Bone marrow mesenchymal stem cell transplantation combined with perindopril treatment attenuates infarction remodelling in a rat model of acute myocardial infarction

Objective: This study was performed to evaluate whether implantation of mesenchymal stem cell (MSC) would reduce left ventricular remodelling from the molecular mechanisms compared with angiotensin-converting enzyme inhibitors (ACEIs) perindopril into ischemic myocardium after acute myocardial infarction. Methods: Forty rats were divided into four groups: control, MSC, ACEI, MSC+ACEI groups. Bone marrow stem cell derived rat was injected immediately into a zone made ischemic by coronary artery ligation in MSC group and MSC+ACEI group. Phosphate-buffered saline (PBS) was injected into control group. Perindopril was administered p.o. to ACEI group and MSC+ACEI group. Six weeks after implantation, the rats were killed and heart sample was collected. Fibrillar collagen was observed by meliorative Masson’s trichome stain. Western Blotting was employed to evaluate the protein expression of matrix metalloproteinase (MMP)-2, matrix metalloproteinase (MMP)-9 in infarction zone. The transcriptional level of MMP2, MMP9 and tissue inhibitor of matrix metalloproteinase (TIMP)-1 in infarction area was detected by reverse transcriptase PCR (RT-PCR) analysis. Results: The fibrillar collagen area, the protein expression of MMP2, MMP9 and the transcriptional level of MMP2, MMP9 mRNA in infarction zone reduced in MSC group, ACEI group, and MSC+ACEI group. No significant difference was detected in the expression of TIMP1 mRNA among the 4 groups. Conclusion: Both MSC and ACEI could reduce infarction remodelling by altering collagen metabolism.

Experimental study of qishen yiqi drop pill combined with bone marrow mesenchymal stem cell transplantation on angiogenesis and cardiac function in mice with myocardial infarction

Objective:To investigate the effects ofQishengyiqi drop pill combined with bone marrow mesenchymal stem cell transplantation on angiogenesis and cardiac function in mice after myocardial infarction through in vitro cell molecular biology experiments.Methods:The animals used in this experiment were male mice with eGFP+/-.Sixty mice were randomly divided into three groups(n=20):myocardial infarction group(MI+PBS),myocardial infarction+mesenchyme plasma stem cell transplantation group(MI+MSCs)and myocardial infarction+Qishenyiqi drip pill combined with mesenchymal stem cell transplantation group(MI+MSCs+QSYQ).Qishenyiqi dripping pills were prepared into a medicinal solution with a concentration of 3.9 mg/mL with distilled water.The MI+MSCs+QSYQ group was orally administered with 0.1 mL/kg/day,and the other two groups were orally administered with an equal amount of normal saline.Mice in each group were adaptively fed continuously for 2 weeks,and the myocardial infarction model was established by ligation of the anterior descending coronary artery by thoracic ligation.Twenty-four hours after the model was established,bone marrow mesenchymal stem cells were isolated from the tibia of the mice and injected intracardiacly Bone marrow-derived mesenchymal stem cells were transplanted,and multiple injections were made around the myocardial infarction area of mice.The control group was injected with the same amount of PBS.0h,3 days,7 days,and 14 days after cell transplantation,observe the stem cell morphology under a microscope;on day 7 of cell transplantation,track the expression of eGFP-positive cells with a fluorescence microscope;before modeling,14 and 21 days after cell transplantation,use Cardiac function was measured by echocardiography.After 21 days of modeling,the mice were sacrificed,and heart samples were taken.The angiogenesis of the mice was observed by immunohistochemical staining and microvascular density determination.Results:The morphological growth of transplanted stem cells was proportional to the time of cell transplantation.Compared with MI+PBS group,CD90.2 and y6A were highly expressed on the surface of bone marrow mesenchymal stem cells in MI+MSCs group and MI+MSCs+QSYQ group,while CD31 and CD117 were almost not expressed.On the 21st day after stem cell transplantation,the values of LVDd and LVSD in MI+MSCs+QSYQ group were significantly lower than those in MI+PBS group and MI+MSCs group.At the same time,LVEF and LVFS increased significantly.The results of quantitative immunohistochemical analysis showed that the angiogenesis density in the MI+MSCs+QSYQ group increased significantly,and the difference between the groups was statistically significant(P<0.05).Conclusion:Qishen Yiqi dripping pills combined with bone marrow mesenchymal stem cell transplantation can not only promote angiogenesis in mice with myocardial infarction,but also play a positive role in improving cardiac function.

Therapeutic and regenerative potential of different sources of mesenchymal stem cells for cardiovascular diseases

Mesenchymalstemcells(MSCs)areidealcandidatesfortreatingmanycardiovasculardiseases.MSCscanmodify the internal cardiac microenvironment to facilitate their immunomodulatory and differentiation abilities,which are essential to restore heart function.MSCs can be easily isolated from different sources,including bone marrow,adipose tissues,umbilical cord,and dental pulp.MSCs from various sources differ in their regenerative and therapeutic abilities for cardiovascular disorders.In this review,we will summarize the therapeutic potential of each MSC source for heart diseases and highlight the possible molecular mechanisms of each source to restore cardiac function.

Chinese preparation Xuesaitong promotes the mobilization of bone marrow mesenchymal stem cells in rats with cerebral infarction

After cerebral ischemia, bone marrow mesenchymal stem cells are mobilized and travel from the bone marrow through peripheral circulation to the focal point of ischemia to initiate tissue regeneration. However, the number of bone marrow mesenchymal stem cells mobilized into peripheral circulation is not enough to exert therapeutic effects, and the method by which blood circulation is promoted to remove blood stasis influences stem cell homing. The main ingredient of Xuesaitong capsules is Panax notoginseng saponins, and Xuesaitong is one of the main drugs used for promoting blood circulation and removing blood stasis. We established rat models of cerebral infarction by occlusion of the middle cerebral artery and then intragastrically administered Xuesaitong capsules（20, 40 and 60 mg/kg per day） for 28 successive days. Enzyme-linked immunosorbent assay showed that in rats with cerebral infarction, middle- and high-dose Xuesaitong significantly increased the level of stem cell factors and the number of CD117-positive cells in plasma and bone marrow and significantly decreased the number of CD54-and CD106-positive cells in plasma and bone marrow. The effect of low-dose Xuesaitong on these factors was not obvious. These findings demonstrate that middle- and high-dose Xuesaitong and hence Panax notoginseng saponins promote and increase the level and mobilization of bone marrow mesenchymal stem cells in peripheral blood.

Protective effect of thodioloside and bone marrow mesenchymal stem cells infected with HIF-1-expressing adenovirus on acute spinal cord injury

Rhodioloside has been shown to protect cells from hypoxia injury,and bone marrow mesenchymal stem cells have a good effect on tissue repair.To study the effects of rhodioloside and bone marrow mesenchymal stem cells on spinal cord injury,a rat model of spinal cord injury was established using the Infinite Horizons method.After establishing the model,the rats were randomly divided into five groups.Rats in the control group were intragastrically injected with phosphate buffered saline(PBS)(5μL).PBS was injected at 6 equidistant points around 5 mm from the injury site and at a depth of 5 mm.Rats in the rhodioloside group were intragastrically injected with rhodioloside(5 g/kg)and intramuscularly injected with PBS.Rats in the mesenchymal stem cell(MSC)group were intramuscularly injected with PBS and intramuscularly with MSCs(8×10^6/mL in a 50-μL cell suspension).Rats in the Ad-HIF-MSC group were intragastrically injected with PBS and intramuscularly injected with HIF-1 adenovirus-infected MSCs.Rats in the rhodioloside+Ad-HIF-MSC group were intramuscularly injected with MSCs infected with the HIF-1 adenovirus and intragastrically injected with rhodioloside.One week after treatment,exercise recovery was evaluated with a modified combined behavioral score scale.Hematoxylin-eosin staining and Pischingert’s methylene blue staining were used to detect any histological or pathological changes in spinal cord tissue.Levels of adenovirus IX and Sry mRNA were detected by real-time quantitative polymerase chain reaction and used to determine the number of adenovirus and mesenchymal stem cells that were transfected into the spinal cord.Immunohistochemical staining was applied to detect HIF-1 protein levels in the spinal cord.The results showed that:(1)compared with the other groups,the rhodioloside+Ad-HIF-MSC group exhibited the highest combined behavioral score(P<0.05),the most recovered tissue,and the greatest number of neurons,as indicated by Pischingert’s methylene blue staining.(2)Compared with the PBS group,HIF-1 protein expression was greater in the rhodioloside group(P<0.05).(3)Compared with the Ad-HIF-MSC group,Sry mRNA levels were higher in the rhodioloside+Ad-HIF-MSC group(P<0.05).These results confirm that rhodioloside combined with bone marrow mesenchymal stem cells can promote the recovery of spinal cord injury and activate the HIF-1 pathway to promote the survival of bone marrow mesenchymal stem cells and repair damaged neurons within spinal cord tissue.This experiment was approved by the Animal Ethics Committee of Gansu University of Traditional Chinese Medicine,China(approval No.2015KYLL029)in June 2015.

Protective Effects of Trimetazidine on Bone Marrow Mesenchymal Stem Cells Viability in an ex vivo Model of Hypoxia and in vivo Model of Locally Myocardial Ischemia

Bone marrow mesenchymal stem cells (MSCs) have shown potential for cardiac repair following myocardial injury,but this approach is limited by their poor viability after transplantation.The present study was to investigate whether trimetazidine (TMZ) could improve survival of MSCs in an ex vitro model of hypoxia,as well as survival,differentiation,and subsequent activities of transplanted MSCs in rat hearts with acute myocardial infarction (AMI).MSCs at passage 3 were examined for their viability and apoptosis under a transmission electron microscope,and by using flow cytometry following culture in serumfree medium and exposure to hypoxia (5% CO2,95% N2) for 12 h with or without TMZ.Thirty Wistar rats were divided into 3 groups (n=10 each group),including groupⅠ(AMI control),groupⅡ (MSCs transplantation alone),and group Ⅲ (TMZ+MSCs).Rat MSCs (4×107) were injected into peri-infarct myocardium (MSCs group and TMZ+MSCs group) 30 min after coronary artery ligation.The rats in TMZ+MSCs group were additionally fed on TMZ (2.08 mg?kg-1?day-1) from day 3 before AMI to day 28 after AMI.Cardiac structure and function were assessed by echocardiography at 28th day after transplantation.Blood samples were collected before the start of TMZ therapy (baseline),and 24 and 48 h after AMI,and inflammatory cytokines (CRP,TNF-α) were measured.Then the sur-vival and differentiation of transplanted cells in vivo were detected by immunofluorescent staining.The cellular apoptosis in the peri-infarct region was detected by using TUNEL assay.Furthermore,apoptosis-related proteins (Bcl-2,Bax) within the post-infarcted myocardium were detected by using Western blotting.In hypoxic culture,the TMZ-treated MSCs displayed a two-fold decrease in apoptosis under serumfree medium and hypoxia environment.In vivo,cardiac infarct size was significantly reduced,and cardiac function significantly improved in MSCs and TMZ+MSCs groups as compared with those in the AMI control group.Combined treatment of TMZ with MSCs implantation demonstrated further decreased MSCs apoptosis,further increased MSCs viability,further decreased infarct size,and further improved cardiac function as compared with MSCs alone.The baseline levels of inflammatory cyto-kines (CRP,TNF-α) had no significant difference among the groups.In contrast,all parameters at 24 h were lower in TMZ+MSCs group than those in MSCs group.Furthermore,Western blotting indicated that the expression of antiapoptotic protein Bcl-2 was upregulated,while the proapoptotic protein Bax was down-regulated in the TMZ+MSCs group,compared with that in the MSCs group.It is suggested that implantation of MSCs combined with TMZ treatment is superior to MSCs monotherapy for MSCs viability and cardiac function recovery.

Fifteen years of bone marrow mononuclear cell therapy in acute myocardial infarction

In spite of modern treatment, acute myocardial infarction(AMI) still carries significant morbidity and mortality worldwide. Even though standard of care therapy improves symptoms and also long-term prognosis of patients with AMI, it does not solve the critical issue, specifically the permanent damage of cardiomyocytes. As a result, a complex process occurs, namely cardiac remodeling, which leads to alterations in cardiac size, shape and function. This is what has driven the quest for unconventional therapeutic strategies aiming to regenerate the injured cardiac and vascular tissue. One of the latest breakthroughs in this regard is stem cell(SC) therapy. Based on favorable data obtained in experimental studies, therapeutic effectiveness of this innovative therapy has been investigated in clinical settings. Of various cell types used in the clinic, autologous bone marrow derived SCs were the first used to treat an AMI patient, 15 years ago. Since then, we have witnessed an increasing body of data as regards this cutting-edge therapy. Although feasibility and safety of SC transplant have been clearly proved, it's efficacy is still under dispute. Conducted studies and meta-analysis reported conflicting results, but there is hope for conclusive answer to be provided by the largest ongoing trial designed to demonstrate whether this treatment saves lives. In the meantime, strategies to enhance the SCs regenerative potential have been applied and/or suggested, position papers and recommendations have been published. But what have we learned so far and how can we properly use the knowledge gained? This review will analytically discuss each of the above topics, summarizing the current state of knowledge in the field.

Influence of Transplantation of Allogenic Bone Marrow Mononuclear Cells on the Left Ventricular Remodeling of Rat after Acute Myocardial Infarction

To probe into the influence of transplantation of allogenic bone marrow mononuclear cells （BM-MNCs） on the left ventricular remodeling of rat after acute myocardial infarction （AMI）, 60 male Wistar rats were evenly divided into three groups at random： control group 1, control group 2 and transplantation group. In control group 1, chest was opened without ligation of coronary artery; in control group 2 and transplantation group, the left anterior descending branch of coronary artery was ligated to establish AMI model. Prepared culture medium and allogenic BM-MNCs suspension were respectively implanted the surrounding area of infracted cardiac muscle via epicardium of control group 2 and transplantation group. Four weeks after the operation, the osteopontin gene （OPN mRNA, P〈0.01）, type Ⅰ collagen （P〈0.01） and angiotensin Ⅱ （AngⅡ, P〈0.01） content in the left ventricular non-infracted myocardium, and the Ang Ⅱ density in blood plasma （P〈0.05） of transplantation group and control group 2 were all significantly higher than that of control group Ⅰ. In the transplantation group, the myocardial OPN InRNA, type Ⅰ collagen and Ang Ⅱ content of non-infracted zone in left ventricle, and the Ang Ⅱ concentration in blood plasma were all significantly lower than those of control group 2 （P〈0.05 for all）. It is concluded that allogenic BM-MNCs transplantation may ease left ventricular remodeling after AMI by inhibiting the synthesis of type Ⅰ collagen in the cardiac muscle and down-regulating the expression of Ang Ⅱ and OPN gene.

Role of bone marrow-derived mesenchymal stem cells in a rat model of severe acute pancreatitis

AIM:To investigate the role and potential mechanisms of bone marrow mesenchymal stem cells(MSCs) in severe acute peritonitis(SAP).METHODS:Pancreatic acinar cells from Sprague Dawley rats were randomly divided into three groups:nonsodium deoxycholate(SDOC) group(non-SODC group),SDOC group,and a MSCs intervention group(i.e.,a co-culture system of MSCs and pancreatic acinar cells + SDOC).The cell survival rate,the concentration of malonaldehyde(MDA),the density of superoxide dismutase(SOD),serum amylase(AMS) secretion rate and lactate dehydrogenase(LDH) leakage rate were detected at various time points.In a separate study,Sprague Dawley rats were randomly divided into either an SAP group or an SAP + MSCs group.Serum AMS,MDA and SOD,interleukin(IL)-6,IL-10,and tumor necrosis factor(TNF)-α levels,intestinal mucosa injury scores and proliferating cells of small intestinal mucosa were measured at various time points after injecting either MSCs or saline into rats.In both studies,the protective effect of MSCs was evaluated.RESULTS:In vitro,The cell survival rate of pancreatic acinar cells and the density of SOD were significantly reduced,and the concentration of MDA,AMS secretion rate and LDH leakage rate were significantly increased in the SDOC group compared with the MSCs intervention group and the Non-SDOC group at each time point.In vivo,Serum AMS,IL-6,TNF-α and MAD level in the SAP + MSCs group were lower than the SAP group;however serum IL-10 level was higher than the SAP group.Serum SOD level was higher than the SAP group at each time point,whereas a significant betweengroup difference in SOD level was only noted after 24 h.Intestinal mucosa injury scores was significantly reduced and the proliferating cells of small intestinal mucosa became obvious after injecting MSCs.CONCLUSION:MSCs can effectively relieve injury to pancreatic acinar cells and small intestinal epithelium,promote the proliferation of enteric epithelium and repair of the mucosa,attenuate systemic inflammation in rats with SAP.

Effect of transplantation of bone marrow stem cells on myocardial infarction size in a rabbit model

BACKGROUND:Intravenous transplantation has been regarded as a most safe method in stem cell therapies.There is evidence showing the homing of bone marrow stem cells(BMSCs) into the injured sites,and thus these cells can be used in the treatment of acute myocardial infarction(Ml).This study aimed to investigate the effect of intravenous and epicardial transplantion of BMSCs on myocardial infarction size in a rabbit model.METHODS:A total of 60 New Zealand rabbits were randomly divided into three groups:control group,epicardium group(group Ⅰ) and ear vein group(group Ⅱ).The BMSCs were collected from the tibial plateau in group Ⅰ and group Ⅱ,cultured and labeled.In the three groups,rabbits underwent thoracotomy and ligation of the middle left anterior descending artery.The elevation of ST segment>0.2 mV lasting for 30 minutes on the lead Ⅱ and Ⅲ of electrocardiogram suggested successful introduction of myocardial infarction.Two weeks after myocardial infarction,rabbits in group Ⅰ were treated with autogenous BMSCs at the infarct region and those in group Ⅱ received intravenous transplantation of BMSCs.In the control group,rabbits were treated with PBS following thoracotomy.Four weeks after myocardial infarction,the heart was collected from all rabbits and the infarct size was calculated.The heart was cut into sections followed by HE staining and calculation of infarct size with an image system.RESULTS:In groups Ⅰ and Ⅱ,the infarct size was significantly reduced after transplantation with BMSCs when compared with the control group(P<0.05).However,there was no significant difference in the infarct size between groups Ⅰ and Ⅱ(P>0.05).CONCLUSION:Transplantation of BMSCs has therapeutic effect on Ml.Moreover,epicardial and intravenous transplantation of BMSCs has comparable therapeutic efficacy on myocardial infarction.

VEGF-expressing Bone Marrow Mesenchymal Stem Cells Transplantation Improved Heart Function of Myocardial Infarct Rabbits

Objectives To treat myocardial infarction with MSCs transplantation combined with VEGF gene therapy in rabbits and to study its mechanisms. Methods Forty-eight rabbits were randomly divided into MI group （n=12）, MSCs group （n=12）, VEGF group （n=12）, MSCs＋VEGF group （M＋V group, n=12）. Rabbit myocardial infarction models were founded by the ligation of left anterior descending artery. 107 MSCs were injected into the infarct-zone in four sites 2 weeks later in MSCs and M＋ V group, phVEGF gene were injected in infarct-zone in VEGF group and MSCs transfected with phVEGF gene were injected in M＋V group. Heart function including LVEDP, LVSP, LVDP, -dp/dtmax, ＋dp/dtmax, were measured in vivo. The hearts were harvested at 4 weeks after transplantation and sectioned for HE stain, immunohistochemical stain of BrdU and VIII factor antigen. Results The left ventricular hemodynamics parameters showed that heart function were improved more in M＋V group than MSCs group, MI group and VEGF group. The numbers of BrdU positive cells in M＋ V group（61±8）were more than in MSCs group （44±8, P 〈 0.01）. The numbers of vessels in infarcted zone were more in M＋V group （49±8） than in MSCs group （33±6, P 〈 0.01）,VEGF group（30±8, P 〈 0.01）and Mlgroup （18±4, P〈0.01）. Conclusions VEGF-expressing MSCs transplantation could improve heart function after myocardial infarction, and they were more effective than sole MSCs transplantation. Keeping more MSCs survival and ameliorating the blood supply of infarct-zone might be involved in the mechanisms.

Human bone marrow-derived mesenchymal stem cells transplanted into damaged rabbit heart to improve heart function

Objective: The present study was designed to test whether transplantation of human bone marrow-derived mesen- chymal stem cells (hMSCs) in New Zealand rabbits with myocardial infarction can improve heart function; and whether engrafted donor cells can survive and transdifferentiated into cardiomyocytes. Methods: Twenty milliliters bone marrow was obtained from healthy men by bone biopsy. A gradient centrifugation method was used to separate bone marrow cells (BMCs) and red blood cells. BMCs were incubated for 48 h and then washed with phosphate-buffered saline (PBS). The culture medium was changed twice a week for 28 d. Finally, hematopoietic cells were washed away to leave only MSCs. Human MSCs (hMSCs) were premarked by BrdU 72 h before the transplantation. Thirty-four New Zealand rabbits were randomly divided into myocardial infarction (MI) control group and cell treated group, which received hMSCs (MI+MSCs) through intramyocardial injection, while the control group received the same volume of PBS. Myocardial infarction was induced by ligation of the left coronary artery. Cell treated rabbits were treated with 5×106 MSCs transplanted into the infarcted region after ligation of the coronary artery for 1 h, and the control group received the same volume of PBS. Cyclosporin A (oral solution; 10 mg/kg) was provided alone, 24 h before surgery and once a day after MI for 4 weeks. Echocardiography was measured in each group before the surgery and 4 weeks after the surgery to test heart function change. The hearts were harvested for HE staining and immunohistochemical studies after MI and cell transplantation for 4 weeks. Results: Our data showed that cardiac function was significantly improved by hMSC transplan- tation in rabbit infarcted hearts 4 weeks after MI (ejection fraction: 0.695±0.038 in the cell treated group (n=12) versus 0.554±0.065 in the control group (n=13) (P<0.05). Surviving hMSCs were identified by BrdU positive spots in infarcted region and transdifferentiated into cardiomyocytes characterized with a positive cardiac phenotype: troponin I. Conclusion: Transplan- tation of hMSCs could transdifferentiate into cardiomyocytes and regenerate vascular structures, contributing to functional im- provement.

Allograftic bone marrow-derived mesenchymal stem cells transplanted into heart infarcted model of rabbit to renovate infarcted heart

Objective: To investigate the directed transplantation of allograftic bone marrow-derived mesenchymal stem cells (MSCs) in myocardial infarcted (MI) model rabbits. Materials and Methods: Rabbits were divided into 3 groups, heart infarcted model with MSCs transplanted treatment (MSCs group, n=12), heart infarcted model with PBS injection (control group, n=20), sham operation with PBS injection (sham group, n=17). MSCs labelled by BrdUrd were injected into the MI area of the MSCs group. The same volume of PBS was injected into the MI area of the control group and sham group. The mortality, LVIDd, LVIDs and LVEF of the two groups were compared 4 weeks later. Tropomyosin inhibitory component (Tn I) and BrdUrd immunohistochemistry identified the engrafted cells 4 weeks after transplantation. Result: The mortality of the MSCs group was 16.7% (2/12), and remarkably lower than the control group's mortality [35% (7/20) (P<0.05)]. Among the animals that survived for 4 weeks, the LVIDd and LVIDs of the MSCs group after operation were 1.17±0.21 cm and 0.74±0.13 cm, and remarkably lower than those of the model group, which were 1.64±0.14 cm and 1.19±0.12 cm (P<0.05); the LVEF of the MSCs group after operation was 63±6%, and remarkably higher than that of the model group, which was 53±6% (P<0.05). Among the 10 cases of animals that survived for 4 weeks in the MSCs group, in 8 cases (80%), the transplanted cells survived in the non MI, MI region and its periphery, and even farther away; part of them differentiated into cardiomyocytes; in 7 cases (70%), the transplanted cells participated in the formation of blood vessel tissue in the MI region. Conclusion: Transplanted allograftic MSCs can survive and differentiate into cardiomyocytes, form the blood vessels in the MI region. MSCs transplantation could improve the heart function after MI.

The mechanism by which exosomes derived from bone marrow mesenchymal stem cells promote the regeneration of renal tubules in acute kidney injury through the regulation of the PTEN signaling pathway by miR-21

Acute kidney injury(AKI)is a significant global health issue with limited current treatment options.This study focused on the mechanism by which exosomes derived from bone marrow mesenchymal stem cells(BMSCs)promote renal tubule regeneration in AKI through the regulation of the PTEN signaling pathway by miR-21.BMSCs were isolated and characterized,and their exosomes were purified.In vitro,renal tubular epithelial cell injury models were established,and the co-culture of exosomes and cells demonstrated enhanced cell proliferation and reduced apoptosis.In vivo,AKI animal models showed improved renal function and histopathological changes after exosome treatment.miR-21 was found to be upregulated in exosomes and recipient cells,targeting PTEN and activating the PI3K/AKT pathway.The signaling network also interacted with other pathways related to renal tubule regeneration.The study highlights the potential of exosome therapy for AKI and provides insights into the underlying molecular mechanisms,although further research is needed to address remaining challenges and translate these findings into clinical applications.

Recent advances in the diagnosis and treatment of acute myocardial infarction

The Third Universal Definition of Myocardial Infarction(MI) requires cardiac myocyte necrosis with an increase and/or a decrease in a patient's plasma of cardiac troponin(cT n) with at least one cT n measurement greater than the 99 th percentile of the upper normal reference limit during:(1) symptoms of myocardialischemia;(2) new significant electrocardiogram(ECG) ST-segment/T-wave changes or left bundle branch block;(3) the development of pathological ECG Q waves;(4) new loss of viable myocardium or regional wall motion abnormality identified by an imaging procedure; or(5) identification of intracoronary thrombus by angiography or autopsy.Myocardial infarction,when diagnosed,is now classified into five types.Detection of a rise and a fall of troponin are essential to the diagnosis of acute MI.However,high sensitivity troponin assays can increase the sensitivity but decrease the specificity of MI diagnosis.The ECG remains a cornerstone in the diagnosis of MI and should be frequently repeated,especially if the initial ECG is not diagnostic of MI.There have been significant advances in adjunctive pharmacotherapy,procedural techniques and stent technology in the treatment of patients with MIs.The routine use of antiplatelet agents such as clopidogrel,prasugrel or ticagrelor,in addition to aspirin,reduces patient morbidity and mortality.Percutaneous coronary intervention(PCI) in a timely manner is the primary treatment of patients with acute ST segment elevation MI.Drug eluting coronary stents are safe and beneficial with primary coronary intervention.Treatment with direct thrombin inhibitors during PCI is non-inferior to unfractionated heparin and glycoprotein Ⅱb/Ⅲa receptor antagonists and is associated with a significant reduction in bleeding.The intra-coronary use of a glycoprotein Ⅱb/Ⅲa antagonist can reduce infarct size.Pre- and post-conditioning techniques can provide additional cardioprotection.However,the incidence and mortality due to MI continues to be high despite all these recent advances.The initial ten year experience with autologous human bone marrow mononuclear cells(BMCs) in patients with MI showed modest but significant increases in left ventricular(LV) ejection fraction,decreases in LV endsystolic volume and reductions in MI size.These studies established that the intramyocardial or intracoronary administration of stem cells is safe.However,many of these studies consisted of small numbers of patients who were not randomized to BMCs or placebo.The recent LateT ime,Time,and Swiss Multicenter Trials in patientswith MI did not demonstrate significant improvement in patient LV ejection fraction with BMCs in comparison with placebo.Possible explanations include the early use of PCI in these patients,heterogeneous BMC populations which died prematurely from patients with chronic ischemic disease,red blood cell contamination which decreases BMC renewal,and heparin which decreases BMC migration.In contrast,cardiac stem cells from the right atrial appendage and ventricular septum and apex in the SCIPIO and CADUCEUS Trials appear to reduce patient MI size and increase viable myocardium.Additional clinical studies with cardiac stem cells are in progress.

Improvement of cardiac function after transplantation of autologous bone marrow mesenchymal stem cells in patients with acute myocardial infarction

Background The infarct size determines the long-term prognosis of patients with acute myocardial infarction (AMI). There is a growing interest in repairing scar area by transplanting bone marrow stem cells. However, effectiveness of intracoronary injection of bone marrow mesenchymal stem cells (BMSCs) in patients with AMI still remains unclear.Methods Sixty-nine patients with AMI after percutaneous coronary intervention (PCI) were randomly divided into intracoronary injection of BMSCs (n=34) and saline (control group, n=35) groups. Serial single positron emission computer tomography (SPECT), cardiac echo and cardiac electromechanical mapping were done at the designed time intervals until six months after transplantation of BMSCs or injection of saline. Results The proportion with functional defect decreased significantly in the BMSCs patients after three months [(13±5)%] compared with that pre-transplantation [(32±11)%] and the control group [(28±10)%] at three month follow-up (P<0.05, respectively). Wall movement velocity over the infracted region increased significantly in the BMSCs group [(4.2±2.5) cm/s vs (2.2±1.3) cm/s, P<0.05], but not in the control group [(2.2±1.5) cm/s vs (2.7±1.7) cm/s, P>0.05]. Left ventricular ejection fraction (LVEF) three months after transplantation in BMSCs group increased significantly compared with that pre-implantation and with that of the control group at three months post-injection [(67±11)% vs (49±9)% and (53±8)%, P<0.05 respectively]. SPECT scan results showed that perfusion defect was improved significantly in BMSCs group at three-month follow-up compared with that in the control group [(134±66)cm2 vs (185±87)cm2, P<0.01]. At the same time, left ventricular end-diastolic volume [(136±31) ml vs (162±27) ml, P<0.05] and end-systolic volume [(63±20) ml vs (88±19) ml, P<0.05] decreased synchronously. The ratio of end-systolic pressure to end-systolic volume [P_ syst/ESV, (2.84±1.30) mmHg/ml vs (1.72±1.23) mmHg/ml, P<0.05] increased significantly. Cardiac electromechnical mapping demonstrated significant improvement at three months after implantation of BMSCs compared with that pre-injection in both cardiac mechanical capability as left line local shorting [LLS, (11.29±1.64)% vs (7.32± 1.86)%, P<0.05] and electrical property as left ventricular endocardial unipolar voltage [UV, (10.38±1.12) mV vs (7.61±1.09) mV, P<0.01]; perfusion defect decreased from (36.2±6.2) % to (20.3±5.31)% (P<0.01). Twenty-four-hour electrocardiographic monitoring demonstrated no arrhythmias occurred at three-months follow-up.Conclusions The transplantation of BMSCs might improve the cardiac function and it is safe and feasible with no deaths or malignant arrhythmias.

Mesenchymal stem cells improve the outcomes of liver recipients via regulating CD4*T helper cytokines in rats

BACKGROUND： Bone marrow mesenchymal stem cells （BMMSCs） exert immunosuppressive activities in transplantation. This study aimed to determine whether BMMSCs reduce acute re- jection and improve outcomes of liver transDlantation in rats.

Timing of transplantation of autologous bone marrow derived mesenchymal stem cells for treating myocardial infarction

It is still unclear whether the timing of intracoronary stem cell therapy affects the therapeutic response in patients with myocardial infarction.The natural course of healing the infarction and the presence of putative homing signals within the damaged myocardium appear to favor cell engraftment during the transendothelial passage in the early days after reperfusion.However,the adverse inflammatory environment,with its high oxidative stress,might be deleterious if cells are administered too early after reperfusion.Here we highlight several aspects of the timing of intracoronary stem cell therapy.Our results showed that transplantation of bone marrow mesenchymal stem cells at 2 4 weeks after myocardial infarction is more favorable for reduction of the scar area,inhibition of left ventricular remodeling,and recovery of heart function.Coronary injection of autologous bone marrow mesenchymal stem cells at 2 4 weeks after acute myocardial infarction is safe and does not increase the incidence of complications.

Effect of transplanted mesenchymal stem cells from rats of different ages on the improvement of heart function after acute myocardial infarction

Background Mesenchymal stem cells （MSCs） transplantation is of therapeutic potential after ischemic injury in both experimental and clinical studies. Clinically, elderly patients are more vulnerable to acute myocardial infarction （AMI）. But little is known about the characteristics of young donor-derived MSCs transplanted to old patients with AMI. The present study was designed to investigate the effect of transplanted MSCs from rats of different ages on the improvement of heart function after AMI. Methods MSCs from Sprague-Dawley （SD） rats were isolated and cultured in vitro. The apoptosis characteristics of MSCs were observed under conditions of ischemia and anoxia. SD rats underwent MI received intramyocardial injection of MSCs from young donor rats （n=-8）, old donor rats （n=-8）, respectively. AMI control group received equal volume physiological saline. Immunofluorescence was used to observe the differentiation of the grafted cells into cardiomyocytes Four weeks after cell transplantation, reverse transcriptase-polymerase chain reaction （RT-PCR） and immunohistochemistry for vascular endothelial growth factor （VEGF）, VIII-factor immunohistochemistry for vessel density, TUNEL, caspase-3 for cardiomyocyte apoptosis, echocardiography and hemodynamic detection for heart function were performed. Results The apoptosis rate of the old donor-derived MSCs group was significantly higher than that of the young donor-derived MSCs group under conditions of ischemia and anoxia （P 〈0.05）. Engrafted MSCs survived, proliferated and differentiated into myocardium-like cells. VEGF gene expression and capillary density in the old donor-derived group were lower than those in the young donor-derived group but higher than those in the control group （P 〈0.05）. The transplantation of old donor-derived MSCs attenuated apoptosis of cadiomyocytes in the peri-infract region compared with the control group and the effect was elevated in young donor-derived MSCs （P 〈0.05）. The heart functions （left ventricle ejection fraction （LVEF）, left ventricle fractional shortening （LVFS）） were improved more significantly in the old donor-derived MSCs group than in the control group and the heart function in the young donor-derived MSCs group further improved （P 〈0.05）. Conclusions Young donor-derived MSCs can improve heart function significantly through angiogenesis and decreasing cardiomyocyte apoptosis when transplanted to the infarcted area.

Granulocyte-macrophage colony stimulating factor improves cardiac function in rabbits following myocardial infarction

Objective: To investigate the therapeutic potency of recombinant human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) in a rabbit myocardial infarction model. Methods: A myocardial infarction was created by the ligation of the major ventricular branch of the left coronary artery in rabbits. After myocardial infarction, the animals were randomly assigned to GM-CSF treatment group, untreated groups and sham-operated group. The rabbits of the treated group were injected into GM-CSF by subcutaneous administration, 10 μg/kg/day, once a day for 5 days. The untreated and sham-operated group received a equal saline in the same manner as treated group. Six weeks later echocardiography and haemodynamic assessment were undertaken to assesse cardiac function. The size of the infarct region of the heart were also studied. Results: The untreated group exhibited significant higher left ventricle end-diastolic pressure, higher central venous pressure, and with significant lower mean blood pressure, lower peak first derivative of left ventricle pressure (dP/dt) than the sham group. Also, Rabbits in untreated group display significant systolic dysfunction shown by the decreased ejection fraction, diastolic dysfunction shown by increasing in the ratio of E wave to A wave (E/A), and display left ventricle enlargement. However, GS-CSF singnificantly prevented heart dysfunction, left ventricle enlargement, and reduced infarct size in treatment group. Conclusion: Administration GM-CSF after cardiac infarction can improve heart function. These findings indicate the technique may be a novel and simple therapeutic method for ischemic myocardium.