CLINICAL RESEARCH: MOLECULAR AND STEM CELL IMAGING
Multimodality Noninvasive Imaging Demonstrates In Vivo Cardiac Regeneration After Mesenchymal Stem Cell Therapy
Luciano C. Amado, MD*, ,
Karl H. Schuleri, MD*,,
Anastasios P. Saliaris, MD*,,
Andrew J. Boyle, MBBS, PhD*,,
Robert Helm, MD*,
Behzad Oskouei, MD*,,
Marco Centola, MD*,,
Virginia Eneboe, VT*,,
Randell Young, MVD ,
Joao A.C. Lima, MD*,
Albert C. Lardo, PhD*,
Alan W. Heldman, MD*, and
Joshua M. Hare, MD*,,1,*
* Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
Institute for Cell Engineering (ICE), Johns Hopkins University School of Medicine, Baltimore, Maryland
OsirisTherapeutics, Baltimore, Maryland
Manuscript received February 27, 2006;
revised manuscript received June 6, 2006,
accepted June 29, 2006.
* Reprint requests and correspondence: Dr. Joshua M. Hare, Johns Hopkins Medical Institutions and Institute for Cell Engineering (ICE), Division of Cardiology, BRB 651, 733 North Broadway, Baltimore, Maryland, 21205. (Email: jhare{at}med.miami.edu).
OBJECTIVES: 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).
BACKGROUND: Although intramyocardial injection of allogeneic MSCs improves global cardiac function after MI, the mechanism(s) underlying this phenomenon are incompletely understood.
METHODS: 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.
RESULTS: 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).
CONCLUSIONS: 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.
|
Abbreviations and Acronyms
| | Ecc = systolic circumferential strain | | FOV = field of view | | LV = left ventricle/ventricular | | MDCT = multi-detector computed tomography | | MI = myocardial infarction | | MMP = matrix metalloproteinase | | MRI = magnetic resonance imaging | | MSC = mesenchymal stem cell | | TIMP = tissue inhibitor of matrix metalloproteinase |
|
This article has been cited by other articles:
|
|
|
|
 
J. M. Hare, J. H. Traverse, T. D. Henry, N. Dib, R. K. Strumpf, S. P. Schulman, G. Gerstenblith, A. N. DeMaria, A. E. Denktas, R. S. Gammon, et al.
A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Study of Intravenous Adult Human Mesenchymal Stem Cells (Prochymal) After Acute Myocardial Infarction
J. Am. Coll. Cardiol.,
December 8, 2009;
54(24):
2277 - 2286.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. H. Schuleri, G. S. Feigenbaum, M. Centola, E. S. Weiss, J. M. Zimmet, J. Turney, J. Kellner, M. M. Zviman, K. E. Hatzistergos, B. Detrick, et al.
Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy
Eur. Heart J.,
November 2, 2009;
30(22):
2722 - 2732.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. H. Seeger, T. Rasper, M. Koyanagi, H. Fox, A. M. Zeiher, and S. Dimmeler
CXCR4 Expression Determines Functional Activity of Bone Marrow-Derived Mononuclear Cells for Therapeutic Neovascularization in Acute Ischemia
Arterioscler Thromb Vasc Biol,
November 1, 2009;
29(11):
1802 - 1809.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. S. Feigenbaum, L. Lemberg, and J. M. Hare
Tracking cell fate with noninvasive imaging.
J. Am. Coll. Cardiol.,
October 20, 2009;
54(17):
1627 - 1628.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Gersh, R. D. Simari, A. Behfar, C. M. Terzic, and A. Terzic
Cardiac Cell Repair Therapy: A Clinical Perspective
Mayo Clin. Proc.,
October 1, 2009;
84(10):
876 - 892.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. C. Quevedo, K. E. Hatzistergos, B. N. Oskouei, G. S. Feigenbaum, J. E. Rodriguez, D. Valdes, P. M. Pattany, J. P. Zambrano, Q. Hu, I. McNiece, et al.
Allogeneic mesenchymal stem cells restore cardiac function in chronic ischemic cardiomyopathy via trilineage differentiating capacity
PNAS,
August 18, 2009;
106(33):
14022 - 14027.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Kraitchman and J. W.M. Bulte
In Vivo Imaging of Stem Cells and Beta Cells Using Direct Cell Labeling and Reporter Gene Methods
Arterioscler Thromb Vasc Biol,
July 1, 2009;
29(7):
1025 - 1030.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-H. Li, T. Y.Y. Lai, Z. Sun, M. Han, E. Moriyama, B. Wilson, S. Fazel, R. D. Weisel, T. Yau, J. C. Wu, et al.
Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery.
J. Thorac. Cardiovasc. Surg.,
May 1, 2009;
137(5):
1225 - 33.e1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Habeler, S. Pouillot, A. Plancheron, M. Puceat, M. Peschanski, and C. Monville
An in vitro beating heart model for long-term assessment of experimental therapeutics
Cardiovasc Res,
February 1, 2009;
81(2):
253 - 259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. H. Schuleri, L. C. Amado, A. J. Boyle, M. Centola, A. P. Saliaris, M. R. Gutman, K. E. Hatzistergos, B. N. Oskouei, J. M. Zimmet, R. G. Young, et al.
Early improvement in cardiac tissue perfusion due to mesenchymal stem cells
Am J Physiol Heart Circ Physiol,
May 1, 2008;
294(5):
H2002 - H2011.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Gottlieb and J. A.C. Lima
Screening High-Risk Patients With Computed Tomography Angiography
Circulation,
March 11, 2008;
117(10):
1318 - 1332.
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Zhang, P. Song, Y. Tang, X.-l. Zhang, S.-h. Zhao, Y.-j. Wei, and S.-s. Hu
Injection of bone marrow mesenchymal stem cells in the borderline area of infarcted myocardium: heart status and cell distribution.
J. Thorac. Cardiovasc. Surg.,
November 1, 2007;
134(5):
1234 - 1240.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
