| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Thorac Cardiovasc Surg 2008;135:799-808
© 2008 The American Association for Thoracic Surgery
Cardiopulmonary Support and Physiology |
a Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University, College of Medicine, Hangzhou, China
b Department of Cardiology, Second Affiliated Hospital, Zhejiang University, College of Medicine, Hangzhou, China
c Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC
d Department of Pharmaceutical and Biomedical Sciences, Medical University of South Carolina, Charleston, SC
Received for publication April 19, 2007; revisions received July 3, 2007; accepted for publication July 9, 2007. * Address for reprints: Ling Wei, MD, Department of Pathology and Laboratory Medicine, 165 Ashley Ave, Medical University of South Carolina, Charleston, SC 29425. (Email: weil{at}musc.edu).
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Methods: Mesenchymal stem cells from green fluorescent protein transgenic mice were cultured under normoxic or hypoxic (0.5% oxygen for 24 hours) conditions. Expression of growth factors and anti-apoptotic genes were examined by immunoblot. Normoxic or hypoxic stem cells were intramyocardially injected into the peri-infarct region of rats 30 minutes after permanent myocaridal infarction. Death of mesenchymal stem cells was assessed in vitro and in vivo after transplantation. Angiogenesis, infarct size, and heart function were measured 6 weeks after transplantation.
Results: Hypoxic preconditioning increased expression of pro-survival and pro-angiogenic factors including hypoxia-inducible factor 1, angiopoietin-1, vascular endothelial growth factor and its receptor, Flk-1, erythropoietin, Bcl-2, and Bcl-xL. Cell death of hypoxic stem cells and caspase-3 activation in these cells were significantly lower compared with that in normoxic stem cells both in vitro and in vivo. Transplantation of hypoxic versus normoxic mesenchymal stem cells after myocardial infarctiion resulted in an increase in angiogenesis, as well as enhanced morphologic and functional benefits of stem cell therapy.
Conclusions: Hypoxic preconditioning enhances the capacity of mesenchymal stem cells to repair infarcted myocardium, attributable to reduced cell death and apoptosis of implanted cells, increased angiogenesis/vascularization, and paracrine effects.
= hypoxia-inducible factor-1; H-MSC = hypoxic mesenchymal stem cell; HP = hypoxic preconditioning; LVEDP = left ventricular end-diastolic pressure; LVSP = left ventricular systolic pressure; MI = myocardial infarction; MSC = mesenchymal stem cell; N-MSC = normoxic mesenchymal stem cell; PBS = phosphate-buffered saline solution; TUNEL = terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling; VEGF = vascular endothelial growth factor
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Bone marrow mesenchymal stem cells (MSCs) are multipotent adult stem cells2 and able to differentiate into endothelial cells, vascular smooth muscle cells, and perhaps even cardiac-like myocytes when transplanted into the ischemic heart.3 Both animal and clinical studies have provided evidence that MSC transplantation can improve cardiac function through possible myogenesis and angiogenesis after MI.4,5 Some studies, however, have failed to observe the therapeutic effects of MSC transplantation6,7; thus, there is a need for further investigation into the use of MSCs and the improvement of transplantation techniques after MI.
A major dilemma in stem cell therapy for ischemic heart diseases is the low survival of transplanted cells in the ischemic and peri-infarcted region.6,8 Most implanted cells may die within 4 days after transplantation into the ischemic heart.9 Endogenous and environmental factors, such as the inflammatory response, may contribute to cell death. Thus, improving grafted cell survival after transplantation is critical for enhancing the efficacy and efficiency of stem cell therapy.
Angiogenesis remains one of the putative mechanisms in cardiac functional recovery after MI and stem cell transplantation.10 Stimulating angiogenesis showed therapeutic effects in ischemic heart disease.11 Transplanted MSCs can stimulate angiogenesis after MI by secreting multiple angiogenic cytokines and differentiating into endothelial cells.12 It can be reasoned that enhancing the MSC's ability to promote angiogenesis will further increase the therapeutic potential of MSC transplantation after MI.
Hypoxic preconditioning (HP) by sublethal hypoxic insult stimulates endogenous mechanisms resulting in multiple responses including protein expressions that protect against future lethal hypoxia and other insults. HP can decrease apoptosis of neurons through induction of hypoxia-inducible factor-1 (HIF-1)13 and protect myocytes from hypoxia and reperfusion injury.14 HP stimulates myocardial angiogenesis to an extent sufficient to exert significant cardioprotection after MI.15
Cell transplantation therapy and HP have been studied as separate research topics. We16 recently demonstrated that in vitro HP of embryonic stem cells significantly increased their survival and tissue repair capabilities after transplantation into the ischemic brain. On the basis of the well-documented manifold benefits of HP, we examined the hypothesis that HP of cultured MSCs would promote their survival in vitro as well as after transplantation. Furthermore, enhanced survival and trophic support would contribute to endothelial differentiation and stimulate angiogenesis. The HP strategy for stem cell transplantation would ultimately benefit functional recovery after MI.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In brief, MSCs were acquired from the femoral and tibial bones of green fluorescent protein (GFP) transgenic mice. MSCs were flushed from the femurs and tibias of GFP mice using a 25-guage needle. Mononuclear cells were suspended in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum and plated in flasks. Cultures were maintained at 37°C in a humidified atmosphere containing 5% carbon dioxide. After 24 hours, nonadherent cells were discarded, and adherent cells were washed three times with phosphate-buffered saline solution (PBS). Fresh complete medium was added and replaced every 4 days. Each primary culture was subcultured 1:2 when MSCs grew to approximately 80% confluence. To confirm the cellular identity of cultured cells, we subjected MSCs to fluorescence-activated cell sorting using CD90, CD34, and CD45 markers, and cultured cells were identified as CD90+ and CD34–/CD45– cells.
Sublethal Hypoxia Protocol
For HP treatment, cells were subcultured 1:2 and cultured for 3 days until confluent. Fresh complete medium was added before hypoxia. Hypoxia treatment was achieved with a well-characterized, finely controlled ProOx-C-chamber system (Biospherix, Redfield, NY) for 24 hours. The oxygen concentration in the chamber was maintained at 0.5%, with a residual gas mixture composed of 5% carbon dioxide and balanced nitrogen.
Cell Death Assays in Vitro
Cell death was assayed using trypan blue staining as described previously.18
Western Blot Analysis
Immunoblot was applied to determine the effect of HP on the expression of growth factors and antiapoptotic genes in MSCs. Cultured cells were lysed with modified radioimmunoprecipitation assay buffer (50 mmol/L HEPES, pH 7.3, 1% sodium deoxycholate, 1% Triton X-100, 0.1% sodium dodecylsulfate, 150 mmol/L NaCl, 1 mmol/L ethylenediaminetetraacetic acid, 1 mmol/L Na3VO4, 1 mmol/L NaF, and protease inhibitor cocktail [Roche, Nutley, NJ]) for 30 minutes, followed by centrifugation at 14,000g for 30 minutes. Protein concentration of each sample was determined with the Bicinchoninic Acid Assay (Sigma Chemical Co, St Louis, Mo). Then, 40 µg of protein per sample was electrophoresed on a 6%- to 15%-gradient gel by sodium dodecylsulfate–polyacrylamide gel electrophoresis in a Hoefer Mini-Gel system (Amersham Biosciences, Piscataway, NJ) and transferred in a Hoefer Transfer Tank (Amersham Biosciences) to polyvinylidene difluoride membrane (Bio-Rad, Hercules, Calif). Membranes were blocked with 7% milk in Tris-buffered saline and 0.2% Tween at room temperature for 2 hours and were then incubated overnight at 4°C with specific primary antibodies. The blots were washed three times with Tris-buffered saline and 0.2% Tween and incubated with alkaline phosphatase–conjugated secondary antibodies for 2 hours at room temperature. The expression signals were detected with 5-bromo-4-chloro-3-indolyl phosphate/nitroblue tetrazolium (BCIP/NBT) solution (Sigma).
Rat Model of MI
Male Wistar rats (280–330 g) were intubated under general anesthesia with 4% chloral hydrate (4 mg/kg, administered intraperitoneally) and ventilated with room air by a small animal ventilator (Vetronics, Lafayette, Ind). MI was induced by permanent ligation of the left anterior descending coronary artery with a 6–0 silk suture.19 Successful performance of coronary occlusion was verified by blanching of the myocardium distal to the coronary ligation. The sham-operation group received the same procedure of thoracotomy without coronary ligation. A minimum of 6 animals was in each experimental group. In our investigation, the MI-induced mortality rate was 
15%. We did not notice a significant difference between groups. The investigation conforms to the "Guide for the Care and Use of Laboratory Animals" published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).
Cell Preparation and Transplantation
MSCs were labeled with Hoechst 33342 to track and count the implanted cells. In brief, sterile Hoechst 33342 was added to culture medium with a final concentration of 10 µmol/mL for 2 hours before transplantation. Then the cells were rinsed 6 times with PBS to remove unbound Hoechst 33342, detached with 0.25% (w/v) trypsin ethylenediaminetetraacetic acid, and suspended in complete medium. Cells were centrifuged and washed with PBS, followed by the final centrifugation and suspension in serum-free medium at 1 x 106 cells per 150 µL. Before transplantation, MSCs in the HP group (H-MSCs) were treated for 24 hours with sublethal hypoxia (0.5% oxygen) and then reoxygenated in 20% oxygen for 2 hours. Half an hour after ligation of the left anterior descending coronary artery, 150 µL of medium containing 1 x 106 cells was directly injected into the ischemic peri-infarct region. MI control rats received MI alone and received the same volume of serum free/cell free medium injection. Experimental groups were divided into four groups of 10 rats each: (1) MI with transplant of normoxic MSCs (N-MSCs), (2) MI with transplant of hypoxia-pretreated MSCs (H-MSCs), (3) MI with injection of control medium, and (4) sham-operated control group.
Immunofluorescence Staining
For immunofluorescence staining, cells on dishes and in heart tissues were fixed with 10% formalin for 10 minutes, permeabilized with 0.2% Triton X-100 for 5 minutes, and blocked with 1% fish gelatin (Sigma) for 1 hour at room temperature. Specimens were then incubated with primary antibodies overnight at 4°C, then washed with PBS three times, and incubated with Cy3-conjugated donkey anti-rabbit immunoglobulin G (1:500; Jackson ImmunoResearsh, West Grove, Pa) or Alexa Fluor 488 anti-goat immunoglobulin G (1:200, Molecular Probes, Carlsbad, Calif) for 1 hour at room temperature. The cells were treated with Hoechst 33342 (1:20000; Molecular Probes, Carlsbad, Calif) for 5 minutes. Dishes or slides were mounted and analyzed under a florescent microscope (BX51, Olympus, Tokyo, Japan).
Measurement of Hemodynamics
Cardiac hemodynamics was measured at 6 weeks after myocardial ischemia. Rats were anesthetized with 4% chloral hydrate (40 mg/kg, intraperitoneally). The carotid artery was isolated and cannulated with a microtip catheter that was connected with an MLT0699 disposable pressure transducer (ADInstrument, Colorado Springs, Colo). Left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximum dp/dt (+dp/dt, pressure rise rate) and minimum dp/dt (–dp/dt, pressure decrease rate), and heart rate were monitored and recorded by the Powerlab/800 data acquisition system (ADInstrument).
Infarct Size Measurement
After measurement of hemodynamics, the animals were humanely sacrificed and the hearts were quickly harvested and divided into three transverse sections. Tissues from the free wall of the left ventricle including infarct and peri-infarct regions were then embedded in optimal cutting temperature (OCT) compound (Sakura Finetek USA Inc, Torrance, Calif). Frozen sections of left ventricular samples were cut at 10-µm thickness and prepared for staining. To determine infarct size, hearts at papillary muscle level were selected and Masson trichrome and hematoxylin–eosin staining were performed. Images were digitized by the NIH image analysis system (National Institutes of Health, Bethesda, Md). Infarct size was calculated by dividing the sum of the planimetered endocardial and epicardial circumferences of the infarcted area by the sum of the total epicardial and endocardial circumferences of the left ventricle.20
Terminal Deoxynucleotidyl Transferase Biotin-dUPT Nick End Labeling (TUNEL) in heart sections
A TUNEL staining kit (DeadEnd Fluorometric TUNEL system, Promega, Madison, Wis) was used to visualize cell death in heart sections. After 10 minutes of fixing by 10% buffered formalin phosphate (Fisher Scientific, Pittsburgh, Pa) and pretreatment with –20°C ethanol/acetic acid (2:1) and 0.2% Triton X-100, the heart sections were incubated in an equilibration buffer as instructed by the kit. The TdT enzyme and nucleotide mix was then added at proportions specified by the kit for 75 minutes at room temperature. The slides were washed with 2x standard saline citrate washing buffer for 15 minutes and followed by three washings with PBS.
Cell and Vessel Counting
Cell count was performed using a design-based stereologic method. For counting caspase-3 positive cells in cultures, 6 fields per dish were randomly chosen under 20x magnification of a fluorescent microscope (n = 4). For counting caspase-3, Hoechst 33342, and GFP-positive cells and vessels in heart sections, every tenth heart section (100 µm apart) across the entire region of interest was counted, and 6 fields per heart section were randomly chosen and photographed under 40x magnification with a fluorescent microscope; this was repeated in 4 separate sections per heart.
Statistical Analysis
The Student two-tailed t test was used for comparison of two experimental groups. Multiple comparisons were done by 1-way analysis of variance followed by the Tukey post hoc test for multiple pairwise examinations. Data are expressed as the mean ± standard error of mean.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, vascular endothelial growth factor (VEGF) and its receptor (Flk-1), angiopoietin-1, and erythropoietin (EPO) and its cognate receptor (EPOR). As expected, sublethal hypoxia significantly increased the HIF-1 protein expression level (3.4-fold) as well as Flk-1, angiopoietin-1, EPO, and EPOR in H-MSCs (
Figure 1).
|
B subunits P65 and P50, and anti-apoptotic proteins Bcl-2 and Bcl-xL. Increased nuclear fractions of P65 and P50 further suggested activation and translocation of these two nuclear factor-B transcription factors (
Figure 2). The hypoxia treated cells also had a significantly lower level of active caspase-3 than did N-MSCs (Figure 2).
|
Figure 3) or caspase-3 staining (data not shown). Serum deprivation increased the ratio of trypan blue and caspase-3 staining positive cells in both N-MSCs and H-MSCs; however, the increases were much less in H-MSCs than in N-MSCs (Figure 3). The percentage of trypan blue positive cells versus total cells was 24.3% ± 5.4% and 39.3% ± 6.8% in H-MSCs and N-MSCs, respectively (n = 4, P < .05), and the percentage of caspase-3 positive cells was 25.6% ± 5.4% and 36.6% ± 6.6%, respectively (n = 4, P < .05) (Figure 3).
|
Figure 4). To test whether HP might prevent delayed MSC cell death, we assessed cell death using TUNEL staining 72 hours after transplantation. In the H-MSC transplantation group, the ratio of TUNEL positive cells was significantly reduced (Figure 4).
|
Figure 5). Between the two transplantation groups, significantly greater total vessel density/area and arteriole density/area were observed in the H-MSC group than in the N-MSC group (n = 6 rats per group, P < .05) (Figure 5). To further clarify whether HP promoted endothelial cell differentiation of MSCs, we calculated the ratio of CD31/Hoechst positive cells versus total transplanted cells pre-labeled with Hoechst. A higher endothelial cell differentiation ratio was identified in the H-MSC transplantation group than in the N-MSC group (n = 6, P < .05) (Figure 5).
|
We also did not identify a noticeable effect of HP on this potential myogenesis.
MSC Transplantation Reduces Infarct Size
Hematoxylin–eosin staining and Masson trichrome staining of cardiac tissue revealed fibrosis in the infarct region 6 weeks after ischemia. Scar formation was evident in the ischemic hearts that received a medium control injection (
Figure 6). The infarct size was reduced in both groups that received MSC transplantation; however, rats receiving H-MSC transplantation showed the smallest infarct size (Figure 6).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
recently reported that transplantation of hypoxic preconditioned MSCs reduced the apoptosis of cardiomyocytes. In the present investigation, we provide new evidence that transplantation of hypoxic preconditioned MSCs promotes heart functional recovery through enhancing implanted cell survival and angiogenesis after MI.
Previous studies have shown that allogeneic MSCs are immunoregulatory and do not induce immune response in vitro22 and in vivo23; xenogeneic bone marrow stromal cells transplanted into ischemic myocardium were immunologically tolerant and feasible.24 Therefore, immunosuppression was not given in the present investigation and no rejection of implanted cells was noticed. Transplanted bone marrow MSCs are sensitive to ischemic and inflammatory microenvironment as is evidenced by stem cell death that often occurs soon after transplantation.6,8,25 This cell death may, in turn, increase the inflammatory response and be an additional burden to the ischemic heart, hindering functional recovery. Gene modification has been investigated to enhance stem cell survival and efficiency of cell transplantation therapy. For instance, overexpression of Akt can reduce apoptosis of MSCs and then enhance the heart functional improvement.26 Our previous study showed that transplantation of embryonic stem cells overexpressing Bcl-2 increased the survival and neuronal differentiation of transplanted cells, as well as functional recovery after cerebral ischemic stroke.27 Whether or not permanent gene modification has a long-term risk of tumorigenesis is not clear,28 which may limit its clinical utility. On the basis of this concern, increasing attention has been paid to short but comprehensive improvements of the quality of transplanted cells. The present study supports that HP may be explored as such a strategy in cell transplantation therapy for ischemic heart diseases.
Considering that up to 90% of grafted cells may die within the first few days of transplantation, the transient cytoprotective effect of HP should be sufficient to protect transplanted cells during the initial critical period after transplantation. Enhanced implanted cell survival can reduce the required number of transplanted cells, and fewer stem cells may actually differentiate better. Transplantation of MSC was performed 30 minutes after MI. In this case, some observed beneficial effects might result from myocardial rescue that prevented negative remodeling during the acute phase. Therapeutic potential of transplantation of MSCs in the chronic phase long after MI remains to be examined. MSCs may provide host tissues and themselves with trophic support. MSCs can express cytokines and growth factors that play important roles in cell survival and angiogenesis, such as VEGF, basic fibroblast growth factor, angiopoietin-1, and EPO.12,29 Our study demonstrates that MSCs express these factors, which are up-regulated by HP, in line with previous studies.21,30 These growth factors exert both autocrine and paracrine effects. HP augmented paracrine signaling and reduced cardiomyocytes apoptosis.21,30 Several transcription factors may be involved in the response to hypoxia, such as activated protein-1, HIF-1, and nuclear factor-B.31 Activation of some growth factor pathways can activate nuclear factor-B and increase the survival genes such as Bcl-2 and Bcl-xL.32 Consistent with these anti-apoptotic effects, caspase-3 activation is suppressed in H-MSCs. It is likely that a combination of these multiple mechanisms is responsible for the increased viability of H-MSCs.
In this study, MI-induced animal death mostly occurred 3 days after surgery, which was not affected by H-MSC transplantation. The lack of the effect on animal mortality suggests that although the hypoxic preconditioned MSCs survives better in the ischemic heart, the increased cell survival is not sufficient to antagonize the initial overwhelming insults and functional failure in the acute phase of MI. Moreover, the H-MSC–promoted cell survival and angiogenesis are expected to primarily benefit long-term tissue repair and function recovery many days after MI, as shown in this investigation.
An earlier study showed that ex vivo HP up-regulated the synthesis of VEGF messenger RNA and stimulated endothelial differentiation of bone marrow stem cells, which together contributed to improved angiogenesis in the ischemic hind limb after transplantation.33 Our finding that HP increased vessel density, area, and the endothelial cell differentiation ratio is consistent with this previous study. The higher vessel density in H-MSC transplantation group is attributable to both enhanced paracrine effect and increased endothelial cell differentiation. Several groups have reported that MSCs can differentiate into cardiomyocytes9,34; other studies question the possibility that MSCs might fuse with host cells after transplantation into the ischemic heart.6,7 Our study identified that, 6 weeks after transplantation, a few MSCs showed characteristic myosin protein expression. Whether transplanted MSCs may undergo cardiac myocyte differentiation is under debate. Moreover, possible fusion and uptake of Hoechst dye by endogenous cells might also affect the endothelial cell counts. In any event, transplanted MSCs helped to repair infarcted myocardium, disregarding the rare events of myogenesis or cell fusion.35
In conclusion, our study demonstrates that transplantation of HP-treated MSCs shows better therapeutic effects in the ischemic heart. The functional benefit of H-MSC transplantation might be explained by several possibilities: (1) HP enhances the autocrine and paracrine signaling of MSCs, which reduces apoptosis of transplanted cells and endogenous cardiomyocytes; (2) the increased survival of H-MSCs provides better and longer trophic support for the reparative process; (3) the increase in survival of engrafted cells contributes to increased angiogenesis. These factors collectively promote tissue repair and may provide a simple but effective new strategy for clinical MSC transplantation therapy. Of note, although HP of MSCs may show the above benefits, transplantation of H-MSCs did not improve short-term animal survival 3 days after MI; its effect on long-term mortality remains to be tested.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Related Article
in stem cell preconditioning: Mechanistic role of hypoxia-related micro-RNAs
This article has been cited by other articles:
|
|
 |
|
  G. N. Jones, D. Moschidou, K. Lay, H. Abdulrazzak, M. Vanleene, S. J. Shefelbine, J. Polak, P. de Coppi, N. M. Fisk, and P. V. Guillot Upregulating CXCR4 in Human Fetal Mesenchymal Stem Cells Enhances Engraftment and Bone Mechanics in a Mouse Model of Osteogenesis Imperfecta Stem Cells Trans Med, January 1, 2012; 1(1): 70 - 78. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Mohsin, S. Siddiqi, B. Collins, and M. A. Sussman Empowering Adult Stem Cells for Myocardial Regeneration Circ. Res., December 9, 2011; 109(12): 1415 - 1428. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. H. Wu, X. M. Mo, Z. C. Han, and B. Zhou Stem Cell Engraftment and Survival in the Ischemic Heart Ann. Thorac. Surg., November 1, 2011; 92(5): 1917 - 1925. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Wang, X. Hu, X. Xie, A. He, X. Liu, and J.-a. Wang Effects of mesenchymal stem cells on matrix metalloproteinase synthesis in cardiac fibroblasts Exp Biol Med, October 1, 2011; 236(10): 1197 - 1204. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Hu, L. Wei, T. M. Taylor, J. Wei, X. Zhou, J.-A. Wang, and S. Ping Yu Hypoxic preconditioning enhances bone marrow mesenchymal stem cell migration via Kv2.1 channel and FAK activation Am J Physiol Cell Physiol, August 1, 2011; 301(2): C362 - C372. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Rangappa, R. Makkar, and J. Forrester Review Article: Current Status of Myocardial Regeneration: New Cell Sources and New Strategies Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2010; 15(4): 338 - 343. [Abstract] [PDF]
|
|
|
|
|
|
S. M. Chacko, S. Ahmed, K. Selvendiran, M. L. Kuppusamy, M. Khan, and P. Kuppusamy Hypoxic preconditioning induces the expression of prosurvival and proangiogenic markers in mesenchymal stem cells Am J Physiol Cell Physiol, December 1, 2010; 299(6): C1562 - C1570. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. K. W. Sim, H. K. Haider, N. Lila, O. Schussler, J. C. Chachques, and L. Ye Genesis of myocardial repair with cardiac progenitor cells and tissue engineering Heart Asia, September 18, 2010; 2(1): 109 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Zacharek, A. Shehadah, J. Chen, X. Cui, C. Roberts, M. Lu, and M. Chopp Comparison of Bone Marrow Stromal Cells Derived From Stroke and Normal Rats for Stroke Treatment Stroke, March 1, 2010; 41(3): 524 - 530. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Won Kim, H. K. Haider, S. Jiang, and M. Ashraf Ischemic Preconditioning Augments Survival of Stem Cells via miR-210 Expression by Targeting Caspase-8-associated Protein 2 J. Biol. Chem., November 27, 2009; 284(48): 33161 - 33168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Umar, Y. P. de Visser, P. Steendijk, C. I. Schutte, E. H. Laghmani, G. T. M. Wagenaar, W. H. Bax, E. Mantikou, D. A. Pijnappels, D. E. Atsma, et al. Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1606 - H1616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shafy, T. Lavergne, C. Latremouille, M. Cortes-Morichetti, A. Carpentier, and J. C. Chachques Association of electrostimulation with cell transplantation in ischemic heart disease J. Thorac. Cardiovasc. Surg., October 1, 2009; 138(4): 994 - 1001. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Lucchinetti, S. M. Zeisberger, I. Baruscotti, J. Wacker, J. Feng, K. Zaugg, R. Dubey, A. H. Zisch, and M. Zaugg Stem Cell-Like Human Endothelial Progenitors Show Enhanced Colony-Forming Capacity After Brief Sevoflurane Exposure: Preconditioning of Angiogenic Cells by Volatile Anesthetics Anesth. Analg., October 1, 2009; 109(4): 1117 - 1126. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Ogle, S. P. Yu, and L. Wei Primed for lethal battle: A step forward to enhance the efficacy and efficiency of stem cell transplantation therapy J. Thorac. Cardiovasc. Surg., September 1, 2009; 138(3): 527 - 527. [Full Text] [PDF]
|
|
|
|
|
|
K. H. Haider, H. W. Kim, and M. Ashraf Hypoxia-inducible factor-1{alpha} in stem cell preconditioning: Mechanistic role of hypoxia-related micro-RNAs J. Thorac. Cardiovasc. Surg., July 1, 2009; 138(1): 257 - 257. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Carriere, T. G. Ebrahimian, S. Dehez, N. Auge, C. Joffre, M. Andre, S. Arnal, M. Duriez, C. Barreau, E. Arnaud, et al. Preconditioning by Mitochondrial Reactive Oxygen Species Improves the Proangiogenic Potential of Adipose-Derived Cells-Based Therapy Arterioscler Thromb Vasc Biol, July 1, 2009; 29(7): 1093 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 B. R. Weil, A. M. Abarbanell, J. L. Herrmann, Y. Wang, and D. R. Meldrum High glucose concentration in cell culture medium does not acutely affect human mesenchymal stem cell growth factor production or proliferation Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2009; 296(6): R1735 - R1743. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Wisel, M. Khan, M. L. Kuppusamy, I. K. Mohan, S. M. Chacko, B. K. Rivera, B. C. Sun, K. Hideg, and P. Kuppusamy Pharmacological Preconditioning of Mesenchymal Stem Cells with Trimetazidine (1-[2,3,4-Trimethoxybenzyl]piperazine) Protects Hypoxic Cells against Oxidative Stress and Enhances Recovery of Myocardial Function in Infarcted Heart through Bcl-2 Expression J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 543 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Bolte, G. Newman, and J. E. J. Schultz Hypertensive state, independent of hypertrophy, exhibits an attenuated decrease in systolic function on cardiac {kappa}-opioid receptor stimulation Am J Physiol Heart Circ Physiol, April 1, 2009; 296(4): H967 - H975. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
