Ann Thorac Surg 2007;83:1491-1498
© 2007 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Therapeutic Potential of Human Umbilical Cord Derived Stem Cells in a Rat Myocardial Infarction Model
Kai Hong Wu, MD, PhDa,*,
Bin Zhou, PhDb,*,
Cun Tao Yu, MDa,
Bin Cui, MDa,
Shi Hong Lu, BSb,
Zhong Chao Han, MD, PhDb,
Ying Long Liu, MDa,*
a Pediatric Cardiac Center, Department of Surgery, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
b State Key Laboratory of Experimental Hematology, National Research Center for Stem Cell Engineering and Technology, Institute of Hematology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
Accepted for publication October 24, 2006.
* Address correspondence to Dr Liu, Pediatric Cardiac Center, Department of Surgery, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 167 Beilishi Rd, Beijing 100037, China (Email: hanzhongchao{at}hotmail.com; pumcwu{at}yahoo.com.cn).
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Abstract
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Background: Cell transplantation offers the promise in the restoration of cardiac function after myocardial infarction. We investigate the therapeutic potential of human umbilical cord derived stem (UCDS) cells in a rat myocardial infarction model.
Methods: Two weeks after induction of myocardial infarction, the surviving rats with left ventricular ejection fraction less than 60% were randomly divided into a phosphate-buffered saline control group and a UCDS cell treated group. Cardiac function was assessed by echocardiography 2 weeks and 4 weeks after cell transplantation. Histologic study and immunofluorescence were performed to investigate differentiation of transplanted cells, capillary and arteriole density, secretion of cytokines, and cardiomyocytes apoptosis.
Results: A statistically significant improvement of cardiac function was observed in the experimental group of rats compared with the control group. Four weeks after transplantation, histologic examination revealed that some of the transplanted UCDS cells survived in the infarcted myocardium and accumulated around arterioles and scattered in capillary networks. We observed some of the cells expressed cardiac troponin-T, von Willebrand factor, and smooth muscle actin, indicating regeneration of damaged myocardium by cardiomyocytic, endothelial, and smooth muscle differentiation of UCDS cells in the infarcted myocardium. The capillary and arteriole density were also markedly increased in the UCDS-cell–treated group. In addition, the apoptotic cells were decreased significantly compared with the phosphate-buffered saline controls.
Conclusions: Our findings demonstrate that transplanted UCDS cells provide benefit in cardiac function recovery after acute myocardial infarction in rats, suggesting UCDS cells represent a promising cell source for future routine cell therapy applications.
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Introduction
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The limited ability of the heart to regenerate damaged tissue after major cardiac injuries results in progressive dysfunctions and consequently leads to heart failure. Cardiac transfer of stem cells can have a favorable impact on tissue regeneration and contractile performance of the infarcted heart [1]. Several cell types including skeletal myoblasts [2], hematopoietic stem cells [3], mesenchymal stem cells [4, 5], endothelial precursors [6, 7], and resident cardiac stem cells [8] have been transplanted into the injured myocardium, but the optimal cell type remains controversial. Adult mesenchymal stem cells have shown great promise in cell therapy applications. However, mesenchymal stem cells are rare in adult bone marrow—most importantly, the number and plasticity significantly decreases with age, which makes it necessary to search for alternative sources of these cells for autologous and allogenic use [9].
In our laboratory, we have established a method that can readily isolate and expand stem cells from human umbilical cord tissues, called umbilical cord derived stem (UCDS) cells. These cells display a fibroblastlike morphology, express mesenchymal markers, and have the potential to differentiate into osteogenic, adipogenic, neurogenic, cardiomyogenic, and endothelial cells [10–12]. The present study was designed to investigate whether transplantation of UCDS cells could improve cardiac function in a rat myocardial infarction model. We also tried to reveal the mechanisms through which the transplanted cells effectively acted in improving cardiac function.
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Material and Methods
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Isolation and Characterization of UCDS Cells
With the consent of the parents, fresh umbilical cords were collected according to the regulations of the Chinese Academy of Medical Sciences and Peking Union Medical College Research Ethics Committee, and the UCDS cells were isolated immediately as described [10, 11]. In brief, after removal of blood vessels, the cord was minced and treated with collagenase II and trypsin. The digested mixture was then passed through a 100-µm filter to obtain cell suspensions. Next, the dissociated cells were centrifuged and plated in culture flasks. The cells were serially passaged and expanded in an incubator at 37°C with 5% CO2. The cell surface markers of UCDS cells were analyzed by flow cytometry (BD, Shanghai, China). Cells were trypsinized and stained with phycoerythrin or isothiocyanate-labeled monoclonal antibodies against CD29, CD31, CD34, CD38, CD44, CD45, CD90, CD105, CD106, CD166, major histocompatibility complex (MHC)-I, and MHC-II (all from Becton Dickinson, San Jose, California). Isotype-matched mouse immunoglobulin served as controls. Osteogenic and adipogenic differentiation of UCDS cells were performed as described before in our laboratory [12]. At the end of the culture, the cells were stained with von Kossa or Oil red-O solution to reveal osteogenic and adipogenic differentiation.
Animals and Induction of Myocardial Infarction
Adult male Sprague-Dawley rats (8 weeks old, n = 30) weighing about 260 to 280 g were used in this study. The Institutional Review Board of the Animal Care Committee of the Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College approved the experimental protocol; and the surgical procedure complied with the "Guide for the Care and Use of Laboratory Animals" (NIH publication No. 85-23, revised 1996). Thirty rats underwent ligation of the left coronary artery to produce myocardial infarction. In brief, after anesthesia with an intraperitoneal administration of pentobarbital sodium at 30 mg/kg, the rats were intubated and mechanically ventilated with a rodent ventilator (TKR 200 Ventilator; Jiangxi Teli Anaesthesia Respiration Equipment Co Ltd, China). The heart was exposed through a left thoracotomy, and the left coronary artery was ligated 3 to 5 mm from its origin between the pulmonary artery conus and the left atrium using a 6-0 polypropylene suture. Two weeks later, the surviving rats with left ventricular ejection fraction (LVEF) less than 60% by ultrasonic assessment (n = 23) were randomized into two groups: a UCDS group (n = 12) and a phosphate-buffered saline (PBS) group (n = 11).
UCDS Cell Preparation and Transplantation
The UCDS cells at the fifth passage were harvested and labeled with fluorescent carbocyanine 1,1’-dioctadecyl-1-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI) dye (Molecular Probes, Beijing, China). Before transplantation, adherent cells were washed and incubated with 2 µg/mL CM-DiI for 5 to 8 minutes at 37°C and 15 minutes on ice. After washing with PBS twice, cells were resuspended in PBS. Then 5 x 106 UCDS cells in 200 µL PBS were injected using a tuberculin syringe into the anterior and lateral aspects of the viable myocardium bordering the infarction. An equal volume of PBS was injected into the control animals. After cell transplantation, cyclosporine was administered subcutaneously (10 mg/kg) every day in UCDS-cell–treated rats for immunosuppression.
Evaluation of Left Ventricular Function
Left ventricular function was assessed by echocardiography before transplantation and 2 weeks and 4 weeks after cell transplantation according to the protocols described [13]. Rats were anesthetized with an intraperitoneal administration of pentobarbital sodium at 30 mg/kg. Parasternal long- and short-axis views were obtained with both M-mode and two-dimensional echocardiography images. Left ventricular ejection fraction (%) was calculated automatically by the echocardiography system. Left ventricular end-diastolic diameter and left ventricular end-systolic diameter were measured perpendicular to the long axis of the ventricle at the midchordal level. We also used left ventricular posterior wall thickening as an index to estimate left ventricular systolic function. These measurements were averaged for at least three consecutive cardiac cycles and were made by an experienced technician who was masked to the group identity.
Histologic Examination and Immunofluorescent Staining
Four weeks after transplantation, all surviving animals underwent the final functional assessment with transthoracic echocardiography. On the following day, the animals were killed with an overdose of ketamine and pentobarbital, and the hearts were removed and washed quickly in PBS and embedded in Tissue-Tek OCT compound (Sakura Fineteck, Torrance, California), cryopreserved in liquid nitrogen. Serial transversal sections were obtained in Leica CM1850 cryostat (Leica, Nussloch, Germany).
To detect differentiation of transplanted UCDS cells, immunofluorescent staining for cardiac, smooth muscle, and vascular endothelial cell specific markers was performed using monoclonal mouse anti–cardiac troponin T (Lab Vision, Fremont, California), rabbit anti–von Willebrand factor (Dako, Hamburg, Germany), and monoclonal mouse anti–
-smooth muscle actin (Dako). Briefly, the frozen sections were fixed in acetone at 4°C for 10 minutes, blocked by blocking solution at room temperature for 20 miutes, and then incubated separately with antibodies overnight at 4°C. After a washing with PBS solution three times, sections were incubated with isothiocyanate- or TRITC-conjugated secondary antibodies (Zhongshan, Beijing, China) for troponin T, von Willebrand factor, and smooth muscle actin.
To determine the capillary density in infarcted myocardium, 1 mg bandeiraea simplicifolia lectin I (BS-1 lectin; Vector Laboratories, Burlingame, California), which is a murine-specific endothelial cell marker, was injected into the left femoral artery 30 minutes before euthanasia. The endothelial cells that were positive for BS-1 lectin staining were counted under fluorescence microscope (Olympus, Tokyo, Japan) to determine the capillary density. Five fields were randomly selected for capillary counts per square millimeter (mm2). For identification of arterioles, sections were stained with a mouse monoclonal anti–-smooth muscle actin. Arteriole vessels (< 40 µm and > 40 µm in diameter) per mm2 section was then calculated using the same method. To identify potential paracrine mechanisms responsible for the therapeutic effect of UCDS cells after myocardial injury, sections of cardiac muscle were examined for colocalization of vascular endothelial growth factor (VEGF) and CM-DiI-labeled transplanted cells.
TUNEL Assay
To determine whether the transplanted UCDS cells could affect apoptosis, terminal-deoxynucleotidytransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays were performed. The frozen sections were stained with mouse monoclonal anti–-sarcomeric actin (Abcam, Cambridge, United Kingdom) for cardiomyocytes; next, they were incubated with isothiocyanate-conjugated terminal deoxynucleotidyl transferase, and then counterstained with 4’,6-diamidino-2-phenylindole (DAPI; Sigma Chemical, St Louis, Missouri). The number of isothiocyanate-TUNEL–positive cells per square millimeter was evaluated, and more than 10 tissue sections in each group were examined.
Statistical Analysis
All data are presented as mean ± SD. Comparisons between groups were made by Student t test using SPSS statistical software (SPSS, Chicago, Illinois). Results were considered statistically significant if p less than 0.05.
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Results
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Morphology and Characterization of UCDS Cells
When initially plated, the isolated cells appeared rounded in shape. After 48 hours of plating, the cells were adherent, elongated, and spindle-shaped (Fig 1A). The subcultured cells were shown in Figure 1B. The UCDS cells can be passaged more than 20 times without detecting signs of senescence in our labortory. When UCDS cells were cultured in osteogenic medium for 15 days, the morphology changed and was positive for von Kossa staining (Fig 1C). These cells were also able to differentiate into adipocytes, as they accumulated different amounts of lipid vacuoles after cultivation in adipogenic medium (Fig 1D). Flow cytometry results showed that UCDS cells highly expressed CD29, CD44, CD90, CD105, CD166, and MHC class I but not CD31, CD34, CD38, CD45, CD106, and MHC class II, similar to the fluorescence-activated cell-sorting results of bone marrow derived mesenchymal stem cells (Fig 1E).
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Fig 1. (A, B) Morphology of primary and subcultured umbilical cord derived stem (UCDS) cells. (C, D) Von Kossa and Oil-red O staining of the UCDS cells after osteogenic and adipogenic induction. (E) Flow cytometry results of UCDS cells. Cells were positive for CD29, CD44, CD90, CD105, CD166 and MHC- I, but not CD31, CD34, CD38, CD45, CD106, and MHC- II. (FITC = isothiocyanate; PE = phycoerythrin.)
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Surgical Outcome of Animal Model
There were 6 early deaths that occurred within 2 weeks of induction of myocardial infarction (20%; 6 of 30); most deaths occurred within 48 hours of induction of myocardial infarction. The remaining 23 of 24 animals, with LVEF less than 60% in ultrasonic assessment [14], were randomly allocated to the UCDS-cell–treated group (n = 12) and the PBS-treated group (n = 11). The mortality over the 4-week period after the second surgical procedure was 16.67% (2 of 12), 9.09% (1 of 11) for UCDS- and PBS- treated groups, respectively. Most deaths also occurred within 48 hours after the injection procedure. Thus, there were 10 rats in both the PBS- and UCDS-cell–treated groups. The surviving rats were followed up by echocardiography before euthanasia.
Assessment of Cardiac Function
There was no significant difference in baseline values between cell-treated and control animals. Two weeks after transplantation, the LVEF improved in the cell transplant group, whereas it decreased in the PBS control group (p < 0.05; Fig 2A). Left ventricular dimensions (left ventricular end-diastolic diameter and end-systolic diameter) were significantly smaller in the UCDS group than in the PBS group (p < 0.05, respectively; Fig 2B, C). The left ventricular posterior wall thickness was also better in UCDS-cell–treated hearts but not in PBS controls, and the difference was significant (p < 0.05; Fig 2D). At the 4-week time point after cell transplantation, similar observations were obtained (Fig 2).
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Fig 2. Echocardiography results. There was no significant difference in baseline values between the two groups. (A) Left ventricular ejection fraction (LVEF) increased in the cell transplantation group; the difference between the two groups was of statistical significance. (B) Left ventricular end-systolic diameter (LVEDs) and (C) left ventricular end-diastolic diameter (LVEDd) were significantly smaller in the umbilical cord derived stem (UCDS) cell group than in the phosphate-buffered saline (PBS) group (p < 0.05, respectively). (D) The left ventricular posterior wall thickness (LVPW) was also better in UCDS-cell–treated hearts but not in PBS controls, and the difference was significant (p < 0.05) during 4 weeks (w) of follow-up.
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Histologic Assessment
The left coronary artery ligation led to a transmural infarction in the anterior wall of all examined rats, and fibrous scar tissue developed in the infarction area (Fig 3A, B). The CM-DiI labeled UCDS cells were detected in islands within the infarct region (Fig 3C). Typically, transplanted cells and sometimes clusters of more than dozens of cells were found in the subepicardial and subendocardial infarct tissue. When examined at higher magnification, transplanted UCDS cells were typically localized or scattered in the network of murine capillaries stained with BS-1 lectin (Fig 3E). Some UCDS cells were found near the large vessels or arterioles stained with smooth muscle actin (Fig 3F).
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Fig 3. (A, B) The left anterior descending ligation led to a transmural infarction in the anterior wall of all examined rats, and fibrous scar tissue developed in the infarction area (black arrows). (C) Carbocyanine 1,1’-dioctadecyl-1-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI) labeled umbilical cord derived stem (UCDS) cells were detected in islands within the infarct region. (D) Nuclei staining using 4’,6-diamidino-2-phenylindole (DAPI) of the same slide. (E) Transplanted UCDS cells (red) scattered in the network of murine capillaries stained with bandeiraea simplicifolia lectin I (green). (F) Some UCDS cells (red) localized in the perivascular area (large vessels or arterioles; white arrow) stained with smooth muscle actin (green). Each figure represents 8 slides in each infarcted myocardium.
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Differentiation of Transplanted UCDS Cells in Ischemic Myocardium
Four weeks after transplantation, the UCDS cells were incorporated predominantly into the border zone of infarcts in cryosectioned slides. Counterstaining of representative slides containing UCDS cells with antibodies against cardiac troponin-T was positive (Fig 4A, B, C, D), suggesting that the transplanted UCDS cells transdifferentiate into relevant cardiomyocytes. Moreover, a subpopulation of UCDS cells expressed von Willebrand factor and smooth muscle actin (Fig 4E, F). These results suggest the ability of UCDS cells to differentiate into cardiomyocytes, smooth muscle cells, and endothelial cells, which may contribute to cardiac function recovery in myocardium damaged rats.
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Fig 4. Differentiation of transplanted umbilical cord derived stem (UCDS) cells. (A) Myocardium was stained with anti–cardiac troponin T. (B) Carbocyanine 1,1’-dioctadecyl-1-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI)–labeled transplanted UCDS cells. (C) The same slide stained with 4’,6-diamidino-2-phenylindole (DAPI). (D) A merge of them showed the UCDS cells were positively stained with troponin T (white arrow). (E) Representative confocal micrographs of endothelial differentiation: red represents transplanted UCDS cells, green represents the slide positively stained with anti–von Willebrand factor. The arrows show some UCDS cells express von Willebrand factor. (F) Representative confocal micrographs of smooth muscle differentiation: red represents transplanted UCDS cells, green represents positively stained with anti--smooth muscle actin. The arrows indicate some UCDS cells express smooth muscle actin. Bar scale = 20 µm.
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Assessment of Capillaries and Arterioles
Capillary and arteriole density in the infarct border zone were determined after immunostaining with BS-1 lectin and anti–-smooth muscle actin. Representative images are shown in Figure 5. Immunfluorescence analysis of BS-1 lectin in the ischemic tissues displayed a significant increase in the capillary density by transplantation of UCDS cells compared with the PBS controls at 4 weeks after implantation (p < 0.05; Fig 5B). The therapeutic action was also evident at the arteriole level, as the numbers of arteriole vessels (< 40 µm and > 40 µm in diameter) were markedly increased in UCDS cell–transplanted myocardium compared with the PBS controls (p < 0.05, respectively; Fig 5D).
Detection of Vascular Endothelial Growth Factor Secretion and Cardiomyocyte Apoptosis
To confirm that transplanted UCDS cells secreted angiogenic cytokines in vivo, sections of cardiac muscle were examined for colocalization of VEGF and the transplanted cells. The DiI-labeled transplanted cells were seen surrounding VEGF immunostaining (Fig 6A, B, C, D), suggesting the local secretion of VEGF from the transplanted UCDS cells. The results of TUNEL assays showed that TUNEL-positive cardiomyocytes were significantly lower in UCDS-cell–transplanted hearts compared with that in PBS controls (Fig 6E, F, G, H).
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Fig 6. Vascular endothelial growth factor secretion and apoptosis inhibition induced by umbilical cord derived stem (UCDS) cells. (A) Carbocyanine 1,1’-dioctadecyl-1-3,3,3’,3’-tetramethylindocarbocyanine perchlorate (CM-DiI)–labeled UCDS cells. (B) Vascular endothelial growth factor stained with isothiocyanate. (C) 4’,6-Diamidino-2-phenylindole (DAPI) stained nuclei blue. (D) The merged figure indicated secretion of vascular endothelial growth factor by transplanted cells in vivo (white arrows). Representative slides stained with antibodies against -sarcomeric actin (E), TUNEL-positive cells (F), and DAPI staining (G) demonstrated cardiomyocytes apoptosis in phosphate-buffered saline (PBS)–injected heart tissue. (H) Terminal-deoxynucleotidytransferase-mediated dUTP-biotin nick end labeling (TUNEL) assays identified fewer apoptotic cardiomyocytes in UCDS-cell–treated hearts compared with those receiving PBS. Normal heart tissue without coronary artery ligation served as negative control.
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Comment
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Myocardial ischemia associated with coronary artery disease and subsequent heart failure is the leading cause of morbidity and mortality. Despite the enormous advances in the understanding and treatment of heart failure that have taken place during the past years, this condition remains a serious, and in fact, a growing problem worldwide [15]. Recent advances suggest cardiac transfer of stem cells can have a favorable impact on tissue regeneration and contractile performance of the infracted heart [1–6, 8]. Although bone marrow derived stem cells represent the main available source for cell therapies, the use of bone marrow derived cells is not always acceptable because of the significant decrease in cell number and proliferation/differentiation capacity with age. In addition, obtaining the therapeutic quantity of bone marrow requires general anesthesia and hospitalization. In this connection, most attention should be paid to tissues containing cells with higher proliferative potency, capability of differentiation, and low risk of contamination [16].
Human umbilical cord is likely a feasible source of stem cells compared with bone marrow for its advantages such as vast abundance, lack of donor attrition, and low risk of viral transmission. In this report, we described the isolation of stem cells from human umbilical cord tissue and demonstrated that UCDS cells were a crowd of undifferentiated stem cells that were similar to bone marrow derived mesenchymal stem cells different from hematopoietic stem cells and cord blood cells, and most importantly, these cells were able to migrate, colonize, and survive in the infarcted myocardium. The UCDS cells can be easily extracted and cryopreserved, allowing for individual patients to store their own samples for possible future autologous use even if there were no immediate indication that stem cell therapy would be required. Special attention should be paid to the expression of MHC molecules. Because MHC usually mediates the allogenic response, the absence of MHC-II molecules and low expression of MHC-I molecules on UCDS cells may have significant implications in that UCDS cells may be used for allogenic cell transplantation with lower risk of alloreactivity and viral infection.
The main findings of the present study suggest that intramyocardial delivery of human UCDS cells can improve left ventricular function and attenuate left ventricular dilatation after myocardial infarction. In this study, we chose to deliver cells 2 weeks after myocardial infarction to avoid cell loss due to intense inflammation and allow baseline evaluation for myocardial damage possible. Our findings showed that local delivery of UCDS cells, 2 weeks after myocardial infarction, is feasible and effective. To track the transplanted cells from the resident tissues, UCDS cells were labeled by red fluorescence before transplantation. Four weeks after transplantation, the labeled cells survived in the scar tissue and were found to accumulate mainly in capillaries and arterioles.
Orlic and colleagues [3] injected hematopoietic stem cells into the myocardium of rats, which were able to repair the damaged myocardial tissue by generating endothelial and cardiomyocytic cells, but the mechanism of cardiomyocyte transdifferentiation is still controversial [17, 18]. We previously demonstrated that UCDS cells have the ability to differentiate into endothelial cells, and thus play a potential role in microcirculation remodeling [11]. In the present study, we revealed that transplanted UCDS cells had the potential to differentiate into cardiomyocytes and smooth muscle cells as well as endothelial cells, strongly supporting the therapeutic potential of UCDS cells in ischemic heart diseases. In addition, capillary and arteriole density in hearts with myocardial infarction was significantly increased, and we also observed the incorporation of some transplanted UCDS cells into the vasculature 4 weeks after transplantation.
Recent advances indicate that stem cells can produce several angiogenic factors, such as VEGF, basic fibroblast growth factor, and stem cell homing factor [19, 20]. We also demonstrated that transplanted UCDS cells in ischemic myocardium secrete VEGF and contributed to therapeutic neovascularization. Thus, transplanted UCDS cells can improve tissue ischemia in part through paracrine mechanisms, but the exact mechanism of VEGF secretion in ischemic tissues is still not fully elucidated at present.
Because the loss of cardiomyocytes is responsible for myocardial degeneration after acute myocardial infarction, preventing ongoing cell apoptosis is generally considered as one of the major mechanisms of cardiac regenerative therapy using stem cells [21]. Our results demonstrated that fewer apoptotic cardiomyocytes in UCDS-cell–treated hearts compared with those receiving PBS. Thus, UCDS cell transplantation can preserve myocardial function, promoting survival of endangered cardiac cells by apoptosis inhibition.
In summary, our study provides encouraging evidence that transplanted UCDS cells can improve cardiac function in a rat myocardial infarction model. The favorable functional effects are probably related to differentiation of UCDS cells within infracted myocardium, increased capillary and arteriole density, secretion of angiogenic factors, and prevention of apoptosis. The use of UCDS cells to repair the infarcted myocardium may be of importance to elderly people in whom the availability of autologous, functional stem cells is limited. Umbilical cords are easy to obtain in segments between 20 cm and 30 cm in length, which allows for the generation of a sufficient cell number in a relatively short time. In addition, UCDS cells can be easily extracted and cryopreserved, allowing for patients to store their own samples for possible future autologous use even if there is no immediate indication that stem cell therapy would be required, suggesting human UCDS cells represent a promising cell source for future routine therapeutic applications. Many issues must be resolved before the safe application of these cells in the clinical setting, however, requiring a complete understanding of the maintenance, storage, induction of immune tolerance, and enhancement of homing and colonization of these cells, and that provides an exciting arena for continued research.
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Acknowledgments
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This work was supported by the Specialized Research Fund for the Doctoral Program of Higher Education (20040023048) from the Ministry of Education of China to Dr Liu, and by the Major State Basic Research and Development Programme of China (973 project, 001CB5101) to Dr Han.
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Footnotes
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* Kai Hong Wu and Bin Zhou contributed equally to this work. 
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References
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Abstract
Introduction
