doi: 10.1161/CIRCULATIONAHA.105.576017
(Circulation. 2005;112:2951-2958.)
© 2005 American Heart Association, Inc.
Molecular Cardiology |
Extracardiac Progenitor Cells Repopulate Most Major Cell Types in the Transplanted Human Heart
From the Department of Medicine, Division of Cardiology (E.M.), Department of Pathology (M.A.L., C.E.M.), University of Washington School of Medicine, Seattle, and Department of Pathology (J.E.S.), Washington University School of Medicine, St Louis, Mo. Dr Saffitz is currently at the Department of Pathology, Harvard Medical School, Boston, Mass.
Correspondence to Charles E. Murry, MD, PhD, University of Washington Center for Cardiovascular Biology and Regenerative Medicine, 815 Mercer St, Room 453, Seattle, WA 98109. E-mail murry{at}u.washington.edu
Received June 10, 2005; de novo received July 14, 2005; revision received August 17, 2005; accepted August 22, 2005.
Background— Extracardiac progenitor cells are capable of repopulating cardiomyocytes at very low levels in the human heart after injury. Here, we explored the extent of endothelial, smooth muscle, and Schwann cell chimerism in patients with sex-mismatched (female-to-male) heart transplants.
Methods and Results— Autopsy specimens from 5 patients and endomyocardial biopsies from 7 patients were used for this study. Endothelial, vascular smooth muscle, and Schwann cells were stained with antibodies against CD31 or Ulex europaeus lectin, smooth muscle 
-actin, and S-100, respectively, and the Y chromosome was identified with in situ hybridization. Biopsy specimens from 1, 4, 6, and 12 months and 5 and 10 years after heart transplantation were evaluated. Y-positive cells were counted by conventional bright-field microscopy and confirmed by confocal microscopy. Endothelial cells showed the highest degree of chimerism, averaging 24.3±8.2% from extracardiac sources. Schwann cells showed the next highest chimerism, averaging 11.2±2.1%; vascular smooth muscle cells averaged 3.4±1.8%. All 3 cell types showed substantially higher chimerism than we previously observed for cardiomyocytes (0.04±0.05%). Endothelial chimerism was much higher in the microcirculation than in larger vessels. Analysis of serial endomyocardial biopsies revealed that high levels of endothelial chimerism occurred as early as 1 month after transplantation (22±6.6%) with no significant increases even up to 10 years after cardiac transplantation.
Conclusions— Extracardiac progenitor cells are capable of repopulating most major cell types in the heart, but they do so with varying frequency. The signals for endothelial progenitor recruitment occur early and could relate to injury during allograft harvest or transplantation. The high degree of endothelial chimerism may have immune implications such as for myocardial rejection or graft vasculopathy.
Key Words: endothelium • pathology • stem cells • transplantation • Y chromosome
This article has been cited by other articles:
 |
|
 |
|
  C. Stamm, Y.-H. Choi, B. Nasseri, and R. Hetzer A heart full of stem cells: the spectrum of myocardial progenitor cells in the postnatal heart Therapeutic Advances in Cardiovascular Disease, June 1, 2009; 3(3): 215 - 229. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Suzuki, V. Iyer, T. Cimato, and J. M. Canty Jr Pravastatin Improves Function in Hibernating Myocardium by Mobilizing CD133+ and cKit+ Bone Marrow Progenitor Cells and Promoting Myocytes to Reenter the Growth Phase of the Cardiac Cell Cycle Circ. Res., January 30, 2009; 104(2): 255 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ziebart, C.-H. Yoon, T. Trepels, A. Wietelmann, T. Braun, F. Kiessling, S. Stein, M. Grez, C. Ihling, M. Muhly-Reinholz, et al. Sustained Persistence of Transplanted Proangiogenic Cells Contributes to Neovascularization and Cardiac Function After Ischemia Circ. Res., November 21, 2008; 103(11): 1327 - 1334. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Reinecke, E. Minami, W.-Z. Zhu, and M. A. Laflamme Cardiogenic Differentiation and Transdifferentiation of Progenitor Cells Circ. Res., November 7, 2008; 103(10): 1058 - 1071. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Shimizu and R. N. Mitchell The Role of Chemokines in Transplant Graft Arterial Disease Arterioscler. Thromb. Vasc. Biol., November 1, 2008; 28(11): 1937 - 1949. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Kerbel, R. Benezra, D. C. Lyden, K. Hattori, B. Heissig, D. J. Nolan, V. Mittal, Y. Shaked, S. Dias, F. Bertolini, et al. Endothelial progenitor cells are cellular hubs essential for neoangiogenesis of certain aggressive adenocarcinomas and metastatic transition but not adenomas PNAS, August 26, 2008; 105(34): E54 - E54. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rupp, M. Koyanagi, M. Iwasaki, J. Bauer, S. von Gerlach, D. Schranz, A. M. Zeiher, and S. Dimmeler Characterization of long-term endogenous cardiac repair in children after heart transplantation Eur. Heart J., August 1, 2008; 29(15): 1867 - 1872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Surdacki, E. Marewicz, E. Wieteska, G. Szastak, T. Rakowski, E. Wieczorek-Surdacka, D. Dudek, J. Pryjma, and J. S. Dubiel Association between endothelial progenitor cell depletion in blood and mild-to-moderate renal insufficiency in stable angina Nephrol. Dial. Transplant., July 1, 2008; 23(7): 2265 - 2273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu Stem Cells and Transplant Arteriosclerosis Circ. Res., May 9, 2008; 102(9): 1011 - 1024. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Schmauss and M. Weis Cardiac Allograft Vasculopathy: Recent Developments Circulation, April 22, 2008; 117(16): 2131 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Lutz, M. Rosenberg, F. Kiessling, V. Eckstein, T. Heger, J. Krebs, A. D. Ho, H. A. Katus, and N. Frey Local injection of stem cell factor (SCF) improves myocardial homing of systemically delivered c-kit + bone marrow-derived stem cells Cardiovasc Res, January 1, 2008; 77(1): 143 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Muller, A. Kazakov, A. Semenov, M. Bohm, and U. Laufs Pressure-induced cardiac overload induces upregulation of endothelial and myocardial progenitor cells Cardiovasc Res, January 1, 2008; 77(1): 151 - 159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Nolan, A. Ciarrocchi, A. S. Mellick, J. S. Jaggi, K. Bambino, S. Gupta, E. Heikamp, M. R. McDevitt, D. A. Scheinberg, R. Benezra, et al. Bone marrow-derived endothelial progenitor cells are a major determinant of nascent tumor neovascularization Genes & Dev., June 15, 2007; 21(12): 1546 - 1558. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. N. Mitchell and P. Libby Vascular Remodeling in Transplant Vasculopathy Circ. Res., April 13, 2007; 100(7): 967 - 978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Anversa, A. Leri, M. Rota, T. Hosoda, C. Bearzi, K. Urbanek, J. Kajstura, and R. Bolli Concise Review: Stem Cells, Myocardial Regeneration, and Methodological Artifacts Stem Cells, March 1, 2007; 25(3): 589 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Kolossov, T. Bostani, W. Roell, M. Breitbach, F. Pillekamp, J. M. Nygren, P. Sasse, O. Rubenchik, J. W. U. Fries, D. Wenzel, et al. Engraftment of engineered ES cell-derived cardiomyocytes but not BM cells restores contractile function to the infarcted myocardium J. Exp. Med., October 2, 2006; 203(10): 2315 - 2327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kaye and M. D. Esler Letter by Kaye and Esler Regarding Article "Extracardiac Progenitor Cells Repopulate Most Major Cell Types in the Transplanted Human Heart" Circulation, June 6, 2006; 113(22): e844 - e844. [Full Text] [PDF]
|
|
|
|
|
|
E. Minami, M. A. Laflamme, C. E. Murry, and J. E. Saffitz Response to Letter Regarding Article "Extracardiac Progenitor Cells Repopulate Most Major Cell Types in the Transplanted Human Heart" Circulation, June 6, 2006; 113(22): e845 - e845. [Full Text] [PDF]
|
|
|
|
 |
|
 C. E. Murry, H. Reinecke, and L. M. Pabon Regeneration Gaps: Observations on Stem Cells and Cardiac Repair J. Am. Coll. Cardiol., May 2, 2006; 47(9): 1777 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rafii and D. Lyden Contribution of Hematopoietic and Vascular Progenitor Cells to the Neoangiogenic Niche Am. Assoc. Cancer Res. Educ. Book, April 1, 2006; 2006(1): 181 - 185. [Full Text] [PDF]
|
|
|
|
 |
|
 M. Esler and D. Kaye Sympathetic Nervous System Neuroplasticity Hypertension, February 1, 2006; 47(2): 143 - 144. [Full Text] [PDF]
|
|