AJP - Heart Calcium Transients and Cell-Sarcomere
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Heart Circ Physiol 287: H2670-H2676, 2004. First published July 29, 2004; doi:10.1152/ajpheart.01071.2003
0363-6135/04 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
287/6/H2670    most recent
01071.2003v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via ISI Web of Science (80)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Nagaya, N.
Right arrow Articles by Kitamura, S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Nagaya, N.
Right arrow Articles by Kitamura, S.

Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis

Noritoshi Nagaya,1,2 Takafumi Fujii,3 Takashi Iwase,1 Hajime Ohgushi,4 Takefumi Itoh,1 Masaaki Uematsu,5 Masakazu Yamagishi,2 Hidezo Mori,3 Kenji Kangawa,6 and Soichiro Kitamura7

Departments of 1Regenerative Medicine and Tissue Engineering, 3Cardiac Physiology, and 6Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565; Departments of 2Internal Medicine and 7Cardiovascular Surgery, National Cardiovascular Center, Osaka; 4Tissue Engineering Research Center, National Institute of Advanced Industrial Science and Technology, Hyogo; and 5Cardiovascular Division, Kansai Rosai Hospital, Hyogo 660-8511, Japan

Submitted 10 November 2003 ; accepted in final form 13 July 2004


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Mesenchymal stem cells (MSCs) are pluripotent cells that differentiate into a variety of cells, including cardiomyocytes and endothelial cells. However, little information is available regarding the therapeutic potency of systemically delivered MSCs for myocardial infarction. Accordingly, we investigated whether intravenously transplanted MSCs induce angiogenesis and myogenesis and improve cardiac function in rats with acute myocardial infarction. MSCs were isolated from bone marrow aspirates of isogenic adult rats and expanded ex vivo. At 3 h after coronary ligation, 5 x 106 MSCs (MSC group, n = 12) or vehicle (control group, n = 12) was intravenously administered to Lewis rats. Transplanted MSCs were preferentially attracted to the infarcted, but not the noninfarcted, myocardium. The engrafted MSCs were positive for cardiac markers: desmin, cardiac troponin T, and connexin43. On the other hand, some of the transplanted MSCs were positive for von Willebrand factor and formed vascular structures. Capillary density was markedly increased after MSC transplantation. Cardiac infarct size was significantly smaller in the MSC than in the control group (24 ± 2 vs. 33 ± 2%, P < 0.05). MSC transplantation decreased left ventricular end-diastolic pressure and increased left ventricular maximum dP/dt (both P < 0.05 vs. control). These results suggest that intravenous administration of MSCs improves cardiac function after acute myocardial infarction through enhancement of angiogenesis and myogenesis in the ischemic myocardium.

left ventricular end-diastolic pressure; cell transplantation; differentiation; homing

INTERRUPTION OF MYOCARDIAL blood flow leads to cardiomyocyte death (20). Although myocyte mitosis and the presence of cardiac precursor cells in adult hearts have recently been reported (6, 17), death of large numbers of cardiomyocytes results in the development of heart failure (16). Thus it would be desirable to induce angiogenesis and myogenesis for the treatment of ischemic heart disease.

Mesenchymal stem cells (MSCs) are pluripotent adult stem cells residing within the bone marrow microenvironment (11, 18). In contrast to their hematopoietic counterparts, MSCs have an adherent nature and are expandable in culture. MSCs can differentiate into not only osteoblasts, chondrocytes, neurons, and skeletal muscle cells but also vascular endothelial cells (19) and cardiomyocytes (23, 24). In vitro, MSCs have the potential to induce a neovascular response in murine Matrigel angiogenesis assay (2). In vivo, local MSC implantation induces therapeutic angiogenesis in a rat model of hindlimb ischemia (1). On the other hand, MSCs directly injected into the infarcted heart have been shown to induce myocardial regeneration and improve cardiac function (21). Stem or progenitor cells have been shown to circulate in peripheral blood and home to ischemic tissues (4). These results raise the possibility that intravenously administered MSCs participate in repair of the ischemic myocardium primarily by angiogenesis, which prevents apoptosis of native cardiomyocytes, and by direct regeneration of lost cardiomyocytes. However, little information is available regarding the therapeutic potential of systemically delivered MSCs for myocardial infarction.

Thus the purpose of this study was to investigate whether 1) intravenously administered MSCs are able to engraft in the ischemic myocardium, 2) transplanted MSCs induce angiogenesis and myogenesis after myocardial infarction, and 3) transplantation of MSCs decreases infarct size and improves cardiac function.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Animals. Male Lewis rats (n = 70) weighing 220–250 g were used in this study. These isogenic rats (n = 8) served as donors and recipients of MSCs to simulate autologous implantation. The Animal Care Committee of the National Cardiovascular Center approved the experimental protocol.

Model of myocardial infarction and cell transplantation. Fifty-one rats underwent ligation of the left coronary artery to produce myocardial infarction, as described previously (15). Briefly, after rats were anesthetized by injection of pentobarbital sodium (30 mg/kg body wt ip), they were artificially ventilated using a volume-regulated respirator. The heart was exposed via a left thoracotomy, and the left coronary artery was ligated 2–3 mm from its origin between the pulmonary artery conus and the left atrium using a 6-0 Prolene suture. At 3 h after coronary ligation, 40 rats survived (78% survival rate): 30 were randomized to receive an intravenous injection of MSCs (MSC group, n = 14) or PBS (control group, n = 16), and 10 received fluorescence-labeled MSCs for examination of MSC differentiation (n = 5) and incorporation (n = 5). Eleven rats underwent a sham operation consisting of thoracotomy and cardiac exposure but without coronary artery ligation. At 3 h after coronary ligation, we administered 5 x 106 MSCs/100 µl in PBS or PBS alone through a catheter inserted into the left jugular vein in ~30 s. The subsequent mortality for 4 wk was 25% in the control group and 14% in the MSC group. This protocol resulted in the creation of three groups: normal rats given PBS (sham group, n = 11), myocardial infarction rats given PBS (control group, n = 12), and myocardial infarction rats given MSCs (MSC group, n = 12).

Expansion of bone marrow MSCs. MSC expansion was performed according to previously described methods (18). Briefly, we killed the male Lewis rats and harvested the bone marrow by flushing the cavity of the femurs and tibias with PBS. Bone marrow cells were introduced into 100-mm dishes and cultured in {alpha}-MEM supplemented with 10% FBS and antibiotics. A small number of cells developed visible symmetrical colonies by day 5–7. Nonadherent hematopoietic cells were removed, and the medium was replaced. The adherent, spindle-shaped MSC population expanded to >5 x 107 cells by approximately four to five passages after the cells were first cultured.

Flow cytometry. Adherent cells were analyzed by fluorescence-activated cell sorting (FACS SCAN flow cytometer, Becton Dickinson). Cells were incubated for 30 min at 4°C with the FITC-conjugated mouse monoclonal antibodies against rat CD34 (clone ICO-115, Santa Cruz Biotechnology) and CD45 and CD90 (clones OX-1 and OX-7, respectively, Becton Dickinson). FITC-conjugated hamster anti-rat CD29 monoclonal antibody (clone Ha2/5, Becton Dickinson) and rabbit anti-rat c-Kit polyclonal antibody (clone C-19, Santa Cruz Biotechnology) were used. Isotype-identical antibodies served as controls.

Echocardiographic studies. Echocardiographic studies were performed by an investigator blinded to treatment allocation 4 wk after coronary ligation. Two-dimensional targeted M-mode traces were obtained at the level of the papillary muscles using an echocardiographic system equipped with a 7.5-MHz phased-array transducer (SONOS 5500, Hewlett-Packard, Andover, MA). Anterior and posterior end-diastolic wall thickness and left ventricular (LV) end-diastolic and end-systolic dimensions were measured by the American Society for Echocardiology leading-edge method from at least three consecutive cardiac cycles. LV fractional shortening was calculated as follows: (LVDd – LVDs)/LVDd x 100, where LVDd is LV diastolic dimension and LVDs is LV systolic dimension. LV volume and ejection fraction were calculated on the basis of the Teichholtz formula.

Hemodynamic studies. Hemodynamic studies were performed 4 wk after coronary ligation. A 1.5-Fr micromanometer-tipped catheter (Millar Instruments) was inserted in the right carotid artery for measurement of mean arterial pressure. Then the catheter was advanced into the LV for measurement of LV pressure. Hemodynamic variables were measured using a pressure transducer (model P23 ID, Gould) connected to a polygraph. After completion of these measurements, the left and right ventricles were excised and weighed. Infarction size was determined as a percentage of the entire LV area, as reported previously (8). Briefly, incisions were made in the LV, so that the tissue could be pressed flat. The circumference of the entire flat LV and the visualized infarcted area, as judged from the epicardial and endocardial sides, was outlined on a clear plastic sheet. The difference in weight between the two marked areas on the sheet was used to determine infarction size and was expressed as a percentage of LV surface area.

Histological examination. To detect fibrosis in cardiac muscle, the LV myocardium (n = 5 each group) was fixed in 10% formalin, cut transversely, embedded in paraffin, and stained with Masson's trichrome. To detect capillary endothelial cells in the peri-infarct area, samples of the harvested muscle (n = 5 each) were embedded in OCT compound (Miles Scientific), snap frozen in liquid nitrogen, and cut into transverse sections. Tissue sections were stained for alkaline phosphatase with an indoxyltetrazolium method. The number of capillary vessels was counted in the peri-infarct area using a light microscope at x200 magnification. The numbers in five high-power fields were averaged and expressed as the number of capillary vessels. These morphometric studies were performed by two examiners who were blinded to treatment.

An additional five rats were used to examine whether transplanted MSCs differentiated into cardiomyocytes or vascular endothelial cells. Suspended MSCs were labeled with fluorescent dyes with a PKH-26 red fluorescent cell linker kit (Sigma Chemical, St. Louis, MO) before implantation, as reported previously (13). Fluorescence-labeled MSCs were intravenously administered 3 h after coronary ligation. This subgroup of rats was killed 4 wk after coronary ligation. After the LV was excised and dissected free, muscle samples were embedded in OCT compound, snap frozen in liquid nitrogen, and cut into sections. Immunofluorescent staining for cardiac and endothelial cell markers was performed using monoclonal mouse antidesmin (Dako), anti-cardiac troponin T (Novo), anticonnexin43 (Sigma Chemical), and polyclonal rabbit anti-von Willebrand factor (Dako). FITC-conjugated IgG antibody (BD Pharmingen and Molecular Probes) was used as a secondary antibody.

At 24 h after intravenous administration of PKH-26-labeled MSCs, cardiac muscle was embedded in OCT compound and snap frozen in liquid nitrogen. Then the cardiac muscle from base to apex was transversely cut into 5-µm slices for calculation of the numbers of transplanted MSCs in the heart (n = 5).

Statistical analysis. Numerical values were expressed as means ± SE unless otherwise indicated. Comparisons of parameters among the three groups were made using one-way analysis of variance (ANOVA) followed by Scheffé's multiple comparison test. Comparisons of parameters between two groups were made by unpaired Student's t-test. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Characterization of cultured MSCs. Most of cultured adherent cells expressed CD29 and CD90 (Fig. 1). In contrast, a majority of adherent cells were negative for CD34 and CD45. A small fraction of the adherent cells expressed c-Kit. Thus we confirmed that the major population of adherent cells was MSCs.



View larger version (16K):
[in this window]
[in a new window]
  		Fig. 1. Flow cytometric analysis of adherent, spindle-shaped mesenchymal stem cell (MSC) population expanded to 4–5 passages. Most of the cells expressed CD29 and CD90 but were negative for CD34 and CD45. Some cells were positive for c-Kit. MI, myocardial infarction.

 
Reduction of myocardial infarct size after MSC transplantation. Moderate-to-large infarcts were observed in Masson's trichrome-stained myocardial sections 4 wk after coronary ligation (control group; Fig. 2A). However, MSC transplantation markedly decreased the infarct size after myocardial infarction (MSC group). Quantitative analysis also demonstrated that cardiac infarct size was significantly smaller in the MSC than in the control group: 24 ± 2 vs. 33 ± 2% (n = 12 each, P < 0.05; Fig. 2B).



View larger version (28K):
[in this window]
[in a new window]
  		Fig. 2. Effect of MSC transplantation on myocardial infarct size 4 wk after myocardial infarction. A: representative Masson's trichrome-stained myocardial sections from control and MSC groups. B: quantitative analysis demonstrating that MSC transplantation significantly decreased infarct size. Values are means ± SE. *P < 0.05 vs. control.

 
Hemodynamic effects of MSC transplantation. At 4 wk after coronary ligation, hemodynamic studies were performed in the sham (n = 11), control (n = 12), and MSC (n = 12) groups. LV end-diastolic pressure showed a marked elevation in the control group (18 ± 1 mmHg); the elevation was significantly attenuated in the MSC group (13 ± 1 mmHg, P < 0.05; Fig. 3A). LV maximum dP/dt was significantly higher in the MSC than in the control group (Fig. 3B). LV minimum dP/dt tended to be lower in the MSC than in the control group (Fig. 3C). Although mean arterial pressure was significantly lower in the control than in the sham group, no decrease was observed in the MSC group (Table 1). Heart rate did not significantly differ among the three groups.



View larger version (22K):
[in this window]
[in a new window]
  		Fig. 3. Effects of MSC transplantation on hemodynamic parameters. LVEDP, LV end-diastolic pressure (A); max dP/dt, LV maximum dP/dt (B); Min dP/dt, LV minimum dP/dt (C); %FS, LV fractional shortening (D). Values are means ± SE. *P < 0.05 vs. sham. {dagger}P < 0.05 vs. control.

 

View this table:
[in this window]
[in a new window]
  		Table 1. Characterization of animals

 
LV diastolic dimension was significantly smaller in the MSC than in the control group (Table 2). Fractional shortening was significantly greater in the MSC than in the control group (Fig. 3D). LV ejection fraction was also higher in the MSC than in the control group (Table 2). Diastolic anterior wall thickness was significantly attenuated in the MSC group compared with the control group.


View this table:
[in this window]
[in a new window]
  		Table 2. Echocardiographic data

 
Myogenesis and angiogenesis induced by MSCs. Red fluorescence-labeled MSCs were intravenously administered 3 h after coronary ligation (n = 5). Semiquantitative analysis demonstrated that ~3% of the transplanted MSCs were incorporated into the heart 24 h after transplantation. At 4 wk after transplantation (n = 5), MSCs were incorporated predominantly into the border zone of infarcts (Fig. 4), whereas few MSCs were detected in the noninfarcted myocardium. Immunofluorescence analyses demonstrated that the engrafted MSCs were positive for desmin (Fig. 4), cardiac troponin T (Fig. 5A), and connexin43 (Fig. 5B). These results suggest the ability of MSCs to engraft in the ischemic myocardium and differentiate into cardiomyocytes. On the other hand, some of the transplanted MSCs were positive for von Willebrand factor and formed vascular structures (Fig. 6). Alkaline phosphatase staining of the ischemic myocardium showed marked augmentation of neovascularization in the MSC group (Fig. 7A). Quantitative analysis demonstrated that capillary density was significantly higher in the MSC than in the control group (n = 5 each; Fig. 7B).



View larger version (75K):
[in this window]
[in a new window]
  		Fig. 4. Distribution of intravenously administered MSCs in myocardium after acute myocardial infarction. Red fluorescence-labeled MSCs were incorporated into ischemic boundary zone of the heart. These cells were positive for desmin (arrows), a cardiac marker. Magnification x400.

 


View larger version (68K):
[in this window]
[in a new window]
  		Fig. 5. Differentiation of transplanted MSCs in ischemic myocardium. Engrafted MSCs were positive (arrows) for cardiac troponin T (A) and connexin43 (B). Magnification x400.

 


View larger version (11K):
[in this window]
[in a new window]
  		Fig. 6. Transplanted MSCs were positive for von Willebrand factor (vWF) and formed vascular structures. Magnification x400.

 


View larger version (66K):
[in this window]
[in a new window]
  		Fig. 7. A: representative samples of alkaline phosphatase staining in peri-infarct area. Magnification x200. B: quantitative analysis of capillary density in peri-infarct area. Values are means ± SE. *P < 0.05 vs. sham. {dagger}P < 0.05 vs. control.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In the present study, we demonstrated that intravenously administered MSCs were capable of engraftment in the ischemic myocardium and that the engrafted MSCs differentiated into cardiomyocytes and vascular endothelial cells, resulting in myogenesis and angiogenesis. We also demonstrated that MSC transplantation decreased myocardial infarct size and improved cardiac function after acute myocardial infarction in rats.

Earlier studies showed that MSCs directly injected into the myocardium or those injected into coronary arteries improve cardiac function after myocardial infarction. However, little information is available regarding the therapeutic potential of systemically delivered MSCs for myocardial infarction. This study demonstrated that intravenous administration of MSCs improves cardiac function after acute myocardial infarction through enhancement of angiogenesis and myogenesis in the ischemic myocardium.

Earlier studies showed that endothelial progenitor cells are mobilized from bone marrow into the peripheral blood in response to tissue ischemia and home to and incorporate into sites of neovascularization (21). Similar to epithelial progenitor cells, in the present study, transplanted MSCs were preferentially attracted to and retained in the border zone of infarcts. This is consistent with recent findings in the ischemic heart (5) or brain (7). Although the underlying mechanisms remain unclear, ischemic tissue may express specific receptors or ligands to facilitate trafficking, adhesion, and infiltration of MSCs to ischemic sites.

In the present study, some of the engrafted MSCs were stained by cardiac proteins such as desmin and cardiac troponin T. Transplanted MSCs also expressed connexin43, a gap junction protein, at contact points with native cardiomyocytes. These results suggest that MSCs differentiated into cardiomyocytes in the ischemic myocardium and formed connections with native cardiomyocytes. In contrast to skeletal myoblasts, which have been used as a tool for myocardial repair, MSCs may have the capacity for electromechanical coupling. Earlier studies demonstrated the importance of the microenvironment for cardiomyogenic differentiation. Possible factors might include direct cell-cell contact (9), electrical and mechanical stimulation (10), and unknown growth factors. On the other hand, recent studies showed that stem cells may fuse with existing native cells (22, 25). Although the mechanisms by which MSCs develop into cardiomyocyte-like cells remain unclear, it is possible that the direct attachment with host cardiomyocytes in the ischemic myocardium contributes to the cardiogenic differentiation of transplanted MSCs. Further studies are necessary to investigate whether engrafted MSCs are actually becoming contractile.

In the present study, some of the transplanted MSCs were positive for an endothelial cell marker and participated in vessel formation. MSC transplantation significantly increased the capillary density in ischemic myocardium. The recently reported phenotypic plasticity of MSCs to transform into endothelial-like cells provides a rationale for their potential role in neovascularization. Hypoxia has been shown to induce MSC migration and capillary-like structure formation by upregulation of membrane type 1 matrix metalloproteinase (3). MSC implantation has been shown to induce therapeutic angiogenesis in a rat model of chronic hindlimb ischemia (1). These findings support the theory that intravenously administered MSCs are able to differentiate into vascular endothelial cells in the ischemic myocardium. Interestingly, MSCs enhance angiogenesis partly by increasing endogenous levels of vascular endothelial growth factor and vascular endothelial growth factor type 2 receptor (7). Together, these findings suggest that MSCs may contribute to neovascularization in the ischemic myocardium not only through their ability to generate capillary-like structures and but also through growth factor-mediated paracrine regulation.

The present study showed that MSC transplantation significantly reduced infarct size and attenuated wall thinning after acute myocardial infarction. Cardiomyocyte apoptosis during ischemia is one of the major contributors to the development of myocardial infarcts (16, 20). It is possible that newly formed vessels after MSC transplantation improve tissue perfusion around the ischemic boundary zone, resulting in functional recovery after acute myocardial infarction. We also demonstrated that transplanted MSCs differentiated into cardiomyocytes in the ischemic myocardium. These results suggest that the decrease in infarct size and the increase in wall thickness may be attributable not only to MSC-induced neovascularization but also to myocardial regeneration. In the present study, MSC transplantation improved cardiac function after acute myocardial infarction, as indicated by a significant decrease in LV end-diastolic pressure, a tendency for an increase in maximum LV dP/dt, and a decrease in minimum LV dP/dt. Thus MSC-induced angiogenesis and myogenesis and the resultant reduced infarct size may have contributed to the hemodynamic improvement after acute myocardial infarction.

The low percentage of MSC migration to the heart is in agreement with some previous studies (5, 14). The present study also showed that only a small percentage of transplanted MSCs were incorporated into the heart. This may be explained by MSC apoptosis (12), tracking in the lung (5), and a dilution of the fluorescent dyes as the cells reproduce. Nevertheless, when MSCs were intravenously administered in an acute phase of myocardial infarction, MSCs induced angiogenesis and myogenesis and modestly, but significantly, improved cardiac function. Thus systemic delivery of MSCs may be beneficial for the treatment of myocardial infarction.

A limitation of this study is that the cell population may be mixed, rather than limited to MSCs, although cell surface markers of cultured cells were consistent with those of previously reported MSCs (12, 18).

In conclusion, intravenously administered MSCs were preferentially attracted to the infarcted myocardium and differentiated into vascular endothelial cells and cardiomyocytes. MSC transplantation decreased the infarct size and improved cardiac function after acute myocardial infarction through enhancement of angiogenesis and myogenesis. Thus MSC transplantation may be a new therapeutic strategy for the treatment of myocardial infarction.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported by Ministry of Health, Labour, and Welfare Cardiovascular Disease Research Grant 16C-6, the New Energy and Industrial Technology Development Organization of Japan Industrial Technology Research Grant Program in '03, Health and Labor Sciences Research Grants-genome 005, and Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research of Japan.


   FOOTNOTES
 

Address for reprint requests and other correspondence: N. Nagaya, Dept. of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan (E-mail: nnagaya{at}ri.ncvc.go.jp)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Al-Khaldi A, Al-Sabti H, Galipeau J, and Lachapelle K. Therapeutic angiogenesis using autologous bone marrow stromal cells: improved blood flow in a chronic limb ischemia model. Ann Thorac Surg 75: 204–209, 2003.[Abstract/Free Full Text]
  2. Al-Khaldi A, Eliopoulos N, Martineau D, Lejeune L, Lachapelle K, and Galipeau J. Postnatal bone marrow stromal cells elicit a potent VEGF-dependent neoangiogenic response in vivo. Gene Ther 10: 621–629, 2003.[CrossRef][ISI][Medline]
  3. Annabi B, Lee YT, Turcotte S, Naud E, Desrosiers RR, Champagne M, Eliopoulos N, Galipeau J, and Beliveau R. Hypoxia promotes murine bone-marrow-derived stromal cell migration and tube formation. Stem Cells 21: 337–347, 2003.[Abstract/Free Full Text]
  4. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, and Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science 275: 964–967, 1997.[Abstract/Free Full Text]
  5. Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, and Leor J. Systemic delivery of bone marrow-derived mesenchymal stem cells to the infarcted myocardium: feasibility, cell migration, and body distribution. Circulation 108: 863–868, 2003.[Abstract/Free Full Text]
  6. Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, and Anversa P. Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344: 1750–1757, 2001.[Abstract/Free Full Text]
  7. Chen J, Zhang ZG, Li Y, Wang L, Xu YX, Gautam SC, Lu M, Zhu Z, and Chopp M. Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res 92: 692–699, 2003.[Abstract/Free Full Text]
  8. Chien YW, Barbee RW, MacPhee AA, Frohlich ED, and Trippodo NC. Increased ANF secretion after volume expansion is preserved in rats with heart failure. Am J Physiol Regul Integr Comp Physiol 254: R185–R191, 1988.[Abstract/Free Full Text]
  9. Fukuhara S, Tomita S, Yamashiro S, Morisaki T, Yutani C, Kitamura S, and Nakatani T. Direct cell-cell interaction of cardiomyocytes is key for bone marrow stromal cells to go into cardiac lineage in vitro. J Thorac Cardiovasc Surg 125: 1470–1480, 2003.[Abstract/Free Full Text]
  10. Iijima Y, Nagai T, Mizukami M, Matsuura K, Ogura T, Wada H, Toko H, Akazawa H, Takano H, Nakaya H, and Komuro I. Beating is necessary for transdifferentiation of skeletal muscle-derived cells into cardiomyocytes. FASEB J 17: 1361–1363, 2003.[Abstract/Free Full Text]
  11. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, and Ogawa S. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103: 697–705, 1999.[ISI][Medline]
  12. Mangi AA, Noiseux N, Kong D, He H, Rezvani M, Ingwall JS, and Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 9: 1195–1201, 2003.[CrossRef][ISI][Medline]
  13. Messina LM, Podrazik RM, Whitehill TA, Ekhterae D, Brothers TE, Wilson JM, Burkel WE, and Stanley JC. Adhesion and incorporation of lacZ-transduced endothelial cells into the intact capillary wall in the rat. Proc Natl Acad Sci USA 89: 12018–12022, 1992.[Abstract/Free Full Text]
  14. Muller P, Pfeiffer P, Koglin J, Schafers HJ, Seeland U, Janzen I, Urbschat S, and Bohm M. Cardiomyocytes of noncardiac origin in myocardial biopsies of human transplanted hearts. Circulation 106: 31–35, 2002.[Abstract/Free Full Text]
  15. Nagaya N, Nishikimi T, Yoshihara F, Horio T, Morimoto A, and Kangawa K. Cardiac adrenomedullin gene expression and peptide accumulation after acute myocardial infarction in rats. Am J Physiol Regul Integr Comp Physiol 278: R1019–R1026, 2000.[Abstract/Free Full Text]
  16. Narula J, Haider N, Virmani R, DiSalvo TG, Kolodgie FD, Hajjar RJ, Schmidt U, Semigran MJ, Dec GW, and Khaw BA. Apoptosis in myocytes in end-stage heart failure. N Engl J Med 335: 1182–1189, 1996.[Abstract/Free Full Text]
  17. Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, and Schneider MD. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100: 12313–12318, 2003.[Abstract/Free Full Text]
  18. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, and Marshak DR. Multilineage potential of adult human mesenchymal stem cells. Science 284: 143–147, 1999.[Abstract/Free Full Text]
  19. Reyes M, Dudek A, Jahagirdar B, Koodie L, Marker PH, and Verfaillie CM. Origin of endothelial progenitors in human postnatal bone marrow. J Clin Invest 109: 337–346, 2002.[CrossRef][ISI][Medline]
  20. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, and Voipio-Pulkki LM. Apoptosis in human acute myocardial infarction. Circulation 95: 320–323, 1997.[Abstract/Free Full Text]
  21. Shake JG, Gruber PJ, Baumgartner WA, Senechal G, Meyers J, Redmond JM, Pittenger MF, and Martin BJ. Mesenchymal stem cell implantation in a swine myocardial infarct model: engraftment and functional effects. Ann Thorac Surg 73: 1919–1925, 2002.[Abstract/Free Full Text]
  22. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y, Meyer EM, Morel L, Petersen BE, and Scott EW. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 416: 542–545, 2002.[CrossRef][Medline]
  23. Toma C, Pittenger MF, Cahill KS, Byrne BJ, and Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105: 93–98, 2002.[Abstract/Free Full Text]
  24. Wang JS, Shum-Tim D, Galipeau J, Chedrawy E, Eliopoulos N, and Chiu RC. Marrow stromal cells for cellular cardiomyoplasty: feasibility and potential clinical advantages. J Thorac Cardiovasc Surg 120: 999–1005, 2000.[Abstract/Free Full Text]
  25. Ying QL, Nichols J, Evans EP, and Smith AG. Changing potency by spontaneous fusion. Nature 416: 545–548, 2002.[CrossRef][Medline]



This article has been cited by other articles:


Home page
 HeartHome page
K Yao, R Huang, J Qian, J Cui, L Ge, Y Li, F Zhang, H Shi, D Huang, S Zhang, et al.
Administration of intracoronary bone marrow mononuclear cells on chronic myocardial infarction improves diastolic function
Heart, September 1, 2008; 94(9): 1147 - 1153.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
M. Morigi, M. Introna, B. Imberti, D. Corna, M. Abbate, C. Rota, D. Rottoli, A. Benigni, N. Perico, C. Zoja, et al.
Human Bone Marrow Mesenchymal Stem Cells Accelerate Recovery of Acute Renal Injury and Prolong Survival in Mice
Stem Cells, August 1, 2008; 26(8): 2075 - 2082.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
C. A. Carr, D. J. Stuckey, L. Tatton, D. J. Tyler, S. J. M. Hale, D. Sweeney, J. E. Schneider, E. Martin-Rendon, G. K. Radda, S. E. Harding, et al.
Bone marrow-derived stromal cells home to and remain in the infarcted rat heart but fail to improve function: an in vivo cine-MRI study
Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H533 - H542.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
P. Au, J. Tam, D. Fukumura, and R. K. Jain
Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature
Blood, May 1, 2008; 111(9): 4551 - 4558.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
G. Chamberlain, J. Fox, B. Ashton, and J. Middleton
Concise Review: Mesenchymal Stem Cells: Their Phenotype, Differentiation Capacity, Immunological Features, and Potential for Homing
Stem Cells, November 1, 2007; 25(11): 2739 - 2749.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
S.-C. Hung, R. R. Pochampally, S.-C. Chen, S.-C. Hsu, and D. J. Prockop
Angiogenic Effects of Human Multipotent Stromal Cell Conditioned Medium Activate the PI3K-Akt Pathway in Hypoxic Endothelial Cells to Inhibit Apoptosis, Increase Survival, and Stimulate Angiogenesis
Stem Cells, September 1, 2007; 25(9): 2363 - 2370.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
W. Li, N. Ma, L.-L. Ong, C. Nesselmann, C. Klopsch, Y. Ladilov, D. Furlani, C. Piechaczek, J. M. Moebius, K. Lutzow, et al.
Bcl-2 Engineered MSCs Inhibited Apoptosis and Improved Heart Function
Stem Cells, August 1, 2007; 25(8): 2118 - 2127.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
M. Shi, J. Li, L. Liao, B. Chen, B. Li, L. Chen, H. Jia, and R. C. Zhao
Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: role in homing efficiency in NOD/SCID mice
Haematologica, July 1, 2007; 92(7): 897 - 904.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
I. A. Potapova, G. R. Gaudette, P. R. Brink, R. B. Robinson, M. R. Rosen, I. S. Cohen, and S. V. Doronin
Mesenchymal Stem Cells Support Migration, Extracellular Matrix Invasion, Proliferation, and Survival of Endothelial Cells In Vitro
Stem Cells, July 1, 2007; 25(7): 1761 - 1768.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
P. A. Schweizer, U. Krause, R. Becker, A. Seckinger, A. Bauer, C. Hardt, V. Eckstein, A. D. Ho, M. Koenen, H. A. Katus, et al.
Atrial-Radiofrequency Catheter Ablation Mediated Targeting of Mesenchymal Stromal Cells
Stem Cells, June 1, 2007; 25(6): 1546 - 1551.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Renal Physiol.Home page
F. Togel, K. Weiss, Y. Yang, Z. Hu, P. Zhang, and C. Westenfelder
Vasculotropic, paracrine actions of infused mesenchymal stem cells are important to the recovery from acute kidney injury
Am J Physiol Renal Physiol, May 1, 2007; 292(5): F1626 - F1635.
[Abstract] [Full Text] [PDF]

Home page
 haematolHome page
A. De Becker, P. Van Hummelen, M. Bakkus, I. Vande Broek, J. De Wever, M. De Waele, and I. Van Riet
Migration of culture-expanded human mesenchymal stem cells through bone marrow endothelium is regulated by matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-3
Haematologica, April 1, 2007; 92(4): 440 - 449.
[Abstract] [Full Text] [PDF]

Home page
 JNMHome page
N. Tran, P. R. Franken, F. Maskali, J. Nloga, P. Maureira, S. Poussier, F. Groubatch, C. Vanhove, J.-P. Villemot, and P.-Y. Marie
Intramyocardial Implantation of Bone Marrow-Derived Stem Cells Enhances Perfusion in Chronic Myocardial Infarction: Dependency on Initial Perfusion Depth and Follow-up Assessed by Gated Pinhole SPECT
J. Nucl. Med., March 1, 2007; 48(3): 405 - 412.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Pevsner-Fischer, V. Morad, M. Cohen-Sfady, L. Rousso-Noori, A. Zanin-Zhorov, S. Cohen, I. R. Cohen, and D. Zipori
Toll-like receptors and their ligands control mesenchymal stem cell functions
Blood, February 15, 2007; 109(4): 1422 - 1432.
[Abstract] [Full Text] [PDF]

Home page
 Circ. Res.Home page
B. A. Pallante, I. Duignan, D. Okin, A. Chin, M. C. Bressan, T. Mikawa, and J. M. Edelberg
Bone Marrow Oct3/4+ Cells Differentiate Into Cardiac Myocytes via Age-Dependent Paracrine Mechanisms
Circ. Res., January 5, 2007; 100(1): e1 - e11.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
S. Schenk, N. Mal, A. Finan, M. Zhang, M. Kiedrowski, Z. Popovic, P. M. McCarthy, and M. S. Penn
Monocyte Chemotactic Protein-3 Is a Myocardial Mesenchymal Stem Cell Homing Factor
Stem Cells, January 1, 2007; 25(1): 245 - 251.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
L. C. Amado, K. H. Schuleri, A. P. Saliaris, A. J. Boyle, R. Helm, B. Oskouei, M. Centola, V. Eneboe, R. Young, J. A.C. Lima, et al.
Multimodality Noninvasive Imaging Demonstrates In Vivo Cardiac Regeneration After Mesenchymal Stem Cell Therapy
J. Am. Coll. Cardiol., November 21, 2006; 48(10): 2116 - 2124.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
M. R. Rosen
Are Stem Cells Drugs?: The Regulation of Stem Cell Research and Development
Circulation, October 31, 2006; 114(18): 1992 - 2000.
[Abstract] [Full Text] [PDF]

Home page
 J. Am. Soc. Nephrol.Home page
U. Kunter, S. Rong, Z. Djuric, P. Boor, G. Muller-Newen, D. Yu, and J. Floege
Transplanted Mesenchymal Stem Cells Accelerate Glomerular Healing in Experimental Glomerulonephritis
J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2202 - 2212.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
D. J. Stuckey, C. A. Carr, E. Martin-Rendon, D. J. Tyler, C. Willmott, P. J. Cassidy, S. J.M. Hale, J. E. Schneider, L. Tatton, S. E. Harding, et al.
Iron Particles for Noninvasive Monitoring of Bone Marrow Stromal Cell Engraftment into, and Isolation of Viable Engrafted Donor Cells from, the Heart
Stem Cells, August 1, 2006; 24(8): 1968 - 1975.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Kanki-Horimoto, H. Horimoto, S. Mieno, K. Kishida, F. Watanabe, E. Furuya, and T. Katsumata
Implantation of Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase Improves Right Ventricular Impairments Caused by Pulmonary Hypertension
Circulation, July 4, 2006; 114(1_suppl): I-181 - I-185.
[Abstract] [Full Text] [PDF]

Home page
 CirculationHome page
S. Kanki-Horimoto, H. Horimoto, S. Mieno, K. Kishida, F. Watanabe, E. Furuya, and T. Katsumata
Synthetic Vascular Prosthesis Impregnated With Mesenchymal Stem Cells Overexpressing Endothelial Nitric Oxide Synthase
Circulation, July 4, 2006; 114(1_suppl): I-327 - I-330.
[Abstract] [Full Text] [PDF]

Home page
 HeartHome page
Y Wang, H E Johnsen, S Mortensen, L Bindslev, R Sejersten Ripa, M Haack-Sorensen, E Jorgensen, W Fang, and J Kastrup
Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention
Heart, June 1, 2006; 92(6): 768 - 774.
[Abstract] [Full Text] [PDF]

Home page
 J. Exp. Med.Home page
A. Y. Khakoo, S. Pati, S. A. Anderson, W. Reid, M. F. Elshal, I. I. Rovira, A. T. Nguyen, D. Malide, C. A. Combs, G. Hall, et al.
Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma
J. Exp. Med., May 15, 2006; 203(5): 1235 - 1247.
[Abstract] [Full Text] [PDF]

Home page
 Stem CellsHome page
B.-R. Son, L. A. Marquez-Curtis, M. Kucia, M. Wysoczynski, A. R. Turner, J. Ratajczak, M. Z. Ratajczak, and A. Janowska-Wieczorek
Migration of Bone Marrow and Cord Blood Mesenchymal Stem Cells In Vitro Is Regulated by Stromal-Derived Factor-1-CXCR4 and Hepatocyte Growth Factor-c-met Axes and Involves Matrix Metalloproteinases
Stem Cells, May 1, 2006; 24(5): 1254 - 1264.
[Abstract] [Full Text] [PDF]

Home page
 Eur Heart JHome page
A. Schaefer, G. P. Meyer, M. Fuchs, G. Klein, M. Kaplan, K. C. Wollert, and H. Drexler
Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial
Eur. Heart J., April 2, 2006; 27(8): 929 - 935.
[Abstract] [Full Text]