Interdisciplinary Approach Needed for Cardiac Stem Cell Therapy to Move Forward

Recent trials and fundamental scientific advances in stem cell and regenerative biology show promise for new treatment options for cardiac disease, researchers say in a paper published online March 8, 2012, ahead of print in the Lancet. However, much work remains and opportunities for multidisciplinary collaboration are aplenty, according to the report, the first in a series on stem cell therapy by the journal.

For the paper, Kenneth R. Chien, MD, of Massachusetts General Hospital (Boston, MA) and colleagues reviewed cell therapy publications over the last 5 years to analyze progress made in both identifying the best cell types to use and the most effective delivery systems to implement.

Optimal Cell Type Remains Unclear

Looking back on research using bone marrow cells, Dr. Chien and colleagues write that although this treatment option seemed safe and capable of encouraging cardiac regenerative properties early on, a newer meta-analysis showed only a small improvement in left ventricular ejection fraction (LVEF) after injection of bone marrow cells.

However, the authors say there still might be potential in using these cells because the “small and inconsistent benefit associated with treatment with bone marrow cells was initially attributed to inefficient delivery.”

Another “compelling strategy” for cardiac repair involves augmentation of endogenous regenerative activity. In theory, this can be done either by stimulating expansion of cardiomyocytes or putative cardiac progenitor cells with a drug or paracrine factor or by propagating cardiac cells with regenerative potential ex vivo and then implanting these cells directly into an injured area. However, early attempts at these techniques have not panned out, the authors say.

Recent results from both the SCIPIO and CADUCEUS trials show no significant increase in adverse events associated with cardiac cell injection, while SCIPIO reported an improvement in LVEF. The authors warn that the “reported improvements should be viewed with caution, since the number of patients in the treatment arm of each study was small, . . . and neither study included a placebo group because of the invasive nature of the treatment.”

Regarding cardiac progenitor cells and the mechanisms by which they might promote regeneration, the authors say there are still “substantial gaps” in knowledge.

“Although c-Kit-positive cells are present at sites of cardiac injury, they do not have a known role in injury response,” they write. “No consensus exists about phenotype definition or isolation technique of these populations, many of which have not been compared.”

However, Joshua M. Hare, MD, of the University of Miami (Miami, FL), told TCTMD in a telephone interview that the authors are “promoting a particular point of view” since there is currently significant controversy in the field about what defines and constitutes a favorable response. His own work treating human subjects with investigational stem cells has made Dr. Hare more optimistic.

“From a more clinical, translational point of view, we’re seeing very significant positive responses with strategies that involve mesenchymal stem cells and cardiac stem cells,” he said.

Proceed with Caution

In the field of genetic fate mapping (a method of establishing the correspondence between individual cells at one stage of development and their progeny at later stages of development) and endogenous cardiac progenitor cells, Dr. Chien and colleagues point out that the “search for cardiac cells and paracrine factors that are capable of triggering cardiac repair has been challenging.”

Because most cases of heart failure are attributable to the left ventricular field, they say that more research needs to be done on the first heart field so as to improve genetic fate mapping abilities.

The authors also caution against clinical use of induced pluripotent stem cell technology since the rarity of phenotypes of cardiac cells with regenerative potential make it difficult to generate enough cells to produce a clinically meaningful effect.

Examining the role of paracrine factors in cardiac regeneration, the authors concur that they hold “key roles” in cardiac pathophysiological mechanisms. However, “neither the identity nor the actions of these putative factors are known.”

Ultimately, they say that “use of paracrine factors to mobilize cardiac cells with regenerative potential is a compelling treatment strategy, especially because it is associated with a potentially smaller risk of tissue disruption than is cell injection.”

But according to Dr. Hare, the paper is “laced with negative statements” and does not give enough credit to existing data. “I’m not disputing that there might be better cells in the future, but what I am saying is that the approaches that have been taken already are yielding very positive results and shouldn’t be dismissed.”

For instance, Dr. Hare cited a study on mesenchymal cells he coauthored last year that was the most cited article from Circulation Research in 2011, a paper the current review neglected to even mention.

“If you just completely ignore a body of work in your review article then it’s not a full and fair review of the literature,” he added.

Delivery System Key

No matter what cardiac regenerative therapy is being implemented, the authors stress the importance of a delivery system that is “safe, effective, and practical.”

Based on available evidence, Dr. Chien and colleagues are skeptical about using intramyocardial injection from the epicardial approach because of the potential of metastatic tumor formation. Use of this approach is “difficult to justify unless another cardiac surgical procedure, such as coronary artery bypass grafting, is indicated,” they say.

With the percutaneous transarterial approach, a decrease in procedural morbidity is offset by an increase in the risk of hematogenous dissemination and an inability to directly visualize the affected area, they say. Also, if the region is occluded, the targeted area of myocardium cannot be accessed.

While the percutaneous transvenous approach solves the morbidity issue, they also do not recommend it because of “poor delivery efficiency and broad dissemination.”

The best delivery system is yet to come, they write.

Government Support Crucial 

To accomplish all they postulate needs to be done, Dr. Chien and colleagues say “the creation of interdisciplinary teams, including partnerships between academia and the private sector,” will be necessary.

“Regenerative therapy in cardiac disease is in an important phase: breaking down of traditional barriers between individual areas of specialization will be challenging, but necessary, if we are to move beyond stem cell biology towards the development of true cardiovascular regenerative therapy,” they conclude. “The fate of the next generation of leading physician-scientists in the specialty, and the fate of patients with heart failure, will probably hinge on the outcome.”

In an accompanying editorial, Dusko Ilic, MD, PhD, of King’s College Medical School (London, United Kingdom), and Julia Polak, MD, DSc, of Imperial College (London, United Kingdom), agree.

“To keep hope alive, governments and the private sector will have to show confidence in stem cell research by continuous investment in a new generation of researchers who will move science forward and translate discoveries into reliable clinical outcomes,” they write.

 

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Sources:
1. Ptaszek LM, Mansour M, Ruskin JN, et al. Stem Cells 1: Towards regenerative therapy for cardiac disease. Lancet. 2012;379:933-942.

2. Ilic D, Polak J. Stem cell based therapy—where are we going? Lancet. 2012;379:877-878.

 

 

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• Stem Cell Therapy Moderately Improves Cardiac Function After Acute MI
• Cardiac Stem Cell Therapy Safe, May Regenerate Heart Tissue
• SCIPIO: Cardiac Stem Cell Treatment Looks Promising in Early Results

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