Abstract
Multimodality Noninvasive Imaging Demonstrates In Vivo Cardiac Regeneration After Mesenchymal Stem Cell Therapy
Luciano C. Amado, Karl H. Schuleri, Anastasios P. Saliaris, Andrew J. Boyle, Robert Helm, Behzad Oskouei, Marco Centola, Virginia Eneboe, Randell Young, Joao A. C. Lima, Albert C. Lardo, Alan W. Heldman, Joshua M. Hare
Mesenchymal stem cell therapy leads to improvement in cardiac function in animal models of ischemic cardiomyopathy; however, controversy exists as to whether this improvement is due to active myocardial regeneration or passive effects on the infarct scar. We used state-of-the-art imaging modalities of magnetic resonance imaging and multi-detector computed tomography to demonstrate a time-dependent regeneration of a rim of sub-endocardial myocardium in the infarct zone. Moreover, this rim developed contractile properties over time and improved local and global cardiac function. These findings have implications for the design of clinical trials studying regenerative therapies.
The purpose of this study was to test the hypothesis, with noninvasive multimodality imaging, that allogeneic mesenchymal stem cells (MSCs) produce and/or stimulate active cardiac regeneration in vivo after myocardial infarction (MI).
Although intramyocardial injection of allogeneic MSCs improves global cardiac function after MI, the mechanism(s) underlying this phenomenon are incompletely understood.
We employed magnetic resonance imaging (MRI) and multi-detector computed tomography (MDCT) imaging in MSC-treated pigs (n = 10) and control subjects (n = 12) serially for a 2-month period after anterior MI. A sub-endocardial rim of tissue, demonstrated with MDCT, was assessed for regional contraction with MRI tagging. Rim thickness was also measured on gross pathological specimens, to confirm the findings of the MDCT imaging, and the size of cardiomyocytes was measured in the sub-endocardial rim and the non-infarct zone.
Multi-detector computed tomography demonstrated increasing thickness of sub-endocardial viable myocardium in the infarct zone in MSC-treated animals (1.0 ± 0.2 mm to 2.0 ± 0.3 mm, 1 and 8 weeks after MI, respectively, p = 0.028, n = 4) and a corresponding reduction in infarct scar (5.1 ± 0.5 mm to 3.6 ± 0.2 mm, p = 0.044). No changes occurred in control subjects (n = 4). Tagging MRI demonstrated time-dependent recovery of active contractility paralleling new tissue appearance. This rim was composed of morphologically normal cardiomyocytes, which were smaller in MSC-treated versus control subjects (11.6 ± 0.2 μm vs. 12.6 ± 0.2 μm, p < 0.05).
With serially obtained MRI and MDCT, we demonstrate in vivo reappearance of myocardial tissue in the MI zone accompanied by time-dependent restoration of contractile function. These data are consistent with a regenerative process, highlight the value of noninvasive multimodality imaging to assess the structural and functional basis for myocardial regenerative strategies, and have potential clinical applications.
