Repeated direct endomyocardial transplantation of allogeneic mesenchymal stem cells: Safety of a high dose, “off-the-shelf”, cellular cardiomyoplasty strategy☆
Introduction
Cardiomyocytes have long been considered to be terminally differentiated, which supported the concept that the heart is incapable of functional repair after cellular destruction. However, recently reparative cardiology has surfaced to be a potential therapeutic option, with the discovery of several groups of progenitor and stem cells capable of improving cardiac function in the ischemic or infarcted failing heart. Suggested mechanisms of benefit for cellular cardiomyoplasty include physical myocardial scaffolding, function as a cytokine repository, myocardial cellular augmentation or regeneration, and/or induction of vascularization. Several cellular sources have been evaluated. Embryonic stem cells can differentiate into different myocardial cell types and may seem to be an ideal choice. However its utilities have to overcome scientific (immunological), political and ethical obstacles. Whole bone marrow and subpopulation preparations have been used in early clinical trials. These resulted in some functional improvement [1], [2]. However, controversy exists on the underlying mechanisms, especially with the absence of supporting evidence for engraftment and differentiation [3]. On the contrary, recent studies have shown that the mesenchymal stem cell (MSC) component of bone marrow engraft in the myocardium [4] and may have favorable paracrine effects [5]. In addition, MSC exhibits properties associated with the avoidance of immunologic detection and subsequent rejection [6]. These data suggest that MSCs may be potentially used as an “off-the-shelf” strategy for allogeneic transfer.
Furthermore, there have been advances in the design of delivery systems for cellular transplantation. Direct percutaneous transendocardial injection delivers cells into the myocardium and so avoids limitations such as nonspecific cell distribution, cell loss in the coronary arterial and venous systems from other modalities including intracoronary infusions [2]. Percutaneous approaches also enable repeated administration of therapeutics that is less invasive than open chest or thoracotomy approaches. Preliminary studies suggest that the number of cells transplanted is important to eventual clinical outcome [7] and to administer sufficient cells, repeated percutaneous delivery may become necessary.
The purposes of this study were to demonstrate that: i) allogeneic MSC can be safely transplanted directly via percutaneous injection catheter in a porcine, human-surrogate healthy model and that ii) cryopreserved high dose MSC administered via repeated dosing is feasible.
Section snippets
Expansion of Bone Marrow MSC
Allogeneic MSCs were isolated, characterized, cultured and expanded at Osiris Therapeutics, Inc (Baltimore, MD) as previously described [8]. Briefly, MSCs isolated from the iliac crests of donor pigs were expanded through 3 passages. Cultures were 95% homogenous and using the same methods, multipotentiality of the resulting cells have been shown with the use of in vitro assays to differentiate MSCs into established lineages. MSCs were washed 3 times with DPBS before storage in freezing medium
Results
The intramyocardial injections were performed with mean total procedure time of 40 ± 10 min. The operators were able to access all ventricular target areas using the Stiletto™ system. For each procedure, the anterior, septal and lateral walls received 7.3 ± 0.9, 6.4 ± 1.1 and 6.1 ± 0.9 injections, respectively. Fig. 1 illustrates 2 examples of deployments of the catheter: Fig. 1A, anterior–posterior fluoroscopic projection with the lateral wall being targeted and the injection needle extended
Discussion
Using a human-surrogate model, we were able to transplant a large quantity of allogeneic MSCs directly into the myocardium and demonstrated, for the first time that repeated administration of these cells is safe and feasible via percutaneous approach.
MSCs have been shown to improve cardiac function in animal models of dilated cardiomyopathy [9] and post-myocardial infarction heart failure [8], [10]. These cells have been shown to exert early paracrine effects, supplying angiogenic,
Conclusions
There is no evidence of local or systemic toxicity associated with endomyocardial injections of MSCs in cryopreservant medium. Repeated endomyocardial transplantation of high dose of these allogeneic cells appeared safe in a large animal, human-surrogate model. Such cellular cardiomyoplasty strategy warrants further evaluation.
Acknowledgments
We acknowledge support from Osiris Therapeutics, Inc., Baltimore, MD and Boston Scientific Corporation, Natick, MA. K.K.P. received funding from the National University Hospital, National Healthcare Group, Singapore.
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Disclosure: This study was funded by Osiris Therapeutics, Inc., and Boston Scientific Corporation.