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Stem cells for myocardial infarction
Cytotherapy, 2015; 17: 243e244
COMMENTARY
Stem cells for myocardial infarction
IAN MCNIECE The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Cardiac ischemia after an acute infarction leads to decreased cardiac function and in many cases, death. In recent years, cellular products have been evaluated for their potential to replace or repair ischemic cardiac tissue and reverse the progression to heart failure. Overall, these studies have demonstrated the safety of cellular products including bone marrow (BM) mononuclear cells and mesenchymal stromal cells (MSCs). In addition to repair of ischemic tissue, studies have evaluated the use of cellular products shortly after infarction, with the goal of decreasing the inflammatory response to tissue necrosis. In particular, MSCs have been shown to exert antiproliferative and anti-inflammatory effects [1,2]. However, the results from clinical trials of cell therapy in cardiac ischemia have been variable, and the optimal cellular therapy remains to be defined. In this issue of Cytotherapy, Chullikana et al. [3] present the results of a clinical study to evaluate allogeneic BM-derived MSCs, which they call stempeucel, in acute myocardial infarction. The phase I/II randomized, double-blinded single-dose study enrolled 20 patients randomly assigned (1:1) to receive stempeucel at a dose of 180 to 220 million cells intravenously (IV) or placebo. There was no overall effect of stempeucel treatment on improvement of cardiac function at 6 months or 2 years versus placebo. The authors conclude that larger studies are needed to define the optimal dose and route of administration. Although the study showed no clinical efficacy, the data add to the growing body of literature demonstrating safety of BM-derived MSCs. A similar study has been reported by Hare et al. [4] that delivered allogeneic BM-derived MSCs IV at doses of 0.5, 1.6 and 5 106 cells/kg. This study
demonstrated a decrease in ventricular arrhythmias, better pulmonary function, and increased left ventricular ejection fraction in the MSC group compared with that in the placebo group. Conflicting results have been reported in other cardiac studies, with both positive and negative results reported for BM-derived mononuclear cells. The difference in results between the studies of Chullikana et al. and Hare et al. may similarly be explained by heterogeneity in patients as shown in the data from the Chullikana study in Figure 4, with left ventricular ejection fraction values ranging from 35% to 55%. A larger randomized trial will certainly be required to fully define the benefit of IV injection of MSCs for acute myocardial infarction. Despite the mixed results reported for applications of stem cells in cardiac disease, there is continued interest in conducting clinical trials to treat heart failure and ischemia. However, in all the positive studies reported to date, the efficacy has been minimal, with only small increases in ejection fraction and decreases in scar tissue. This is not particularly surprising, given the complexity of the heart as an organ system. Ischemic damage involves death of several cell types, including cardiomyocytes, cardiac stem and progenitor cells, vascular endothelial cells and stromal cells. It is unlikely that any one cell type can replace all of these cells. Data from Hatzistergos et al. [5] demonstrated in a pig myocardial infarction model (female recipients) that injection of allogeneic male MSCs resulted in a 20fold increase of endogenous c-kitþ cardiac stem cells in ischemic tissue. This suggests that one action of MSCs may be to repair the microenvironment, allowing for resident stem cells to migrate into the ischemic tissue and produce new cardiomyocytes.
Correspondence: Ian McNiece, PhD, Director, Stem Cell Transplantation and Cellular Therapy Clinical Laboratories, MD Anderson Cancer Center, 1515 Holcombe Blvd, Room P14.2920b, Houston, TX 77030. E-mail: [email protected] (Received 8 January 2014; accepted 8 January 2014) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.01.002
244
I. McNiece
This study has led to proposals to undertake combination cell therapy with the use of MSCs plus c-kitþ cardiac stem cells. MSCs may also work through a paracrine effect increasing production of cytokines and growth factors. In particular, MSCs produce vascular endothelial growth factor, which is a key factor for angiogenesis, stimulating endothelial cell proliferation. Some reports demonstrate new vessel formation, with donor MSCs detectable in the vascular structures. New vessel formation is key for tissue repair, and injection of endothelial cells in models of hind limb ischemia demonstrate the potential of the use of endothelial cells to facilitate generation of vessels in vivo. This raises the potential of using multiple cell types to achieve optimal tissue repair: MSCs to repair the microenvironment and produce growth factors, c-kitþ cells to provide new cardiomyocytes and endothelial cells to provide new vessel formation. Such comination therapy trials would be complex, raising questions regarding the timing of injection of each cell population, the dose
of each population and coordination of production of the cell products. References [1] Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890e6. [2] Klyushnenkova E, Shustova V, Mosca J, Mosely A, McIntosh K. Human mesenchymal stem cells induce unresponsiveness in preactivated but not naive alloantigen specific T cells. Exp Hematol 1999;27. abstract 325. [3] Chullikana A, Majumdar A, Gottipamula S, et al. Randomized double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy 2015;17:250e61. [4] Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebocontrolled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277e86. [5] Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010;107:913e22.
COMMENTARY
Stem cells for myocardial infarction
IAN MCNIECE The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
Cardiac ischemia after an acute infarction leads to decreased cardiac function and in many cases, death. In recent years, cellular products have been evaluated for their potential to replace or repair ischemic cardiac tissue and reverse the progression to heart failure. Overall, these studies have demonstrated the safety of cellular products including bone marrow (BM) mononuclear cells and mesenchymal stromal cells (MSCs). In addition to repair of ischemic tissue, studies have evaluated the use of cellular products shortly after infarction, with the goal of decreasing the inflammatory response to tissue necrosis. In particular, MSCs have been shown to exert antiproliferative and anti-inflammatory effects [1,2]. However, the results from clinical trials of cell therapy in cardiac ischemia have been variable, and the optimal cellular therapy remains to be defined. In this issue of Cytotherapy, Chullikana et al. [3] present the results of a clinical study to evaluate allogeneic BM-derived MSCs, which they call stempeucel, in acute myocardial infarction. The phase I/II randomized, double-blinded single-dose study enrolled 20 patients randomly assigned (1:1) to receive stempeucel at a dose of 180 to 220 million cells intravenously (IV) or placebo. There was no overall effect of stempeucel treatment on improvement of cardiac function at 6 months or 2 years versus placebo. The authors conclude that larger studies are needed to define the optimal dose and route of administration. Although the study showed no clinical efficacy, the data add to the growing body of literature demonstrating safety of BM-derived MSCs. A similar study has been reported by Hare et al. [4] that delivered allogeneic BM-derived MSCs IV at doses of 0.5, 1.6 and 5 106 cells/kg. This study
demonstrated a decrease in ventricular arrhythmias, better pulmonary function, and increased left ventricular ejection fraction in the MSC group compared with that in the placebo group. Conflicting results have been reported in other cardiac studies, with both positive and negative results reported for BM-derived mononuclear cells. The difference in results between the studies of Chullikana et al. and Hare et al. may similarly be explained by heterogeneity in patients as shown in the data from the Chullikana study in Figure 4, with left ventricular ejection fraction values ranging from 35% to 55%. A larger randomized trial will certainly be required to fully define the benefit of IV injection of MSCs for acute myocardial infarction. Despite the mixed results reported for applications of stem cells in cardiac disease, there is continued interest in conducting clinical trials to treat heart failure and ischemia. However, in all the positive studies reported to date, the efficacy has been minimal, with only small increases in ejection fraction and decreases in scar tissue. This is not particularly surprising, given the complexity of the heart as an organ system. Ischemic damage involves death of several cell types, including cardiomyocytes, cardiac stem and progenitor cells, vascular endothelial cells and stromal cells. It is unlikely that any one cell type can replace all of these cells. Data from Hatzistergos et al. [5] demonstrated in a pig myocardial infarction model (female recipients) that injection of allogeneic male MSCs resulted in a 20fold increase of endogenous c-kitþ cardiac stem cells in ischemic tissue. This suggests that one action of MSCs may be to repair the microenvironment, allowing for resident stem cells to migrate into the ischemic tissue and produce new cardiomyocytes.
Correspondence: Ian McNiece, PhD, Director, Stem Cell Transplantation and Cellular Therapy Clinical Laboratories, MD Anderson Cancer Center, 1515 Holcombe Blvd, Room P14.2920b, Houston, TX 77030. E-mail: [email protected] (Received 8 January 2014; accepted 8 January 2014) ISSN 1465-3249 Copyright Ó 2015, International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jcyt.2015.01.002
244
I. McNiece
This study has led to proposals to undertake combination cell therapy with the use of MSCs plus c-kitþ cardiac stem cells. MSCs may also work through a paracrine effect increasing production of cytokines and growth factors. In particular, MSCs produce vascular endothelial growth factor, which is a key factor for angiogenesis, stimulating endothelial cell proliferation. Some reports demonstrate new vessel formation, with donor MSCs detectable in the vascular structures. New vessel formation is key for tissue repair, and injection of endothelial cells in models of hind limb ischemia demonstrate the potential of the use of endothelial cells to facilitate generation of vessels in vivo. This raises the potential of using multiple cell types to achieve optimal tissue repair: MSCs to repair the microenvironment and produce growth factors, c-kitþ cells to provide new cardiomyocytes and endothelial cells to provide new vessel formation. Such comination therapy trials would be complex, raising questions regarding the timing of injection of each cell population, the dose
of each population and coordination of production of the cell products. References [1] Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 2003;31:890e6. [2] Klyushnenkova E, Shustova V, Mosca J, Mosely A, McIntosh K. Human mesenchymal stem cells induce unresponsiveness in preactivated but not naive alloantigen specific T cells. Exp Hematol 1999;27. abstract 325. [3] Chullikana A, Majumdar A, Gottipamula S, et al. Randomized double-blind, phase I/II study of intravenous allogeneic mesenchymal stromal cells in acute myocardial infarction. Cytotherapy 2015;17:250e61. [4] Hare JM, Traverse JH, Henry TD, Dib N, Strumpf RK, Schulman SP, et al. A randomized, double-blind, placebocontrolled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009;54:2277e86. [5] Hatzistergos KE, Quevedo H, Oskouei BN, Hu Q, Feigenbaum GS, Margitich IS, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res 2010;107:913e22.