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Cardiovascular Research 2006 71(3):405-407; doi:10.1016/j.cardiores.2006.05.025
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Copyright © 2006, European Society of Cardiology

Post-infarct heart repair with granulocyte-colony stimulating factor: Is it a utopian goal?

Pasquale Pagliaro*

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Regione Gonzole 10, 10043, Orbassano (TO), Italy

* Tel.: +39 011 6705430; fax: +39 011 9038639. Email address: pasquale.pagliaro{at}unito.it

Received 15 May 2006; accepted 29 May 2006

See article by Misao et al. [16] (pages 455–465) in this issue.

For many years, the regeneration of the myocardium in which cells have been lost as a result of myocardial infarction (MI) and other forms of cardiac pathology has been a utopian goal of cardiologists. Recent experimental studies and early-phase clinical trials supported the possibility of enhancing cardiac repair as an achievable therapeutic target. Yet, disappointing, negative results have been reported both in experimental and clinical studies [1–3]. There can be several reasons for negative results. Certainly, the fact that we do not know the exact physiology of stem cells is one of the reasons.

We do not know yet the ideal cell type: bone marrow stem cells (BMSCs), cardiomyoplasty cardiomyocytes, skeletal myoblasts, and resident stem cells have been tested, and among BMSCs several cell lines (MSCs, EPCs, etc.) have been proposed [1–3]. We do not know the underlying mechanism of cellular regeneration (transdifferentiation, fusion, and/or paracrine effects). Finally, we do not know whether myocardial repair can be better achieved via cellular transplantation (intramyocardial, intracoronary, and/or systemic delivery) or mobilization of primitive BMSCs by cytokines. Each of these approaches may be adequate for specific patients. Undoubtedly, mobilization of BMSCs might offer a noninvasive therapeutic approach that is appealing for both physicians and patients. The bone marrow is a large reservoir of adult stem cells distal from the heart that can be enrolled for cell-mediated cardiac repair via regeneration of healthy myocardial tissue and recovery of cardiac function. These could be accomplished by neo-angiogenesis, cardiogenesis, and/or paracrine effects.

In its natural progression, MI leads to scar formation and subsequent reduced cardiac performance. Signals between the bone marrow, the peripheral circulation, and the infarcted myocardium are surely present in both acute and chronic phases [4,5]. Evidently, these signals are not enough and/or require an adequate regulation in orchestrating the process of mobilization, homing, incorporation, survival, proliferation, and differentiation of stem cells that leads to myocardial regeneration [1–6].

Granulocyte-colony stimulating factor (G-CSF or filgrastrim) is well known for its mobilizing and chemotactic abilities [4–14]. It is a signaling factor that is expressed after MI and seems to be involved in the pathophysiological healing process [4,5]. Several experimental studies on animal models showed that following MI, administration of G-CSF improves left ventricular (LV) function and reduces LV remodeling and old infarct-scar size [6,8,9]. The beneficial effects of G-CSF have been attributed either to bone marrow-derived cells recruited into the infarcted myocardium, due to cardiomyocyte regeneration and/or acceleration of the healing process [6,8], or to a direct activation of the Jak-Stat pathway [9].

Prompted by these results, several clinical studied have been performed in an attempt to reproduce such a beneficial effect [10–14]. The majority of these clinical studies reported that in patients with MI, treatment with G-CSF to mobilize BMSCs is feasible and safe, with no or little discomfort. In some clinical studies, G-CSF therapy seemed to be effective in improving post-ischemic heart function. The therapeutic effect has been attributed to BMSC-associated promotion of myocardial regeneration and neovascularization [11]. It has also been reported that improvement is seen in ventricular function and prevention of left ventricular remodeling even 1 year after acute MI [10]. In another study, 6 months after MI and G-CSF therapy a scant improvement, if any, in ventricular function was observed [5]. When, in patients with MI, G-CSF therapy was accompanied by intracoronary infusion of collected peripheral blood stem cells, improved cardiac function and angiogenesis were observed; however, an aggravation of restenosis has also been reported [7]. A study in which patients with severe chronic ischemic heart disease were enrolled in a treatment with G-CSF reported improved symptoms, but not improved myocardial ischemia. The effects seemed to be related to mobilization of stem cells, and patients were described as "mobilizers" vs. "poor mobilizers". In this study, an adverse effect on ejection fraction could not be excluded [12]. Many of these studies were conducted on a small number of patients without a placebo control group.

In more recent randomized, placebo-controlled trials [13,14], the BMSC mobilization with G-CSF treatment was confirmed to be safe but had no influence on infarct size, left ventricular function, or coronary restenosis. These findings are in line with the absence of effect on heart function and myocyte regeneration observed in a nonhuman primate model treated with the G-CSF and stem cell factor protocol, despite an enhanced angiogenesis in the infarcted myocardium [15].

In summary, in the post-infarct period G-CSF might have a direct effect on cardiomyocytes [9] and may recruit BMSCs into the infarcted area [5,6,8]. However, though a significant difference from controls was seen in some studies, including the study published in the present issue of Cardiovascular Research by Misao et al. [16], G-CSF has been shown to have little if any effect on cardiac function both in clinical [7,13,14] and experimental studies [6,8,9,15].

In their study, Misao et al. [16] conclude that "neither the direct effects of G-CSF on cardiomyocytes nor its ability to mobilize BMSCs are sufficient to elicit all the beneficial post-MI effects of G-CSF. Instead, the observed therapeutic efficacy of G-CSF may reflect both of those modes of action." In particular, they report that the CXCR4/SDF-1 axis plays an important role in the G-CSF-mediated recruitment of CXCR4+ cells into the infarcted myocardium. Moreover, they suggest that the upregulation of matrix metalloproteinase-1 (MMP-1) may explain the G-CSF-mediated reduction in scar size. Finally, the authors suggest that the role of the Jak/Stat pathway may be different in the ischemia (permanent occlusion) and the ischemia/reperfusion model. This last hypothesis is particularly intriguing, because this pathway, when activated, may induce either a positive [9] or a negative inotropic effect [17]. Therefore, the difference in the Jak/Stat pathway response might determine the negative [12], null [5,13–15], or positive [6,8–10,16] inotropic effect observed after G-CSF therapy.

The findings of Misao et al. [16] represent little steps forward in our understanding of the physiology of G-CSF. A scientific foundation in medical practice is of paramount importance. According to William Osler (1902): "A physician without physiology practices a sort of pop-gun pharmacy, hitting now the disease and again the patient, he himself not knowing which" [18]. Yet, how many therapies do we use whose mechanism of action is not fully understood? An honest answer to this question is: "several"! Even the mechanisms of action of widely used ACE inhibitors are not fully understood [19]. Therefore, with this concept in mind, we should perform and support our studies on stem cell therapy for cardiac repair. We should pursue our studies to acquire as much of a scientific base as possible, step by step, while trying and verifying safe therapies in humans. The body of evidence favoring a beneficial role of BMSCs in cardiac disease cannot and should not be ignored.

From recent trials, we know that in ischemic diseases, treatment with G-CSF (i) is safe, (ii) enhances spontaneous mobilization of BMSCs, (iii) can improve symptoms, and (iv) does not endanger myocardial performance. The future therapeutic application and capacity of secreted factors to modulate tissue repair after MI relies on the intrinsic potency of factors and on the optimal localization and timing of a combination of signaling factors to stimulate stem cells to regenerate the infarcted heart. It would be worthwhile to investigate pharmacological strategies that are able to transform ‘poor mobilizers’ into ‘good mobilizers’. In agreement with Misao et al. [16], I suggest that "development of new methods, such as combination therapies using G-CSF and other agents, should be investigated."


   Acknowledgments
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 Acknowledgments
References
 
The author wishes to thank Jennifer Marie Lee for the English language revision. The author is supported by Compagnia di S. Paolo, University of Turin, Regione Piemonte, MIUR (FIRB and PRIN funds) and INRC.


   References
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 Acknowledgments
 References
 

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