Challenges for heart disease stem cell therapy

Abstract

Cardiovascular diseases (CVDs) are the leading cause of death worldwide. The use of stem cells to improve recovery of the injured heart after myocardial infarction (MI) is an important emerging therapeutic strategy. However, recent reviews of clinical trials of stem cell therapy for MI and ischemic heart disease recovery report that less than half of the trials found only small improvements in cardiac function. In clinical trials, bone marrow, peripheral blood, or umbilical cord blood cells were used as the source of stem cells delivered by intracoronary infusion. Some trials administered only a stem cell mobilizing agent that recruits endogenous sources of stem cells. Important challenges to improve the effectiveness of stem cell therapy for CVD include: (1) improved identification, recruitment, and expansion of autologous stem cells; (2) identification of mobilizing and homing agents that increase recruitment; and (3) development of strategies to improve stem cell survival and engraftment of both endogenous and exogenous sources of stem cells. This review is an overview of stem cell therapy for CVD and discusses the challenges these three areas present for maximum optimization of the efficacy of stem cell therapy for heart disease, and new strategies in progress.

Keywords: engraftment; expansion; homing; mobilization; survival.

Figure 1

Types of stem cells in use for heart disease therapy.– Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2011–2012. All Rights Reserved.

Figure 2

Expansion of stem cells. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2011–2012. All Rights Reserved. Notes: Currently, increased numbers of autologous hematopoietic, mesenchymal, cardiac, endothelial, and skeletal stem cells can be generated by expansion in culture with proliferation specific conditions. Adult cells such as fibroblasts or adipocytes may be dedifferentiated in culture to stem cells (iPS cells). MSCs, iPS cells, and ESCs can be induced to differentiate and proliferate in cell culture. Use of differentiated MSCs, iPS cells, and ESCs is in preclinical development. Abbreviations: ESC, embryonic stem cell; iPS, induced pluripotent stem; MSC, mesenchymal stem cell.

Figure 3

Stem cell mobilization and homing. Growth factors and cytokines stimulate the mobilization of the stem cells from their niche to injured tissue. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2011–2012. All Rights Reserved. Notes: Flt-ligand is a growth factor; interleukins refer to interleukin-1, -3, -6, -7, -8, -11, and -12 cytokines; homing factors MCP-3, GRO-1, HGF, FGF-2, and IGF-1 are produced in the heart and promote endogenous and exogenous stem cells homing to the injured tissue; survival and implantation of stem cells in the tissue may result in differentiation, secretion of paracrine factors, and/or stimulation of angiogenesis to restore blood flow and remodel tissue. Abbreviations: G-CSF, granulocyte colony-stimulating factor; Gm-CSF, granulocyte-macrophage colony-stimulating factor; SCF, stem cell factor/c-kit ligand; SDF-1, stromal cell-derived factor 1; MCP-3, monocyte chemotactic protein-3; GRO-1, growth regulated oncogene 1; HGF, hepatic growth factor; FGF-2, fibroblast growth factor; IGF-1, insulin-like growth factor.

Figure 4

Bone marrow-derived stem cell mobilization. Bone marrow stem cells may be mobilized by reducing the ligand SDF-1 and increasing the stem cell receptor CXCR4 to create a chemotatic gradient with the peripheral blood. G-CSF treatment increases MMP-9 to regulate changes in SDF-1/CXCR4 pathway, which is dependent on plasmin activation of MMP-9. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2011–2012. All Rights Reserved. Abbreviations: CXCR4, C-X-C receptor 4; G-CSF, granulocyte colony-stimulating factor; MMP-9, matrix metalloproteinase-9; SDF-1, stromal-derived factor-1.

Figure 5

Plasminogen regulates CXCR4 after G-CSF stimulation. (A) CXCR4 immunostaining of bone marrow from Plg+/+ and Plg−/− mice treated with saline (control) or G-CSF. CXCR4 expressing cells (brown color) increased two fold after G-CSF treatment in Plg+/+ mice, but CXCR4 did not change in Plg−/− mice. (B) Lentivirus expression of act MMP-9 in Plg−/− restored CXCR4 expression. Plasminogen activation of MMP-9 is required for CXCR4 expression after G-CSF treatment. Note: Reproduced with permission from Gong Y, Fan Y, Hoover-Plow J. Plasminogen regulates stromal cell-derived factor-1/CXCR4-mediated hematopoietic stem cell mobilization by activation of matrix metalloproteinase-9. Arterioscler Thromb Vasc Biol. 2011;31(9):2035–2043. Abbreviations: CXCR4, C-X-C receptor 4; G-CSF, granulocyte colony-stimulating factor; MFI, mean fluorescence intensity; MMP-9, matrix metalloproteinase-9; Plg, plasminogen.