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Arman T Askari

Stromal Cell-Derived Factor-1 Mediates Stem Cell Homing and Tissue Regeneration

The search for alternative treatments for congestive heart failure remains an ongoing venture. Exciting research over the last 2 years has changed the long held dogma that the heart cannot regenerate itself. The work of many groups can be summarized by the following concept: increasing the number of CD117+ (c-kit+) stem cells in cardiac tissue or in the coronary circulation within 2 days of a myocardial infarction results in regeneration of myocardial tissue and improved cardiac function.

Animal studies by Orlic, Anversa and colleagues have demonstrated that either the direct injection of bone marrow-derived CD117+ stem cells in the infarct border zone at the time of myocardial infarction (Orlic et al., 2001a), or mobilization of these stem cells prior to myocardial infarction results in regeneration of cardiac myocytes and improved left ventricular (LV) function (Orlic et al., 2001b). In a critical experiment, Itescu and colleagues extended the window of therapeutic opportunity by demonstrating that the intravenous infusion of bone marrow-derived stem cells 2 days after myocardial infarction led to decreased infarct size, increased vascular density and improved left ventricular function (Kocher et al., 2001).

These rodent studies have led to early clinical trials that have demonstrated that the intracoronary infusion of bone marrow-derived or circulating progenitor cells within days of a myocardial infarction is (i) safe and (ii) appears to result in increased myocardial perfusion and improved left ventricular function (Assmus et al., 2002).

These studies all suggested that there exists a mechanism by which stem cells are homed to the heart. Stem cell homing to bone marrow has been well studied; however, since the heart was thought to be unable to regenerate, no myocardial stem cell homing factor(s) have been identified.

In an attempt to understand whether there existed a limited temporal window following myocardial infarction during which myocardial regeneration and stem cell homing to the heart was possible, we studied the effects of stem cell mobilization with granulocyte- colony-stimulating factor (G-CSF) in rats with an ischemic cardiomyopathy, 2 months after myocardial infarction (Askari et al., 2003). G-CSF-mediated stem cell mobilization 2 months after myocardial infarct (MI) did not result in stem cell engraftment into the infarct zone or improvement in left ventricular function despite a 25 fold increase in the number of circulating CD117+ cells. This finding suggested that in order for stem cell mobilization to be efficacious at a time remote from the MI, the signaling for stem cell homing needed to be reestablished.

Our group has been championing the concept of using autologous skeletal myoblast (SKMB) transplantation as a vector for gene therapy (Figure). SKMB are obtained from skeletal muscle and SKMB transplantation as an adjunct to coronary artery bypass surgery is currently undergoing clinical trials (Menasche et al., 2003). We envisioned that SKMB transplantation could be used as a means to deliver a stem cell homing factor so that following surgery, G-CSF therapy could be used to induce myocardial regeneration. In a control experiment in which we injected SKMB 2 months after MI, followed by G-CSF therapy, we observed that the transplantation of SKMB led to reestablishment of stem cell homing to the myocardial tissue. This observation offered us a model with which we could identify the myocardial stem cell homing factor(s). We used a gene array strategy as well as a candidate gene approach strategy to identify potential homing factors using the following criteria. The factor had to: (i) not be expressed in normal tissue, (ii) be expressed within 2 h following MI, (iii) be expressed at least 2 d following MI, (iv) not be expressed 30 d after MI, and (v) had to be expressed following SKMB transplantation. Both strategies identified stromal cell derived factor-1 (SDF-1) as a potential myocardial stem cell homing factor.

We cloned SDF-1 and made cells that had our SDF-1 or a control vector stably integrated. Whereas transplantation of control cells had no effect, transplantation of SDF-1-expressing cells into hearts 2 months following MI, reestablished stem cell homing. A 20-fold increase in the number of CD117+ cells engrafted into the infarct zone 4 weeks following cell transplantation combined with G-CSF therapy was observed.

Since chronic SDF-1 therapy could lead to homing of naturally released stem cells, we tested whether transplantation of SDF-1 expressing cells 2 months after MI without stem cell mobilization would lead to improved left ventricular function. We found an 80% increase in cardiac function (as measured by shortening fraction) 4 weeks following transplantation of SDF-1 expressing cells (12 weeks after MI). There was no change in cardiac function in animals transplanted with control cells. We further demonstrated regeneration of myocardial function by showing normalization of myocardial strain, a sensitive measure of local contractility, within the infarct zone.

Our findings demonstrate that the detailed analysis of the biological responses to tissue injury not only give us insight into how damage occurs, but can also yield insight into how the body attempts to repair itself. In the case of the heart, these “healing pathways” are only expressed for a short time following injury, and may be why myocardial damage is usually irreversible. Furthermore, our study indicates that deciphering these “healing pathways” and re-establishing their expression at a time remote from injury offers an avenue of novel therapeutics that ultimately may not require introduction of exogenous, autologous, or allogeneic stem cells.

Injection of SDF-1 protein or expression vector into the myocardium following myocardial infarction, will likely result in preservation/regeneration of myocardial tissue and significantly reduce the risk of congestive heart failure. Similarly, transplantation of cells engineered to express SDF-1 at the time of left ventricular assist device implantation could ultimately allow assist devices to be used as bridges to myocardial regeneration. Such a strategy could potentially offer therapy to a critically ill patient population that in the present day has limited treatment options.

References

Bone marrow cells regenerate infarcted myocardium.
Orlic D et al.
NHGRI, NIH, Bethesda, MD, USA.
Nature 410:701-705, Apr. 2001a.
Summary: Through direct transplantation of a specific side population of bone-marrow-derived stem cells into the border zone of a myocardial infarction, the authors demonstrated that infarcted myocardium could be regenerated. They revealed the homing and differentiating capabilities of freshly infarcted myocardium.

Mobilized bone marrow cells repair the infarcted heart, improving function and survival.
Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk L, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P.
New York Medical College, Valhalla, NY, USA.
PNAS 98:10344-10349, Aug. 2001b.
Summary: The authors demonstrate that stem cell mobilization using G-CSF and SCF, prior to and following MI results in improved LV function following MI. Although scientifically important, these data are not clinically useful as one would need to predict the timing of an MI to realize the benefits of this therapy.

Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function.
Kocher AA, Schuster MD, Szabolcs MJ, Takuma S, Burkhoff D, Wang J, Homma S, Edwards NM, Itescu S.
Columbia University, New York, NY, USA.
Nat Med 7:430-436, Apr. 2001.
Summary: The authors revealed that systemic delivery of angioblasts within 2 days of an MI resulted in homing of these cells to the myocardium, neoangiogenesis within the infarct zone, less apoptosis and improved LV function.

Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI).
Assmus B, et al.
University of Frankfurt, Frankfurt, Germany.
Circulation 106:3009-3017, Dec. 2002.
Summary: The findings of this study suggest improvement in LV systolic function with intra-coronary delivery of either bone marrow derived stem cells or circulating endothelial progenitor cells delivered within 3-5 days of an MI. They also demonstrated the safety of stem cell delivery after MI.

Stromal cell-derived factor-1 mediates stem cell homing and tissue regeneration in ischemic cardiomyopathy.
Askari AT et al.
Cleveland Clinic Foundation, Cleveland, Ohio, USA.
Lancet 362:697-702, Aug. 2003.
Summary: The authors identify SDF-1 as an integral factor for stem cell homing and tissue regeneration following MI, and that re-expression of SDF-1 weeks after MI can result in homing of stem cells to the infarct zone and recovery of cardiac function. Their approach to delivering SDF-1 combined gene and cell therapy.

Autologous skeletal myoblast transplantation for severe post infarction left ventricular dysfunction.
Menasche P, et al.
Hopital Bichat, Paris, France.
J Am Coll Cardiol 41:1078-83 Apr. 2003.
Summary: The authors demonstrated the feasibility and safety of autologous SKMB transplantation in ischemic cardiomyopathy. At the dose of cells used (nearly 900 million per patient), they may have increased the arrhythmogenic potential.
[Discovery Medicine, 3(18):46-47, 2003]

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