Cell Transplantation 25(9) Abstracts

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Cell Transplantation, Vol. 25, pp. 1591-1607, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691501
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Evaluation of Multiple Biological Therapies for Ischemic Cardiac Disease

Amalia A. Winters,* Sophia Bou-Ghannam,† Hallie Thorp,† Jose A. Hawayek,* Donald L. Atkinson,* Courtney E. Bartlett,* Francisco J. Silva,* Edward W. Hsu,† Alonso P. Moreno,†‡ David A. Grainger,† and Amit N. Patel*†

*University of Utah School of Medicine, Salt Lake City, UT, USA
†Department of Bioengineering, University of Utah, Salt Lake City, UT, USA
‡Nora Eccles Cardiovascular and Training Research Institute, Salt Lake City, UT, USA

The development of cell- and gene-based strategies for regenerative medicine offers a therapeutic option for the repair and potential regeneration of damaged cardiac tissue post-myocardial infarction (MI). Human umbilical cord subepithelial cell-derived stem cells (hUC-SECs), human bone marrow-derived mesenchymal stem cells (hBM-MSCs), and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), all derived from human tissue, have been shown to have in vitro and in vivo therapeutic potential. Additionally, S100a1, VEGF165, and stromal-derived factor-1α (SDF-1α) genes all have the potential to improve cardiac function and/or effect adverse remodeling. In this study, we compared the therapeutic potential of hBM-MSCs, hUCSECs, and hiPSC-CMs along with plasmid-based genes to evaluate the in vivo potential of intramyocardially injected biologics to enhance cardiac function in a mouse MI model. Human cells derived from various tissue types were expanded under hypoxic conditions and injected intramyocardially into mice that had undergone left anterior descending (LAD) artery ligation. Similarly, plasmids were also injected into three groups of mice after LAD ligation. Seven experimental groups were studied in total: (1) control (saline), (2) hBM-MSCs, (3) hiPSC-CMs, (4) hUC-SECs, (5) S100a1 plasmid, (6) VEGF165 plasmid, and (7) SDF-1α plasmid. We evaluated echocardiography, hemodynamic catheterization measurements, and histology at 4 and 12 weeks postbiologicinjection. Significant improvement was observed in cardiac function and contractility in hiPSC-CM and S100a1 groups and a significant reduction in left ventricle scar within the hUC-SEC group and a slight improvement in the SDF-1a and VEGF165 groups compared to the control group. These results demonstrate the potential for new biologic therapies to reduce scar burden and improve contractile function.

Key words: Mesenchymal stem cells (MSCs); Umbilical cord; Cell transplantation; Induced pluripotent stem cells (iPSCs); Gene therapy

Received May 4, 2016; final acceptance June 14, 2016. Online prepub date: May 10, 2016.
Address correspondence to Amit N. Patel, M.D., M.S., University of Utah, 30 N 1900 E SOM 3c127, Salt Lake City, UT 84132, USA. Tel: 801-587-7946; Fax: 801-585-3936; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1609-1622, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X690215
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Sustained IGF-1 Secretion by Adipose-Derived Stem Cells Improves Infarcted Heart Function

Luiza L. Bagno,*† Deivid Carvalho,* Fernanda Mesquita,* Ruy A. Louzada,*‡ Bruno Andrade,* Taís H. Kasai-Brunswick,* Vivian M. Lago,* Grazielle Suhet,* Debora Cipitelli,* João Pedro Werneck-de-Castro,*‡§ and Antonio C. Campos-de-Carvalho*¶

*Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
†Division of Cardiology, Rush University Medical Center, Chicago, IL, USA
‡Escola de Educacao Fisica e Desportos, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
§Division of Endocrinology and Metabolism, Rush University Medical Center, Chicago, IL, USA
¶Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil

The mechanism by which stem cell-based therapy improves heart function is still unknown, but paracrine mechanisms seem to be involved. Adipose-derived stem cells (ADSCs) secrete several factors, including insulin-like growth factor-1 (IGF-1), which may contribute to myocardial regeneration. Our aim was to investigate whether the overexpression of IGF-1 in ADSCs (IGF-1-ADSCs) improves treatment of chronically infarcted rat hearts. ADSCs were transduced with a lentiviral vector to induce IGF-1 overexpression. IGF-1-ADSCs transcribe 100- to 200-fold more IGF-1 mRNA levels compared to nontransduced ADSCs. IGF-1 transduction did not alter ADSC immunophenotypic characteristics even under hypoxic conditions. However, IGF-1-ADSCs proliferate at higher rates and release greater amounts of growth factors such as IGF-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) under normoxic and hypoxic conditions. Importantly, IGF-1 secreted by IGF-1-ADSCs is functional given that Akt-1 phosphorylation was remarkably induced in neonatal cardiomyocytes cocultured with IGF-1-ADSCs, and this increase was prevented with phosphatidylinositol 3-kinase (PI3K) inhibitor treatment. Next, we tested IGF-1-ADSCs in a rat myocardial infarction (MI) model. MI was performed by coronary ligation, and 4 weeks after MI, animals received intramyocardial injections of either ADSCs (n = 7), IGF-1-ADSCs (n = 7), or vehicle (n = 7) into the infarcted border zone. Left ventricular function was evaluated by echocardiography before and after 6 weeks of treatment, and left ventricular hemodynamics were assessed 7 weeks after cell injection. Notably, IGF-1-ADSCs improved left ventricular ejection fraction and cardiac contractility index, but did not reduce scar size when compared to the ADSC-treated group. In summary, transplantation of ADSCs transduced with IGF-1 is a superior therapeutic approach to treat MI compared to nontransduced ADSCs, suggesting that gene and cell therapy may bring additional benefits to the treatment of MI.

Key words: Cell therapy; Gene therapy; Myocardial infarction; Adipose-derived stem cells (ADSCs); Insulin-like growth factor-1 (IGF-1) overexpression

Received October 14, 2016; final acceptance June 7, 2016. Online prepub date: November 30, 2015.
Address correspondence to Antônio Carlos Campos de Carvalho, Universidade Federal do Rio de Janeiro (UFRJ), Instituto de Biofísica Carlos Chagas Filho, CCS, bloco G, Ilha do Fundão, 21941-902 Rio de Janeiro, Brazil. Tel: +55-21/2562-6558; Fax: +55-21/2280-8193; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1623-1633, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X689767
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Therapeutic Potential of Adipose-Derived Therapeutic Factor Concentrate for Treating Critical Limb Ischemia

Vaclav Prochazka,* Jana Jurčikova,† Ondrej Laššak,† Kateřina Vitkova,† Lubomir Pavliska,† Ludmila Porubova,‡ Piotr P. Buszman,§ Agata Krauze,§ Carlos Fernandez,§ František Jalůvka,¶ IvetaŠpačkova,# Ivo Lochman,** Dvořačkova Jana,†† Stephanie Merfeld-Clauss,‡‡§§ Keith L. March,‡‡§§ Dmitry O. Traktuev,‡‡§§ and Brian H. Johnstone¶¶

*Radiodiagnostic Institute, University Hospital Ostrava, Ostrava, Czech Republic
†Department of Deputy Director of Science and Research, University Hospital Ostrava, Ostrava, Czech Republic
‡4MEDi-CBTD, Ostrava, Czech Republic
§Center for Cardiovascular Research and Development, American Heart of Poland Inc., Kostkowice, Poland
¶Department of Surgery, University Hospital Ostrava, Ostrava, Czech Republic
#Laboratoře AGEL a.s., Novy Jičin, Czech Republic
**SPADIA LAB a.s., Ostrava, Czech Republic
††Department of Pathology,University Hospital Ostrava, Ostrava, Czech Republic
‡‡Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
§§Richard L. Roudebush Veterans Affairs Medical Center, Indianapolis, IN, USA
¶¶NeuroFX Inc., Indianapolis, IN, USA

Transplantation of adipose-derived stem cells (ADSCs) is an emerging therapeutic option for addressing intractable diseases such as critical limb ischemia (CLI). Evidence suggests that therapeutic effects of ADSCs are primarily mediated through paracrine mechanisms rather than transdifferentiation. These secreted factors can be captured in conditioned medium (CM) and concentrated to prepare a therapeutic factor concentrate (TFC) composed of a cocktail of beneficial growth factors and cytokines that individually and in combination demonstrate disease-modifying effects. The ability of a TFC to promote reperfusion in a rabbit model of CLI was evaluated. A total of 27 adult female rabbits underwent surgery to induce ischemia in the left hindlimb. An additional five rabbits served as sham controls. One week after surgery, the ischemic limbs received intramuscular injections of either (1) placebo (control medium), (2) a low dose of TFC, or (3) a high dose of TFC. Limb perfusion was serially assessed with a Doppler probe. Blood samples were analyzed for growth factors and cytokines. Tissue was harvested postmortem on day 35 and assessed for capillary density by immunohistochemistry. At 1 month after treatment, tissue perfusion in ischemic limbs treated with a high dose of TFC was almost double (p < 0.05) that of the placebo group [58.8 ± 23 relative perfusion units (RPU) vs. 30.7 ± 13.6 RPU; mean ± SD]. This effect was correlated with greater capillary density in the affected tissues and with transiently higher serum levels of the angiogenic and prosurvival factors vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF). The conclusions from this study are that a single bolus administration of TFC demonstrated robust effects for promoting tissue reperfusion in a rabbit model of CLI and that a possible mechanism of revascularization was promotion of angiogenesis by TFC. Results of this study demonstrate that TFC represents a potent therapeutic cocktail for patients with CLI, many of whom are at risk for amputation of the affected limb.

Key words: Mesenchymal stem cells (MSCs); Stromal vascular fraction; Therapeutic factor concentrate (TFC); Critical limb ischemia (CLI); Rabbit

Received July 20, 2015; final acceptance April 24, 2016. Online prepub date: October 30, 2015.
Address correspondence to Vaclav Prochazka, M.D., Ph.D., M.Sc., University Hospital Ostrava, 17. listopadu 1790/5, 708 52 Ostrava-Poruba, Czech Republic. Tel: +420597372544; Fax: +420597372544; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1635-1643, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X690189
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Pulmonary Retention of Adipose Stromal Cells Following Intravenous Delivery Is Markedly Altered in the Presence of ARDS

Hongyan Lu,*†‡§ Todd Cook,*†‡ Christophe Poirier,¶ Stephanie Merfeld-Clauss,*†‡§ Irina Petrache,†‡§¶ Keith L. March,*†‡§ and Natalia V. Bogatcheva*†‡§

*Division of Cardiology, Indiana University, Indianapolis, IN, USA
†Indiana Center for Vascular Biology and Medicine, Indiana University, Indianapolis, IN, USA
‡VC-CAST Signature Center, Indiana University, Purdue University, Indianapolis, IN, USA
§Roudebush Veteran Affairs Medical Center, Indianapolis, IN, USA
¶Division of Pulmonary and Critical Care Medicine, Indiana University, Indianapolis, IN, USA

Transplantation of mesenchymal stromal cells (MSCs) has been shown to effectively prevent lung injury in several preclinical models of acute respiratory distress syndrome (ARDS). Since MSC therapy is tested in clinical trials for ARDS, there is an increased need to define the dynamics of cell trafficking and organ-specific accumulation. We examined how the presence of ARDS changes retention and organ-specific distribution of intravenously delivered MSCs isolated from subcutaneous adipose tissue [adipose-derived stem cells (ADSCs)]. This type of cell therapy was previously shown to ameliorate ARDS pathology. ARDS was triggered by lipopolysaccharide (LPS) aspiration, 4 h after which 300,000 murine CRE+ ADSCs were delivered intravenously. The distribution of ADSCs in the lungs and other organs was assessed by real-time polymerase chain reaction (PCR) of genomic DNA. As anticipated, the majority of delivered ADSCs accumulated in the lungs of both control and LPS-challenged mice, with minor amounts distributed to the liver, kidney, spleen, heart, and brain. Interestingly, within 2 h following ADSC administration, LPS-challenged lungs retained significantly lower levels of ADSCs compared to control lungs (~7% vs. 15% of the original dose, respectively), whereas the liver, kidney, spleen, and brain of ARDS-affected animals retained significantly higher numbers of ADSCs compared to control animals. In contrast, 48 h later, only LPS-challenged lungs continued to retain ADSCs (~3% of the original dose), whereas the lungs of control animals and nonpulmonary organs in either control or ARDS mice had no detectable levels of ADSCs. Our data suggest that the pulmonary microenvironment during ARDS may lessen the pulmonary capillary occlusion by MSCs immediately following cell delivery while facilitating pulmonary retention of the cells.

Key words: Acute respiratory distress syndrome (ARDS); Adipose-derived stem cells (ADSCs); Transplantation; Retention

Received September 24, 2015; final acceptance June 2, 2016. Online prepub date: November 25, 2015.
Address correspondence to Natalia V. Bogatcheva, Ph.D., ICVBM, 1481 W 10th Street, C3105, Indianapolis, IN 46202, USA. Tel: (317) 988-4535;

Fax: (317) 988-9325; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1645-1652, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691123
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Activation of Endogenous Cardiac Stem Cells by Apelin-13 in Infarcted Rat Heart

Ning Kun Zhang, Yi Cao, Zhi Ming Zhu, Nan Zheng, Li Wang, Xiao Hong Xu, and Lian Ru Gao

Center of Cardiology, Navy General Hospital, Beijing, China

Our previous study demonstrated that the apelin–APJ pathway contributed to myocardial regeneration and functional recovery after bone marrow-derived mesenchymal stem cell (BM-MSC) transplantation during the differentiation of BM-MSCs into cardiomyogenic cells in acute myocardial infarction (AMI) rat models. However, the underlying mechanisms by which apelin promotes cardiac repair and functional recovery have not been completely clarified. In the present study, we investigated whether apelin could mobilize and activate endogenous cardiac stem cells and progenitors, thereby mediating regeneration and repair of the myocardium after AMI in rat models. Six-week-old male Sprague–Dawley rats underwent AMI and received apelin-13 (200 ng, n = 10) or an equivalent volume of saline by intramyocardial injection (n = 10); there was also a sham operation group (n = 8). Proliferation of endogenous cardiac stem cells was analyzed by immunofluorescence staining in rat infarcted myocardium, and heart function was evaluated by echocardiography at 28 days after apelin-13 injection. Treatment with apelin-13 led to a significant increase of Ki-67+-c-kit+/Sca-1+/Flk-1+ endogenous cardiac stem or progenitor cells in the border zone and infarct zone of rat hearts at 28 days after myocardial infarction (MI). Significant increases in the expression of c-kit, Sca-1, and Flk-1 on both levels of transcription and translation were confirmed by real-time polymerase chain reaction (RT-PCR) and Western blot. Treatment of apelin-13 also resulted in a significant reduction of infarct size and improvement of cardiac function post-MI. We conclude that apelin-13 is able to enhance mobilization, survival, and proliferation of endogenous myocardial stem cells in the injured heart, providing a novel mechanistic explanation for how apelin-13 might repair the heart and improve cardiac function. Thus, apelin-13 or pharmacological agonists of the APJ receptor could act as novel therapies for heart regeneration.

Key words: Apelin-13; Endogenous cardiac stem cells (eCSCs) or progenitors; Acute myocardial infarction (AMI)

Received September 20, 2015; final acceptance June 13, 2016. Online prepub date: February 26, 2016.
Address correspondence to Yi Cao, M.D., Center of Cardiology, Navy General Hospital, N6 Fucheng Road, 100048 Beijing. China. Tel: 86-10-66958481; Fax: 86-10-68780127; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it  or Lian Ru Gao, M.D., Center of Cardiology, Navy General Hospital, N6 Fucheng Road, 100048 Beijing, China. Tel: 86-10-66958589; Fax: 86-10-68780127; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1653-1663, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X689794
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Cardiac-Derived Extracellular Matrix Enhances Cardiogenic Properties of Human Cardiac Progenitor Cells

Roberto Gaetani,* Christopher Yin,* Neha Srikumar,* Rebecca Braden,* Pieter A. Doevendans,† Joost P. G. Sluijter,† and Karen L. Christman*

*Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA, USA
†Department of Cardiology, DH&L, University Medical Center Utrecht, Utrecht, The Netherlands

The use of biomaterials has been demonstrated as a viable strategy to promote cell survival and cardiac repair. However, limitations on combinational cell–biomaterial therapies exist, as cellular behavior is influenced by the microenvironment and physical characteristics of the material. Among the different scaffolds employed for cardiac tissue engineering, a myocardial matrix hydrogel has been shown to promote cardiogenesis in murine cardiac progenitor cells (mCPCs) in vitro. In this study, we investigated the influence of the hydrogel on Sca-1-like human fetal and adult CPCs (fCPCs and aCPCs) when encapsulated in three-dimensional (3D) material in vitro. fCPCs encapsulated in the myocardial matrix showed an increase in the gene expression level of cardiac markers GATA-4 and MLC2v and the vascular marker vascular endothelial growth factor receptor 2 (VEGFR2) after 4 days in culture, and a significant increase in GATA-4 up to 1 week. Increased gene expression levels of Nkx2.5, MEF2c, VEGFR2, and CD31 were also observed when aCPCs were cultured in the matrix compared to collagen. Cell survival was sustained in both hydrogels up to 1 week in culture with the myocardial matrix capable of enhancing the expression of the proliferation marker Ki-67 after 4 days in culture. When encapsulated CPCs were treated with H2O2, an improved survival of the cells cultured in the myocardial matrix was observed. Finally, we evaluated the use of the myocardial matrix as hydrogel for in vivo cell transplantation and demonstrated that the gelation properties of the hydrogel are not influenced by the cells. In summary, we showed that the myocardial matrix hydrogel promotes human CPC cardiogenic potential, proliferation, and survival and is a favorable hydrogel for 3D in vitro culture. Furthermore, we demonstrated the in vivo applicability of the matrix as a potential vehicle for cell transplantation.

Key words: Cardiac tissue engineering; Cardiac progenitor cells (CPCs); Cardiac extracellular matrix; Cardiac regeneration

Received October 23, 2015; final acceptance June 15, 2016. Online prepub date: November 16, 2015.
Address correspondence to Karen L. Christman, Department of Bioengineering, University of California, San Diego, 2880 Torrey Pines Scenic Drive, La Jolla, CA 92037, USA. Tel: (858) 822-7863; Fax: (858) 246-1489; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1665-1674, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X690206
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

Uterine-Derived CD11b Cells Significantly Increase Vasculogenesis and Promote Myocardial Healing in Ischemic Cardiomyopathy

Kota Hatta,* Yuemei Zhang,* Jun Wu,* Zhou Sun,* Richard D. Weisel,*† and Ren-Ke Li*†

*Toronto General Research Institute, University Health Network, Division of Cardiovascular Surgery, Toronto, ON, Canada
†Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada

Ischemic heart disease is the leading cause of mortality in industrialized countries. Cell transplantation could restore function of the ischemic heart likely through the mechanism of cell-induced angiogenesis. We have previously shown that cells isolated from uteri increase angiogenesis and alleviate cardiac dysfunction when transplanted after MI. However, which uterine cell type contributes to angiogenesis is unknown. Here we report that uterine-derived CD11b cells significantly increase vasculogenesis and promote myocardial healing in ischemic cardiomyopathy. We have established a novel and simple methodology for uterine CD11b cell isolation and enrichment and demonstrate that this technique can be used for purifying and establishing viable CD11b cell cultures in rats. The isolated fresh CD11b cells were transplanted into ischemic rat hearts 5 days after injury. Following transplantation, vasculogenesis significantly increased in ischemic cardiac tissue, which reduced infarct size and restored myocardial function and perfusion compared with controls. Thus, uterine CD11b cells have the potential to promote functional healing when implanted after ischemic cardiomyopathy. Importantly, we have demonstrated a novel means by which CD11b cells can be easily purified and cultured for cell transplantation.

Key words: Ischemic cardiomyopathy; Heart failure; Angiogenesis; Uterus; CD11b stem cells

Received September 14, 2015; final acceptance May 26, 2016. Online prepub date: November 30, 2015.
Address correspondence to Ren-Ke Li, M.D., Ph.D. Toronto General Research Institute, University Health Network, Toronto Medical Discovery Tower, Room 3-702, 101 College Street, Toronto, ON M5G 1L7, Canada. Tel: 1-416-581-7492; Fax: 1-416-581-7493; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1675-1687, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X689901
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Identification of Bone Marrow Cell Subpopulations Associated With Improved Functional Outcomes in Patients With Chronic Left Ventricular Dysfunction: An Embedded Cohort Evaluation of the FOCUS-CCTRN Trial

Doris A. Taylor,* Emerson C. Perin,* James T. Willerson,* Claudia Zierold,† Micheline Resende,* Marjorie Carlson,† Belinda Nestor,* Elizabeth Wise,‡ Aaron Orozco,* Carl J. Pepine,‡ Timothy D. Henry,§¶ Stephen G. Ellis,# David X. M. Zhao,** Jay H. Traverse,¶ John P. Cooke,††‡‡ Robert C. Schutt,††‡‡ Aruni Bhatnagar,§§ Maria B. Grant,‡ Dejian Lai,¶¶ Brian H. Johnstone,## Shelly L. Sayre,¶¶ Lem Moyé,¶¶ Ray F. Ebert,*** Roberto Bolli,§§ Robert D. Simari,††† and Christopher R. Cogle,‡ for the Cardiovascular Cell Therapy Research Network (CCTRN)

*Texas Heart Institute, CHI St. Luke’s Health, Houston, TX, USA
†University of Minnesota School of Medicine, Minneapolis, MN, USA
‡University of Florida College of Medicine, Gainesville, FL, USA
§Cedars-Sinai Heart Institute, Los Angeles, CA, USA
¶Minneapolis Heart Institute Foundation at Abbott, Minneapolis, MN, USA
#Cleveland Clinic Foundation, Cleveland, OH, USA
**Wake Forest School of Medicine, Winston-Salem, NC, USA
††Houston Methodist DeBakey Heart & Vascular Center, Houston, TX, USA
‡‡Houston Methodist Research Institute, Houston, TX, USA
§§University of Louisville, Louisville, KY, USA
¶¶University of Texas School of Public Health, Houston, TX, USA
##Indiana University School of Medicine, Indianapolis, IN, USA
***National Heart, Lung, and Blood Institute, Bethesda, MD, USA
†††University of Kansas School of Medicine, Kansas City, KS, USA

In the current study, we sought to identify bone marrow-derived mononuclear cell (BM-MNC) subpopulations associated with a combined improvement in left ventricular ejection fraction (LVEF), left ventricular endsystolic volume (LVESV), and maximal oxygen consumption (VO2 max) in patients with chronic ischemic cardiomyopathy 6 months after receiving transendocardial injections of autologous BM-MNCs or placebo. For this prospectively planned analysis, we conducted an embedded cohort study comprising 78 patients from the FOCUS-Cardiovascular Cell Therapy Research Network (CCTRN) trial. Baseline BM-MNC immunophenotypes and progenitor cell activity were determined by flow cytometry and colony-forming assays, respectively. Previously stable patients who demonstrated improvement in LVEF, LVESV, and VO2 max during the 6-month course of the FOCUS-CCTRN study (group 1, n = 17) were compared to those who showed no change or worsened in one to three of these endpoints (group 2, n = 61) and to a subset of patients from group 2 who declined in all three functional endpoints (group 2A, n = 11). Group 1 had higher frequencies of B-cell and CXCR4+ BM-MNC subpopulations at study baseline than group 2 or 2A. Furthermore, patients in group 1 had fewer endothelial colony-forming cells and monocytes/macrophages in their bone marrow than those in group 2A. To our knowledge, this is the first study to show that in patients with ischemic cardiomyopathy, certain bone marrow-derived cell subsets are associated with improvement in LVEF, LVESV, and VO2 max at 6 months. These results suggest that the presence of both progenitor and immune cell populations in the bone marrow may influence the natural history of chronic ischemic cardiomyopathy—even in stable patients. Thus, it may be important to consider the bone marrow composition and associated regenerative capacity of patients when assigning them to treatment groups and evaluating the results of cell therapy trials.

Key words: Bone marrow; Heart failure; Ischemic cardiomyopathy; Stem cells; Cell therapy

Received September 28, 2015; final acceptance June 9, 2016. Online prepub date: November 19, 2015.
Address correspondence to Lem Moyé, University of Texas-Houston, School of Public Health, 1200 Herman Pressler, E-1009, Houston, TX 77030, USA. Tel: (713) 500-9518; Fax: (713) 486-0981; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1689-1699, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691295
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

The ixCELL-DCM Trial: Rationale and Design

Timothy D. Henry,* Gary L. Schaer,† Anthony DeMaria,‡ David Recker,§ Ann E. Remmers,§ James Goodrich,§ and Amit N. Patel¶

*Cedars-Sinai Heart Institute, Los Angeles, CA, USA
†Rush University Medical Center, Chicago, IL, USA
‡University of California, San Diego, San Diego, CA, USA
§Vericel Corporation, Cambridge, MA, USA
¶University of Utah Health Care, Salt Lake City, UT, USA

Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient’s own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90+ mesenchymal stem cells (MSCs), and CD45+CD14+ autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM). This ongoing randomized, double-blinded, placebo-controlled phase 2b trial (ixCELL-DCM) was designed to assess the efficacy, safety, and tolerability of catheter-based transendocardial injection of ixmyelocel-T in patients with heart failure due to IDCM. Patients (N = 114) with New York Heart Association class III or IV symptomatic heart failure due to IDCM, who have left ventricular ejection fraction ≤35% and an automatic implantable cardioverter defibrillator, but are ineligible for revascularization procedures, were randomly assigned (1:1 ratio) to ixmyelocel-T or placebo (vehicle control). The primary efficacy endpoint is a composite of the total number of deaths, cardiovascular hospitalizations, or unplanned clinic visits to treat acutely decompensated heart failure during the 12 months following treatment administration. Secondary endpoints include the win ratio analysis for hierarchical occurrences of clinical events in the primary endpoint, total numbers of clinical events, left ventricular structure and function, and quality-of-life assessments. ixCELL-DCM is one of the largest cell therapy trials in heart failure patients to date and the first double-blinded, placebo-controlled study of ixmyelocel-T administered via transendocardial catheter-based injections in patients with heart failure secondary to IDCM.

Key words: Heart failure (HF); Ischemic dilated cardiomyopathy (IDCM); Ixmyelocel-T; Stem cell therapy

Received January 6, 2016; final acceptance June 13, 2016. Online prepub date: March 22, 2016.
Address correspondence to Timothy D. Henry, M.D., 127 S. San Vicente Boulevard, Suite A3100, Los Angeles, CA 90048, USA. Tel: (424) 315-2699; Fax: (310) 423-3522; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1701-1711, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368916X691484
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
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Autologous CD34+ Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study

Timothy D. Henry,* Gary L. Schaer,† Jay H. Traverse,‡ Thomas J. Povsic,§ Charles Davidson,¶ Joon Sup Lee,# Marco A. Costa,** Theodore Bass,†† Farrell Mendelsohn,‡‡ F. David Fortuin,§§ Carl J. Pepine,¶¶ Amit N. Patel,## Norbert Riedel,*** Candice Junge,††† Andrea Hunt,‡‡‡ Dean J. Kereiakes,§§§ Christopher White,¶¶¶ Robert A. Harrington,### Richard A. Schatz,**** Douglas W. Losordo,††† and the ACT34-CMI Investigators

*Cedars-Sinai Heart Institute, Los Angeles, CA, USA
†Rush University Medical Center, Chicago, IL, USA
‡Minneapolis Heart Institute, Minneapolis, MN, USA
§Duke Clinical Research Institute, Duke Medicine, Durham, NC, USA
¶Northwestern Memorial Hospital, Chicago, IL, USA
#University of Pittsburgh Medical Center, Pittsburgh, PA, USA
**University Hospitals Case Medical Center, Cleveland, OH, USA
††UF Health Jacksonville, University of Florida, Jacksonville, FL, USA
‡‡Cardiology P.C., Farmington, CT, USA
§§Mayo Clinic, Phoenix, AZ, USA
¶¶University of Florida, Gainesville, FL, USA
##University of Utah Health Care, Salt Lake City, UT, USA
***Aptinyx Inc., Evanston, IL, USA
†††Caladrius Biosciences Inc., New York City, NY, USA
‡‡‡Baxalta Healthcare, Bannockburn, IL, USA
§§§The Christ Hospital Health Network, Cincinnati, OH, USA
¶¶¶Ochsner Health System, New Orleans, LA, USA
###Stanford University School of Medicine, Stanford, CA, USA
****Scripps Clinic, San Diego, CA, USA

An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34+ stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34+ stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 105 CD34/kg body weight), and high dose (5 × 105 CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA® mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III–IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34+cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34+ cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

Key words: Refractory angina; Stem cell therapy; Myocardial ischemia

Received January 15, 2016; final acceptance June 13, 2016. Online prepub date: May 4, 2016.
Address correspondence to Timothy D. Henry, 127 S. San Vicente Boulevard, Suite A3100, Los Angeles, CA 90048, USA. Tel: (424) 315-2699; Fax: (310) 423-3522; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it


Cell Transplantation, Vol. 25, pp. 1713-1721, 2016
0963-6897/16 $90.00 + .00
DOI: http://dx.doi.org/10.3727/096368915X690314
E-ISSN 1555-3892
Copyright © 2016 Cognizant, LLC.
Printed in the USA. All rights reserved

RESCUE-HF Trial: Retrograde Delivery of Allogeneic Umbilical Cord Lining Subepithelial Cells in Patients With Heart Failure

Jorge Tuma,* Antonio Carrasco,† Jorge Castillo,† Carlos Cruz,* Alvaro Carrillo,* Jose Ercilla,* Carlos Yarleque,* Jaime Cunza,* Courtney E. Bartlett,‡ Amalia A. Winters,‡ Francisco J. Silva,‡ and Amit N. Patel‡

*Division of Interventional Cardiology and Regenerative Medicine, Clínica Maisón de Santé, Lima, Peru
†Instituto de Criopreservació n y Terapia Celular, Lima, Peru
‡University of Utah School of Medicine, Salt Lake City, UT, USA

Cell therapy is an evolving option for patients with end-stage heart failure. First-generation cell therapy trials have had marginal success. Our goal was to evaluate retrograde delivery of allogeneic umbilical cord subepithelial cells (UCSECs) in patients with heart failure. A prospective open-label dose escalation study of the safety and feasibility of UCSECs infused retrogradely into the coronary sinus was performed. Patients received a single dose of either 100 million (M), 200M, or 400M cells. The patients were followed for 2 years. Twenty-four patients were successfully enrolled in the study. The patients had UCSEC infusion without procedure-related complications. The ejection fraction in patients receiving UCSECs demonstrated improvement compared to baseline; from 25.4% (±5.5) at screening to 34.9% (±4.1) at 12 months. End-systolic diameter decreased significantly from 59.9 (±5.3) mm to 52.6 (±2.7) mm (p < 0.05). Retrograde UCSEC delivery was safe and feasible in all three dosage groups. Patients receiving 200M and 400M UCSECs showed signs of early improvement in left ventricular ejection fraction (LVEF) and remodeling. This study provides the basis for a larger clinical trial in heart failure (HF) patients using the middle or high dose of UCSECs.

Key words: Heart failure (HF); Umbilical cord; Cell transplantation; Coronary sinus; Retrograde approach

Received May 4, 2016; final acceptance June 26, 2016. Online prepub date: January 13, 2016.
Address correspondence to Amit N. Patel, M.D., M.S., University of Utah, 30 N 1900 E SOM 3c127, Salt Lake City, UT 84132, USA. Tel: 801-587-7946; Fax: 801-585-3936; E-mail: This e-mail address is being protected from spambots. You need JavaScript enabled to view it