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Abstract

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

The results of large-scale clinical trials involving granulocyte colony-stimulating factor (G-CSF)-based mobilization of bone marrow stem cells to improve cardiac remodeling and function after acute myocardial infarction have been disappointing. These trials came about as the result of an explosion of animal studies reporting dramatic successes with this therapeutic approach and small-scale nonrandomized, nonblinded clinical trials suggesting beneficial effects in humans as well. It would be rash to conclude, however, that G-CSF-based stem cell therapies for repairing the injured or failing heart are not worth pursuing. Recent advances in basic science not only help explain the failure of the larger clinical trials but have revitalized interest into using G-CSF-based or G-CSF-related therapies for the injured heart. This article will provide an overview of recent advances that have been made in the direct protective actions of G-CSF on cardiac cells, the mobilization of stem cells from the bone marrow, and the delivery of these cells to the heart. Such knowledge could be readily exploited to make G-CSF-based therapy a reality for the clinician.

Granulocyte colony-stimulating factor (G-CSF) is a 25-kDa glycoprotein cytokine that is commonly used clinically (filgrastim) to treat neutropenia and for bone marrow transplantation protocols, because it potently induces the mobilization of bone marrow stem cells (BMSCs) into the blood, including hematopoietic stem cells, mesenchymal stem cells, and endothelial progenitor cells (EPCs). G-CSF is produced by a number of cell types and organs, most notably by the infarcted heart.1 In that context, G-CSF subserves a primitive injury-repair response mechanism in the body. Much excitement was generated by animal studies from 2001 and on showing that an increased presence of BMSCs in the heart following G-CSF administration was associated with reduced left ventricular remodeling and improved cardiac function after acute myocardial infarction (AMI).2,3 Several possible explanations were proposed to explain the beneficial effects of G-CSF, including a direct protective effect of G-CSF on heart cells, induction of matrix metalloproteinases and proangiogenic mediators either directly or via a paracrine action of BMSCs, and the differentiation of recruited BMSCs into vascular cells and cardiac myocytes (myocardial regeneration).4,5 Although G-CSF-induced angiogenesis in the infarcted heart is established, unresolved are the relative contributions of a direct action of G-CSF on endothelial cells, a paracrine action of hematopoietic stem cells and EPCs on resident endothelial cells, and recruited EPC incorporation into the endothelium. The idea that recruited BMSCs differentiate into cardiac myocytes to any significant degree is now generally discounted.3,5 In any event, given that it is easily administered by subcutaneous injection, G-CSF seemed a very attractive therapeutic avenue to repair and perhaps even regenerate the injured myocardium following delayed reperfusion therapy. Although percutaneous coronary intervention and other reperfusion therapies have markedly improved survival after AMI, 30% to 40% of patients develop heart failure within 5 years due to the damage sustained by the heart.1,2

Even though a dozen or so small preliminary nonrandomized clinical trials supported the idea that G-CSF could be of benefit in late treatment of AMI, results of recent randomized double-blind placebo-controlled clinical studies (Table I) have been disappointing,4,6–8 as discussed in several recent editorials.9–13 Rather than marking the demise of this once-promising therapeutic approach, however, these disappointing outcomes actually argue the need for further basic research that has strong translational underpinnings, especially when the dramatic results observed in the animal studies are kept in mind. In fact, even before the results of the clinical trials became known, a number of fundamental insights arose from basic research that would have made a successful outcome in the clinical trials nothing short of a miracle. These issues include observations that the health of BMSCs is adversely affected by age as well as cardiovascular risk factors and disease,2,14 the homing of BMSCs to the heart and their engraftment is dependent on a number of factors and cellular receptors (some of which also contribute to an inflammatory response),15,16 and effective delivery of BMSCs to the heart is a complicated matter that may be obfuscated by microvasculature obstruction.12 A detailed consideration of these and other relevant issues in G-CSF-based stem cell therapy for repairing the heart is not our intention, as there are already several recent excellent articles that cover this subject.2,5,14,15,17 Rather, here and in the next article in this series, we will summarize a few select observations that have emerged recently from basic science that should help shape the next round of clinical trials on G-CSF-based stem cell therapy for the heart (Figure 1).

Table I.  Notable Randomized, Double-Blind, Placebo-Controlled Clinical Trials Assessing Cardiac Benefits of G-CSF
TrialDesign/End PointConclusion
Stem Cells in Myocardial Infarction (STEMMI)678 patients with ST-elevation MI after PCIBMSC mobilization with subcutaneous G-CSF is safe
 G-CSF (10 µg/kg body weight) or placebo for 6 days 1 or 2 days after the STEMINo further improvement in ventricular function after AMI compared with recovery in the placebo group
 Systolic wall thickening detected by MRI 
Reinfusion of Enriched Progenitor Cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI)7Improvement of global LV function by quantitative LV angiography after 4 monthsModerate but significant improvement in ejection fraction
 204 patients: intracoronary infusion of infarct-related artery with autologous mononuclear BMSCs or placebo 3 to 6 days after AMI 
Front-Integrated Revascularization and Stem Cell Liberation In Evolving Acute Myocardial Infarction by Use of Granulocyte Colony-Stimulating Factor (FIRSTLINE-AMI)856 patients with ST-elevation MIImproved LV wall thickening and wall motion in the infarction zone at rest and with dobutamine stress
 G-CSF (10 µg/kg body weight) or standard care for 6 days after PCIGreater metabolic activity in the infarct zone at 4 months
 End point: echo assessment of morphologic and functional parameters at rest and with inotropic challenge at 35 days and 4 months; 18FDG-PET assessment of metabolic activityComparable rates of restenosis between groups
Regenerate Vital Myocardium by Vigorous Activation of Bone Marrow Stem Cells (REVIVAL-2)4114 patients with successful PCI within 12 hours of onset of symptomsSmall reductions in infarct size from baseline to follow up in both groups, but no difference between the groups
 G-CSF (10 µg/kg body weight) or placebo for 5 days starting 5 days after AMISmall improvement in LV ejection fraction from baseline to follow up in both groups, but no difference between the groups
 MI size (technetium Tc-99m sestamibi scintigraphy) and LV function (MRI) at baseline and 4 and 6 monthsNo difference in regional or LV function between G-CSF and placebo groups
Abbreviations: AMI, acute MI; BMSC, bone marrow stem cell; FDG-PET, fluorodeoxyglucose positron emission tomography; G-CSF, granulocyte colony-stimulating factor; LV, left ventricular; MI, myocardial infarction; MRI, magnetic resonance imaging; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation MI.
image

Figure 1. Stages involved in stem cell-based therapy for the heart that are susceptible to manipulation to improve outcome. When endogenously produced from the injured heart or administered, the hematopoietic cytokine granulocyte colony-stimulating factor receptor (G-CSF) stimulates the release of bone marrow stem cells (BMSCs) into the blood, including hematopoietic stem cells (HSCs), mesenchymal stem cells (MSCs), and endothelial progenitor cells (EPCs). These cells then home to the heart to initiate myocardial repair via several mechanisms: paracrine growth-stimulatory and reparative actions, as well as formation of new cardiac muscle and blood vessels. G-CSF also has direct protective effects on cells of the heart. The various stages in cell-based therapy for the heart that could be targeted for enhancement are shown in the shaded boxes/oval. Mobilization and/or production of new stem cells can be enhanced using drugs (eg, myelosuppressives) or combinational therapy with other hematopoietic cytokines (eg, flt3 ligand). Bioengineering approaches can be employed to enhance both the viability and function of the BMSCs in the infracted heart, as well as their homing potential. Several approaches are available to enhance delivery of the G-CSF-mobilized BMSCs to the heart. Homing to particular regions of the heart is effected by a number of factors, including cytokines such as stem cell factor-1 (and its receptor CD117), chemokines such as stromal cell-derived factor-1 (its receptor CXCR4) and monocyte chemotactic protein-3, nuclear/cellular “debris” (eg, high mobility group box chromosomal protein 1), and integrins (eg, CD18) and adhesion molecules (eg, intercellular adhesion molecule 1). Molecular biology and bioengineering approaches that target either cardiac myocytes or endothelial cells, or the cardiac microenvironment, can be employed to enhance homing. Much less is known about the factors that control either stem cell engraftment or their (trans)differentiation into cardiac cell types, although matrix metalloproteinases (MMPs) (eg, MMP-2) are thought to be involved in engraftment. Unsettled is what importance, if any, engraftment and differentiation play in repairing the injured heart in G-CSF-based therapy. The Figure was created using the software ScienceSlides 2007 version 2.0 from VisiScience Inc (Chapel Hill, NC).

Direct Protective Effects of G-CSF on Cardiac Myocytes

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

Besides promoting mobilization of BMSCs to the injured myocardium, a growing body of evidence indicates that G-CSF has direct effects on the heart that are protective.5 Conceivably, G-CSF may also act to create a more hospitable milieu in the injured myocardium for stem cell homing and engraftment. In this context, there are conflicting reports that G-CSF acts on the heart to either reduce or enhance expression of stromal cell-derived factor-1 (SDF-1),14,18 a chemokine that plays a critical role in BMSC homing to the injured myocardium. Thus, the timing of G-CSF delivery and dosage levels may favor one beneficial action (cardioprotection) to the detriment of the other (BMSC mobilization) and vice versa. Obviously, a better understanding of the direct actions of G-CSF on the heart is needed.

Although originally thought to be confined to certain types of blood cells, the G-CSF receptor (designation CD114) has been shown to be expressed on both cardiac myocytes and endothelial cells.19 CD114 is a member of the class I receptor cytokine superfamily that couples to multiple intracellular signaling pathways following activation of JAK tyrosine kinases, which subsequently phosphorylate docking sites on the cytoplasmic receptor domains that are involved in recruiting other signaling proteins (Figure 2). In a mouse model, administration of G-CSF during the acute stage of myocardial infarction was observed to promote survival of cardiac myocytes and improve cardiac function. Evidence was found that G-CSF has a direct protective effect on cardiac myocytes through the induction of antiapoptotic proteins downstream of STAT3 activation, a well-established survival mechanism in cardiac myocytes.20 Besides STAT3 activation, G-CSF also activates Akt/protein kinase B in the heart, another protective molecule, while downregulating the expression of molecules associated with adverse cardiac remodeling (particularly fibrosis), such as angiotensin II type 1 receptor, transforming growth factor-β1, and tumor necrosis factor α.21,22 G-CSF was also shown to reduce endothelial cell apoptosis and increase vascularization in infarcted hearts.23

image

Figure 2. The principal intracellular signaling pathways linked to activation of the granulocyte colony-stimulating factor receptor (G-CSF). The receptor (CD114) is a member of the class I cytokine receptor superfamily that undergoes dimerization upon binding G-CSF, thereby activating the JAK kinase associated with its cytoplasmic portion. These kinases phosphorylate docking sites on the cytoplasmic regions of the receptors that serve to recruit various scaffold proteins linked to the activation of signaling cascades (mitogen-activated protein kinases, including Raf [RIGHTWARDS ARROW] MEK1/2 [RIGHTWARDS ARROW] Erk1/2; PI 3-kinase [RIGHTWARDS ARROW] Akt/PKB) or the STAT family of transcription factors. Three signaling events (activation of STAT3, PKB, and ERK1/2) that have been linked to cellular protection are marked with an asterisk. The Figure was obtained from ScienceSlides 2007 version 2.0 (VisiScience Inc, Chapel Hill, NC).

In addition, G-CSF may have direct actions on the myocardium that are reparative, as subcutaneous administration of G-CSF was reported to markedly improve the function of failing mouse hearts with large, healed myocardial infarctions.21 The geometry of the infarct scar was changed from elongated and thin to short and thick and was accompanied by hypertrophy among surviving cardiac myocytes and reduced myocardial fibrosis. The reparative actions of G-CSF have also been noted in doxorubicin-induced cardiomyopathy and were suggested to involve extracellular signal-regulated kinase activation.24,25 Finally, another potentially protective action of G-CSF that is direct and may reduce inducible arrhythmias in the infarcted heart is increased connexin 43 expression.26

Despite clear evidence that G-CSF has direct protective effects on the myocardium, a recent study by Misao and colleagues18 presents convincing evidence that recruitment of BMSCs plays a critical role in the beneficial actions of G-CSF on the infarcted heart. Or does it? These investigators used AMD3100 (plerixafor), a specific SDF-1 receptor (CXCR4) inhibitor, to block SDF-1-mediated recruitment of bone marrow-derived CD34+ cells in rabbits subjected to a 30-minute ischemia-reperfusion myocardial infarction protocol (day 0) and then treated with G-CSF (days 3–7) or saline. Some rabbits also received AMD3100. When assessed on day 28 post-myocardial infarction, G-CSF treatment improved left ventricular ejection fraction and end-diastolic dimension and reduced scar area. As expected, G-CSF increased mobilization of CXCR4+ bone marrow cells into the infarcted area, which showed up-regulated expression of SDF-1 and the collagenase matrix metalloproteinase-1. All of the beneficial effects of G-CSF were blocked with AMD3100, which did not, however, affect upregulation of SDF-1 or activation of STAT3. One consideration that could be overlooked, however, is that the study used healthy, juvenile rabbits. Another recent study by Lehrke and colleagues27 found that G-CSF lacks therapeutic efficacy for post-myocardial infarction remodeling in old mice because of an age-related loss in its direct ability to prevent peri-infarct apoptosis of cardiac myocytes. Clearly, more needs to be learned about the impact of aging on the reparative mechanisms of cardiac myocytes, especially because 4 of 5 patients with coronary artery disease are aged 65 years or older. The unsettledness created by studies such as those of Lehrke and colleagues27 and Misao and associates18 perhaps also highlights the need for more of a systematic approach in research, with a greater focus on clinically relevant animal models.

Factors Affecting Stem Cell Mobilization and Function

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

The mobilization and function of autologous BMSCs, in particular EPCs, is adversely affected by coronary heart disease risk factors, most notably age, as well as a number of other factors (Table II).14,15 Consequently, both the quality and quantity of BMSCs mobilized by G-CSF in the clinical setting may be insufficient to affect cardiac repair. Understanding the processes responsible for these declines and/or devising strategies to boost BMSC numbers and function are relatively new areas of investigation. The statins (3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors) represent one of several promising pharmacologic approaches likely to have some prophylactic value. As discussed elsewhere,14 the statins increase circulating EPC numbers and survival, while enhancing neovascularization and reendothelialization.

Table II.  Factors Affecting BMSC (Especially EPC) Mobilization, Recruitment, or Function
 Factor
DecreaseAge
 Cardiac transplantation with graft vasculopathy
 Coronary heart disease risk factors (eg, diabetes, hypertension, smoking, hypercholesterolemia)
 Chronic renal failure/dialysis
 Congestive heart failure: NYHA class III or IV
 Chronic obstructive pulmonary disease
 C-reactive protein
 Hemodynamic loading42
 Oxidized low-density lipoprotein
 Preeclampsia
 Rheumatoid arthritis
IncreaseAngiotensin-converting enzyme inhibitor
 Acute myocardial infarction/unstable angina
 Chemokines: SDF-1
 Congestive heart failure: NYHA class I or II
 Coronary artery bypass graft surgery off-pump (reduced function/viability with on-pump)
 Cytokines: G-CSF, GM-CSF, IL-6, LIF, SCF-1
 CXCR4 antagonists (eg, AMD3100)
 Estradiol
 Growth factors: PDGF, VEGF, FCF, HGF, IGF
 Nitric oxide (eNOS)
 Physical activity
 PPARγ antagonists
 Pregnancy
 Statins
 Stroke
Abbreviations: BMSC, bone marrow stem cell; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cell; FGF, fibroblast growth factor; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; HGF, hepatocyte growth factor; IGF, insulin-like growth factor; IL-6, interleukin 6; LIF, leukemia inhibitory factor; NYHA, New York Heart Association; PDGF, platelet-derived growth factor; PPAR, peroxisome proliferator-activated receptor; SCF-1, stem cell factor-1; SDF-1, stromal cell-derived factor-1; VEGF, vascular endothelial growth factor. Data are from Ballard and Edelberg14 and Wojakowski et al.15

A number of agents have been shown to synergize with G-CSF in enhancing BMSC mobilization and cardiac repair. The drug AMD3100, which is currently under clinical investigation, results in the rapid (within hours) mobilization of BMSCs from the bone marrow in contrast to the slower release (peak levels after 4 or 5 days) observed with G-CSF.28 Together, AMD3100 and G-CSF have a synergistic effect on BMSC mobilization and, recently, were shown to synergistically stimulate angiogenesis in the ischemic hind limb. The straightforward applicability of the AMD3100/G-CSF combination for repairing the heart is questionable, however, given that ADM3100 blocks BMSC homing, which would seem to necessitate strategies to manipulate ADM3100 pharmacokinetics.

An attractive alternative to AMD3100 may be the retinoic acid receptor α-agonist VTP195183, which was recently reported to synergize with G-CSF in mobilizing BMSCs.29 The basis for the synergism is likely explained by the action of VTP195183 to increase the number of bone marrow neutrophils, which are acted on by G-CSF to release proteases that digest the matrix that normally retains stem cells within the marrow. VTP195183 is currently being studied in a phase I/II clinical trial. Myelosuppressives, such as cyclophosphamide and 5-fluorouracil, also mobilize BMSCs but do so in a more sustained time course than G-CSF.30 In a rabbit model of myocardial infarction, myelosuppressives were found to act synergistically with G-CSF in enhancing cardiac repair and functional recovery, ostensibly through enhanced BMSC recruitment to the heart because of increased cardiac expression of SDF-1 and circulating BMSCs. As noted by the authors of the study, however, combination therapy with G-CSF and myelosuppressives for heart treatment is complicated by the potential cardiotoxicity associated the myelosuppressives.

The most promising therapeutic strategy to improve BMSC mobilization for infarct repair would be to exploit the synergistic actions observed when G-CSF is given along with certain hematopoietic cytokines, including stem cell factor (SCF) and flt3 ligand (FL).31 Along these lines, the efficacy of G-CSF in combination with either SCF or FL, was compared with G-CSF alone or vehicle in regenerating cardiac tissue and improving left ventricular (LV) function in a mouse model of myocardial infarction with cytokine treatment starting 4 hours after reperfusion.32 At 5 weeks, LV function (in both infarct and nonischemic regions) was improved in both combination treatment groups but not in mice receiving G-CSF alone, although LV end-diastolic dimensions, LV diameter, and LV volume were smaller in all cytokine groups. The combination of G-CSF plus FL was most effective in repairing the injured heart, both functionally and histopathophysiologically, and was associated with the increased expression of surface antigens/adhesion molecules (CD62L and CD11a) on mobilized BMSCs that facilitate homing to the heart. Using radioablated mice reconstituted with bone marrow from enhanced green fluorescent protein transgenic mice, these authors were able to document enhanced transdifferentiation of the mobilized BMSCs into different cardiac cell compartments (cardiac myocytes and presumably endothelial cells) in cytokine-treated mice, but the extent was much smaller in mice treated with G-CSF alone. Several conclusions can be drawn from this important study: (1) postinfarct combinational cytokine therapy with G-CSF plus FL or SCF limits adverse LV remodeling and improves LV performance to a much greater extent than G-CSF alone; (2) treatments that prime or sensitize BMSC to improve homing are likely to be more effective than agents that simply increase circulating BMSC numbers; and (3) paracrine actions by recruited BMSCs or direct cytokine effects are critically important in cytokine therapy as evidenced by the marked functional improvement in the nonischemic region of the injured heart.

Cardioprotective Actions of G-CSF

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References
  • Activates antiapoptotic, survival, or regenerative signaling in cardiac cells
  • Mobilizes bone marrow-derived stem cells that once homed to the heart
  • Secretes factors that stimulate cell survival, growth, angiogenesis, or tissue repair mechanisms
  • Transdifferentiates into cardiac cells (myocytes and endothelial cells)

Factors that Synergize With G-CSF to Mobilize BMSCs

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References
  • AMD3100 (Plerixafor)
  • FL (flt3 ligand)
  • Myelosuppressives
  • RARα agonists

Another therapeutic approach to be explored would be to use molecular biology to reengineer BMSCs to enhance their function and survivability in the injured heart, which represents an inhospitable environment. Several recent studies illustrate this approach. Much greater improvement in cardiac function following AMI was noted in rats injected with mesenchymal stem cells engineered to overexpress SDF-1 than with unmodified mesenchymal stem cells, which themselves had a marked beneficial effect.33 The enhanced repair observed with the engineered mesenchymal stem cells was attributed to a direct preservative effect of SDF-1 on cardiac myocytes within the infarct zone, and possibly a trophic/protective effect of SDF-1 on the stem cells themselves. Similar results have been reported using mesenchymal stem cells engineered to overexpress antiapoptotic proteins Akt34,35 or Bcl-2.36 In another study, cardiac function, infarct size, and capillary density were even further improved in a rat model when hearts were injected 2 weeks after permanent ligation of the left anterior descending artery with mesenchymal stem cells transfected with a vascular endothelial growth factor expression plasmid compared with cell or plasmid treatments alone.37

Delivery

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

A concern that might explain the disappointing results of the clinical trials assessing the benefits of G-CSF therapy in myocardial infarction is whether sufficient numbers of BMSCs can migrate to relevant areas of the heart. The recently published results of 2 small studies (1 randomized, 1 nonrandomized), however, offer little hope that intracoronary infusion of G-CSF mobilized BMSCs is any better than G-CSF or placebo alone.38,39 But even with intracoronary infusion, the phenomenon of microvasculature obstruction associated with postreperfusion injury may thwart effective stem cell delivery.12 One pharmacologic solution might be the use of a synthetic prostacyclin analog.40 Alternatively, direct intramyocardial administration of BMSCs may be required. The recently announced Myocardial Stem Cell Administration After Acute Myocardial Infarction (MYSTAR) study,41 a multicenter, prospective, randomized, single-blind clinical trial, is designed to compare early and late intracoronary delivery of BMSCs with combined percutaneous intramyocardial and intracoronary delivery, to patients with AMI following successful percutaneous coronary intervention. Of course, intramyocardial injections are not as simple and, for that reason, not as attractive of a therapeutic course as one based solely on subcutaneous injection of G-CSF, but the proof will ultimately lie in the results. In this context, it needs to be noted that clinical studies comparing cell-based therapy with classical pharmacologic approaches (eg, angiotensin converting enzyme inhibitors or statins) to improve the remodeling process and cardiac function in heart failure will eventually need to be undertaken.

Overview and Preview

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

A growing body of evidence from basic science supports the conclusion that cell-based therapies to improve cardiac function and even regenerate damaged heart tissue is not some utopian goal. Although the results of large-scale clinical trials involving G-CSF-based mobilization of BMSCs have been disappointing to date, recent advances have been made in understanding the factors that regulate the homing of stem cells to the injured heart, as well as their survival and actions once there. In some respects, the clinical trials may have jumped the gun, but the rapid pace of research means that stem cell-based cardiac therapy should readily translate into clinical practice in the near future. In the next article, we will examine what is known concerning the role of different stem cells (EPCs, mesenchymal stem cells, and resident cardiac stem cells) in repairing the heart, the issue of stem cell engraftment, the controversy of cellular transdifferentiation, and bioengineering approaches that could be used as adjunctive therapy with stem cell treatments.

Hematopoietic Cytokines of Interest for Infarct Repair

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References

Flt3 ligand (Flt3L or FL) acts via receptor tyrosine kinase CD135 and is important for lymphocyte (B cell and T cell) development, but not for other blood cells. Impacts on early hematopoietic precursor cells and acts synergistically with G-CSF in promoting BMSC mobilization and engraftment.

Granulocyte colony-stimulating factor (G-CSF, aka colony-stimulating factor 3) stimulates production and release of granulocytes and bone marrow stem cells; stimulates survival, proliferation, and differentiation of neutrophil precursors, and function of mature neutrophils.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates production and release of granulocytes and monocytes, and their progenitors.

Stem cell factor (SCF or c-kit ligand) acts via CD117 (c-Kit) receptor and is important in early hematopoietic stages for survival, proliferation, and differentiation of hematopoietic stem cells. Acts synergistically with G-CSF and GM-CSF.

Data from COPE: Horst Ibelgaufts' Cytokines & Cells Online Pathfinder Encyclopaedia (http://www.copewithcytokines.de) and Wikipedia Portal:Molecular and Cellular Biology (http://en.wikipedia.org/wiki/Portal: Molecular_and_Cellular_Biology).

References

  1. Top of page
  2. Abstract
  3. Direct Protective Effects of G-CSF on Cardiac Myocytes
  4. Factors Affecting Stem Cell Mobilization and Function
  5. Cardioprotective Actions of G-CSF
  6. Factors that Synergize With G-CSF to Mobilize BMSCs
  7. Delivery
  8. Overview and Preview
  9. Hematopoietic Cytokines of Interest for Infarct Repair
  10. References
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    Wojakowski W, Kucia M, Kazmierski M, et al. Circulating stem/progenitor cells in stable ischemic heart disease and acute coronary syndromes - relevant reparatory mechanism? Heart. 2007 Mar 29; [Epub ahead of print].
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    Vandervelde S, van Luyn MJ, Rozenbaum MH, et al. Stem cell-related cardiac gene expression early after murine myocardial infarction. Cardiovasc Res. 2007;73:783793.
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