascular Surgery, Deutsches Herzzentrum Berlin, Berlin, Germany
2Department of Anesthesiology, Deutsches Herzzentrum Berlin, Berlin, Germany
3Pediatric Bone Marrow Transplant Program, Charité, Universitätsmedizin Berlin, Berlin, Germany
4BCRT-Berlin-Brandenburg Center for Regenerative Therapies, Berlin, Germany

In end-stage heart failure, mechanical ventricular assist devices (VAD) are being used as bridge-to-transplantation, as a bridge-to-recovery, or as the definitive therapy. We tested the hypothesis that myocardial implantation of autologous bone marrow mononuclear cells (BMNC) increases the likelihood of successful weaning from left VAD (LVAD) support. Ten patients (aged 14-60 years) with deteriorating heart function underwent LVAD implantation and concomitant implantation of autologous BMNC. Bone marrow was harvested prior to VAD implantation and BMNC were prepared by density centrifugation. Two patients received a pulsatile, extracorporeal LVAD and eight a nonpulsatile implantable device. Between 52 and 164 × 107 BMNC containing between 1 and 12 × 106 CD34+ cells were injected into the LV myocardium. There was one early and one late death. The median time on LVAD support was 243 days (range 24-498 days). Repeated echocardiographic examinations under increased hemodynamic load revealed a significant improvement of LV function in one patient. Three patients underwent heart transplantation, and four patients remain on LVAD support >1 year without evidence of recovery. Only one patient was successfully weaned from LVAD support after 4 months, and LV function has remained stable ever since. In patients with endstage cardiomyopathy, intramyocardial injection of BMNC at the time of LVAD implantation does not seem to increase the likelihood of successful weaning from VAD support. Other cell-based strategies should be pursued to harness the potential of cell therapy in LVAD patients.

Key words: Heart failure; Bone marrow; Assist device; Regeneration; Myocardium; Surgery

Address correspondence to Christof Stamm, M.D., Deutsches Herzzentrum Berlin, Cardiothoracic and Vascular Surgery, Augustenburger Platz 1, 13353 Berlin, Germany. Tel: +49-30 4593 9238; E-mail: stamm@dhzb.de




Cell Transplantation, Vol. 16, pp. 951-961, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

REVIEW
Cardiac Cell-Based Therapy: Cell Types and Mechanisms of Actions

Geraldo A. Ramos and Joshua M. Hare

The Interdisciplinary Stem Cell Institute, Miller School of Medicine, University of Miami, Miami, FL, USA

Over the past decade, the concept that the heart could undergo cardiac regeneration has rapidly evolved. Studies have indicated that numerous sites in the body harbor stem or progenitor cells, prompting clinical trials of these potential therapeutic cell-based approaches. Most notable are the series of trials utilizing either skeletal myoblasts or autologous whole bone marrow. More recently the quest has focused on specific bone marrow constituents, most notably the mesenchymal stem cell, which has several unique advantages including immunoprivilege, immunosuppression, and the ability to home to areas of tissue injury. Most recently, cells have been identified within the heart itself that are capable of self-replication and differentiation. The discovery of cardiac stem cells offers not only a potential therapeutic approach but also provides a plausible target for endogenous activation as a therapeutic strategy. Together the new insights obtained from studies of cell-based cardiac therapy have ushered in new biological paradigms and enormous potential for novel therapeutic strategies for cardiac disease.

Key words: Heart failure; Stem cells; Myocardial infarction; Cell therapy

Address correspondence to Joshua M. Hare, M.D., Division of Cardiology, Miller School of Medicine, University of Miami, Clinical Research Building, 1120 NW 14th Street, Miami, FL, 33136, USA. Tel: (305)-243-1998; E-mail: JHare@med.miami.edu




Cell Transplantation, Vol. 16, pp. 963-970, 2007
0963-6897/07 $90.00 + 00
E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
Printed in the USA. All rights reserved.

REVIEW
Adipose-Derived Cells

Emanuele Meliga,1 Brian M. Strem,2 H. J. Duckers,1 and Patrick W. Serruys1

1Thoraxcenter, Erasmus University Medical Center Rotterdam, 3000 CA Rotterdam, The Netherlands
2Cytori Therapeutics, Inc., San Diego, CA 92121, USA

Heart failure is by far the most common cause of hospitalization in Western countries, with onerous economic consequences. Cell therapy holds great promise for use in tissue regeneration and is increasingly used in an effort to improve outcomes in cardiac disease. Recently it has been shown that adipose tissue, in addition to committed adipogenic, endothelial progenitor cells and pluripotent vascular progenitor cells, also contains multipotent cell types (adipose-derived stem cells, ADSCs) that, in cell culture conditions, have shown to have an impressive developmental plasticity including the ability to undergo multilineage differentiation and self-renewal. ADSCs express multiple CD marker antigens similar to those observed on MSCs and are also capable of secreting a large number of angiogenesis-related cytokines, including vascular endothelial growth factor, granulocyte/macrophage colony stimulating factor, stromal-derived factor-1a, and hepatocyte growth factor. Adipose tissue can be harvested in large quantities with minimal morbidity in several regions of the body and, on average, 100 ml of human adipose tissue yields about 1 x 106 stem cells. Studies conducted in porcine AMI models have shown a significant LV functional improvement, with no report of any potentially fatal arrhythmias. The APOLLO trial, a prospective, double blind, randomized, placebocontrolled trial currently in the recruiting phase, is a "first-in-man" study that explores the safety and feasibility of ADSC transplantation in patients with acute MI.

Key words: Cardiac regeneration; Adipose-derived stem cells; Heart failure; Acute myocardial infarction

Address correspondence to Prof. P. W. Serruys, M.D., Ph.D., Director of the Interventional Cardiology Department, Thoraxcenter, Erasmus MC, Eramus University, Dr Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands. Tel: 0031104635260; E-mail: p.w.j.c.serruys@erasmusmc.nl




Cell Transplantation, Vol. 16, pp. 971-975, 2007
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E-ISSN 1555-3892
Copyright © 2007 Cognizant Comm. Corp.
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REVIEW
Myocyte Replacement Therapy: Skeletal Myoblasts

Warren Sherman

Division of Cardiology, Department of Medicine, College of Physicians & Surgeons, Columbia University, New York, NY, USA

Skeletal myoblasts function as precursors to adult skeletal myocytes. More so than other muscle progenitors, their capacity for de novo self-renewal and their positive functional effects in the cardiac environment have been demonstrated, even though they do not attain a cardiomyocyte phenotype. Autologous skeletal myoblasts are easily procured by established methods and can be administered into diseased myocardium safely and without technical difficulty, features that at this time set them apart from any other myogenic cell. Clinical studies in patients with chronic myocardial disease have consistently reported modest improvements in ventricular function and clinical status. Data from the Myogenesis Heart efficiency and Regeneration Trial (MYOHEART) trial are currently being evaluated. Larger, randomized, placebo-controlled studies in patients with congestive heart failure due to postinfarction systolic left ventricular dysfunction are under way, such as Myoblast Autologous Grafting in Ischemic Cardiomayopathy (MAGIC) and Multicenter Study of the Safety and Cardiovascular Effects Of Myoblasts in Congestive Heart Failure (MARVEL). The future role of skeletal myoblasts in the clinical setting will be determined by the results of randomized trials as well as by the investigation of subsequent generations of myoblasts, engineered for enhanced efficacy.

Key words: Congestive heart failure; Left ventricular function; Skeletal myoblasts; Myocyte replacement; Catheter delivery; Implantation; Cell therapy

Address correspondence to Warren Sherman, M.D., Center for Interventional Vascular Therapies, Columbia University Medical Center, 161 Ft. Washington Avenue, IP-519, New York, NY 10032, USA. Tel: 212-342-0886 or 212-305-7060; Fax: 212-342-3680; E-mail: ws2157@columbia.edu