MINI-FOCUS: CELL-BASED THERAPY: EDITORIAL COMMENT
Better Regenerative Output After Cellular InputHealing Hearts by Combining Basic Fibroblast Factor and Cell-Based Therapy*
Stefanie Dimmeler, PhD ,* and
Marc Tjwa, MD, PhD ,
Leibniz AG, Centre for Molecular Medicine, University of Frankfurt, Frankfurt, Germany
Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Frankfurt, Germany
Vesalius Research Center, Flemish Institute of Biotechnology, University of Leuven, Leuven, Belgium
* Reprint requests and correspondence: Dr. Stefanie Dimmeler, Institute of Cardiovascular Regeneration, Centre for Molecular Medicine, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany (Email: Dimmeler{at}em.uni-frankfurt.de).
Key Words: cell therapy • regeneration • stem cells • growth factors
Despite the availability of multiple treatment options, chronic ischemic heart disease (IHD) and heart failure remain major causes of morbidity and mortality. New therapeutic strategies are currently being developed with the aim to reduce ischemic injury, replace damaged tissue, and improve post-ischemic cardiac function. In the past decade, high hopes were put on 2 such novel concepts, namely cell-based therapy (1) and therapeutic angiogenesis (2). Both treatments provided exciting results in animal models of IHD, and their therapeutic efficacies are currently being investigated in clinical trials. However, although cell-based therapy in patients was safe and modestly improved left ventricular ejection fraction in patients with acute myocardial infarction, its efficacy in reversing established heart failure during chronic IHD is less established (1). Another outstanding issue remains: which cells—bone marrow-derived or tissue resident stem/progenitor cells—represent the highest potential for cardiac regeneration when transplanted or infused (1). Moreover, the concept of improving IHD by therapeutic angiogenesis using clinical administration of angiogenic factors such as basic fibroblast growth factor (bFGF or FGF-2) has been poised with limited therapeutic effects, in part due to safety issues and difficulties in efficient formulation and/or delivery (2). Hence, we are forced to put more efforts at the bench and better characterize the mechanisms and effects of these new treatments, which might, in turn, result in better translation at the bedside.
In this issue of the Journal, Takehara et al. (3) elegantly studied, in a porcine model of chronic IHD, the combined effects of therapeutic angiogenesis and cell-based therapy. In a first set of experiments, they randomized pigs with IHD (induced 1 month earlier via temporary coronary artery occlusion) to receive an epicardial implantation of slow-releasing bFGF hydrogels, and tested the effect of bFGF on myocardial revascularization and contractile function (evaluated by clinically relevant methods). At 4 weeks after implantation, local sustained bFGF therapy had stimulated myocardial perfusion by the enhanced formation of arterioles in the infarct and border zone, yet one has to note that the effects were not critically compared with a control group with empty hydrogels. Nevertheless, these positive effects after bFGF therapy were associated with higher left ventricular ejection fraction of the ischemic heart, though it remains unclear whether the infarct size was reduced. Thus, consistent with earlier studies by others (2), local sustained bFGF therapy efficiently stimulated the revascularization of chronically ischemic pig hearts.
In a second set of experiments (3), the investigators again randomized chronically ischemic pigs but now combined local bFGF therapy with intramyocardial injection of human cardiosphere-derived cells (hCDCs), which are regarded as putative cardiac stem cells (4). Compared with bFGF therapy alone, cotransplantation of hCDCs strongly amplified the positive effects of bFGF therapy on infarct size, left ventricular ejection fraction, and regional wall motion at 4 weeks after treatment. Further genetic labeling experiments revealed that bFGF therapy stimulated the cardiac differentiation and fusion of hCDCs in vivo, suggesting that at least part of the additive effects of this combined growth factor/cell-based strategy might be related to improved cardiac regeneration.
Notably, the concept of combining growth factor and cell-based therapy is not novel. Indeed, previous studies already identified the beneficial effects of applying pro-angiogenic growth factors (e.g., vascular endothelial growth factor or stromal-derived factor-1) to enhance the efficacy of cell-based therapy (for review, see Dimmeler and Leri [5]) and that prolonged delivery of antiapoptotic growth factors such as insulin-like growth factor-1 by means of biotinylated nanofibers improved left ventricular function after myocardial infarction in rodents, demonstrating that modulation of the local cellular microenvironment can improve cell therapy (6). Still, the current results by Takehara et al. (3) might provide some interesting new insights. Given the observation of stronger revascularization of the ischemic myocardium, it is conceivable that local bFGF therapy enhanced the efficacy of hCDC transplantation indirectly via providing an attractive microenvironment, highly permissive for donor cell engraftment, survival, and integration (a "cardiogenic niche") (Fig. 1). Indeed, by using magnetic resonance imaging-based in vivo cell tracking, the investigators observed, compared with hCDCs alone, a stronger engraftment of hCDCs after bFGF therapy in chronically ischemic hearts at 4 weeks after injection (3). This effect was functionally relevant as it was associated with smaller infarcts and higher left ventricular ejection fraction.
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Figure 1 Proposed Concept of Combined bFGF and Cell-Based Therapy
In part by enhancing myocardial revascularization, but perhaps also via direct effects, local basic fibroblast growth factor (bFGF) therapy promotes the formation of cardiogenic niches in the chronically ischemic heart, and these niches augment the engraftment and cardiac commitment (via bona fide differentiation as well as cell fusion) of transplanted cells such as human cardiosphere-derived cells. As a result, cardiac regeneration is stimulated, contractile dysfunction is ameliorated, and established heart failure might be reversed.
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However, Takehara et al. (3) also present results that may suggest some direct beneficial effects of bFGF on the transplanted hCDCs. Indeed, bFGF stimulated the activation of various signaling pathways in hCDCs in vitro, including Akt (3). As Akt was previously shown (7) to be critical for survival of transplanted cells in the ischemic heart, one might speculate that bFGF directly supported the survival (and subsequent engraftment) of injected hCDCs. However, because the investigators did not dissect the underlying mechanisms, it is impossible to discriminate between a direct effect of bFGF on apoptosis and indirect effects on cell survival by improved oxygen supply to the tissue.
Another direct effect of bFGF might be the enhanced commitment of hCDCs to mature cardiomyocytes via increased cell fusion but, importantly, also independently of cell fusion via enhanced bona fide cardiac differentiation (3) (Fig. 1). This might have been unexpected given the notion that, unlike fibroblast growth factor 8b and members of the Wnt, bone morphogenetic protein/transforming growth factor, and Notch pathway (8), bFGF is not considered as a standard stimulator of cardiac differentiation. Yet, bFGF was previously shown (9) to control the differentiation of resident cardiac precursor cells; the underlying mechanisms remain, however, an outstanding issue. Takehara et al. (3) did, unfortunately, not show the in vivo functional integration and electrical coupling of hCDC-derived cardiomyocytes beyond any doubt.
Another important finding by Takehara et al. (3) is the therapeutic effect of hCDC injection in a large animal model of IHD. These data nicely corroborate earlier observations with hCDCs in rodent models of acute IHD (4), but are also the first to evidence the therapeutic efficacy of human cardiac stem cell transplantation in a model of chronic IHD. Further investigations are warranted to identify the potential of hCDCs in clinical cell-based therapy.
One aspect of the study by Takehara et al. (3) focused on comparing the therapeutic efficacy of injecting hCDCs versus human bone marrow-derived mesenchymal stem cells (hMSCs) in bFGF-treated ischemic pigs. As the investigators found that, in contrast to hCDCs, cotransplantation of hMSCs failed to convey extra effects on infarct size or functional recovery beyond those obtained by bFGF therapy alone, their results suggested the superiority of using hCDCs over hMSCs in the context of cell-based therapy. These data were corroborated by findings that bFGF therapy failed to stimulate cardiac differentiation of hMSCs in vivo. It remains unclear why the investigators found, in contrast to many others (1), little benefit of hMSCs, but one might speculate that it had to do with technical disparities in culturing and expansion (e.g., the investigators added bFGF to the culture), and the use of frozen cells, which had to be thawed before application, potentially resulting in inferior engraftment and survival.
A last important insight situates around the application of biodegradable hydrogels for sustained release of recombinant proteins (3). As these hydrogels lasted only up to 3 weeks in vivo (3), they are suitable for clinical application. Besides creating a cardiogenic niche for transplanted cells, this form of sustained drug delivery might also revive the field of therapeutic angiogenesis (2).
In summary, Takehara et al. (3) provide compelling evidence in a large animal model that the functional recovery of chronically ischemic hearts via cell-based therapy is improved by sustained local release of bFGF, at least in part via promoting transplant engraftment and cardiac regeneration. With their slow-release hydrogels, the investigators now have a powerful platform to test the efficacy to augment cell-based therapy of alternative angiogenic factors—such as vascular endothelial- placental-, and platelet-derived growth factors—and perhaps even of growth factor cocktails including other cardioprotective cytokines such as insulin-like growth factor-1, hepatocyte growth factor, and granulocyte colony-stimulating factor. Conversely, because of the enhanced engraftment of transplants, the investigators are in a privileged position to carefully dissect the cardio-regenerative potential of various candidate (stem) cell types (1). In any case, it will be important to determine, following combined therapy, the long-term fate of transplanted cells as well as the sustained improvement of cardiac function leading to reduced morbidity and mortality over time.
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Footnotes
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* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Dimmeler S, Burchfield J, Zeiher AM. Cell-based therapy of myocardial infarction Arterioscler Thromb Vasc Biol 2008;28:208-216.[Abstract/Free Full Text]2. Boodhwani M, Sodha NR, Laham RJ, Sellke FW. The future of therapeutic myocardial angiogenesis Shock 2006;26:332-341.[CrossRef][Web of Science][Medline] 3. Takehara N, Tsutsumi Y, Tateishi K, et al. Controlled delivery of basic fibroblast growth factor promotes human cardiosphere-derived cell engraftment to enhance cardiac repair for chronic myocardial infarction J Am Coll Cardiol 2008;52:1858-1865.[Abstract/Free Full Text] 4. Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens Circulation 2007;115:896-908.[Abstract/Free Full Text] 5. Dimmeler S, Leri A. Aging and disease as modifiers of efficacy of cell therapy Circ Res 2008;102:1319-1330.[Abstract/Free Full Text] 6. Davis ME, Hsieh PC, Takahashi T, et al. Local myocardial insulin-like growth factor 1 (IGF-1) delivery with biotinylated peptide nanofibers improves cell therapy for myocardial infarction Proc Natl Acad Sci U S A 2006;103:8155-8160.[Abstract/Free Full Text] 7. Mangi AA, Noiseux N, Kong D, et al. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts Nat Med 2003;9:1195-1201.[CrossRef][Web of Science][Medline] 8. Koyanagi M, Bushoven P, Iwasaki M, Urbich C, Zeiher AM, Dimmeler S. Notch signaling contributes to the expression of cardiac markers in human circulating progenitor cells Circ Res 2007;101:1139-1145.[Abstract/Free Full Text] 9. Rosenblatt-Velin N, Lepore MG, Cartoni C, Beermann F, Pedrazzini T. FGF-2 controls the differentiation of resident cardiac precursors into functional cardiomyocytes J Clin Invest 2005;115:1724-1733.[CrossRef][Web of Science][Medline]
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