Cardiac stem cells: Current knowledge and future prospects

Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs.Since the inception of the field several decades ago,regenerative medicine therapies,namely stem cells,have received significant attention in preclinical studies and clinical trials.Apart from their known potential for differentiation into the various body cells,stem cells enhance the organ's intrinsic regenerative capacity by altering its environment,whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration.Recently,research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells(CSCs/CPCs).The global burden of cardiovascular diseases’morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy.This review will discuss the nature of each of the CSCs/CPCs,their environment,their interplay with other cells,and their metabolism.In addition,important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells.Moreover,the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration.Finally,the novel role of nanotechnology in cardiac regeneration will be explored.

New directions in cardiac stem cell therapy: An update for clinicians

The emergence of cardiac stem cell therapy can be traced to late 2001, when studies in small animal models of myocardial infarction suggested that stem cells could engraft, proliferate, and regenerate myo-cardium. Subsequent animal laboratory studies showed improved cardiac function, perfusion and survival compared to controls (Figure 1). Within two years, the first clinical trials of stem cell therapy began to appear, and we now have several trials of intracoronary infusion of bone marrow cells with more than one year follow-up. Although this clinical therapy has proven to be safe, the magnitude of improvement in objective measures like ejection fraction has been modest, and the therapy has not entered clinical practice. In the absence of a large prospective randomized trial, the field has moved back to the laboratory. This manuscript aims to provide clinicians with a broad overview of this complex field by briefly reviewing the existing status of clinical myocardial regeneration therapy, then describing selected examples from the laboratory research approaches that may provide a platform for new and potentially increasingly effective clinical strategies.

Stem cell therapies in cardiac diseases: Current status and future possibilities

Cardiovascular diseases represent the world’s leading cause of death. In thisheterogeneous group of diseases, ischemic cardiomyopathies are the mostdevastating and prevalent, estimated to cause 17.9 million deaths per year.Despite all biomedical efforts, there are no effective treatments that can replacethe myocytes lost during an ischemic event or progression of the disease to heartfailure. In this context, cell therapy is an emerging therapeutic alternative to treatcardiovascular diseases by cell administration, aimed at cardiac regeneration andrepair. In this review, we will cover more than 30 years of cell therapy in cardiology,presenting the main milestones and drawbacks in the field and signalingfuture challenges and perspectives. The outcomes of cardiac cell therapies arediscussed in three distinct aspects: The search for remuscularization byreplacement of lost cells by exogenous adult cells, the endogenous stem cell era,which pursued the isolation of a progenitor with the ability to induce heart repair,and the utilization of pluripotent stem cells as a rich and reliable source ofcardiomyocytes. Acellular therapies using cell derivatives, such as microvesiclesand exosomes, are presented as a promising cell-free therapeutic alternative.

Hypoxia-stressed cardiomyocytes promote early cardiac differentiation of cardiac stem cells through HIF-1α/Jagged1/Notch1 signaling

Hypoxia is beneficial for the differentiation of stem cells transplanted for myocardial injury,but mechanisms underlying this benefit remain unsolved. Here, we report the impact of hypoxia-induced Jagged1 expression in cardiomyocytes(CMs) for driving the differentiation of cardiac stem cells(CSCs).Forced hypoxia-inducible factor 1α(HIF-1α) expression and physical hypoxia(5% O_2) treatment could induce Jagged1 expression in neonatal rat CMs. Pharmacological inhibition of HIF-1α by YC-1 attenuated hypoxia-promoted Jagged1 expression in CMs. An ERK inhibitor(PD98059), but not inhibitors of JNK(SP600125), Notch(DAPT), NF-κB(PTDC), JAK(AG490), or STAT3(Stattic) suppressed hypoxiainduced Jagged1 protein expression in CMs. c-Kit^+ CSCs isolated from neonatal rat hearts using a magnetic-activated cell sorting method expressed GATA4, SM22α or vWF, but not Nkx2.5 and cTnI.Moreover, 87.3% of freshly isolated CSCs displayed Notch1 receptor expression. Direct co-culture of CMs with BrdU-labeled CSCs enhanced CSCs differentiation, as evidenced by an increased number of BrdU^+/Nkx2.5^+ cells, while intermittent hypoxia for 21 days promoted co-culture-triggered differentiation of CSCs into CM-like cells. Notably, YC-1 and DAPT attenuated hypoxia-induced differentiation.Our results suggest that hypoxia induces Jagged1 expression in CMs primarily through ERK signaling,and facilitates early cardiac lineage differentiation of CSCs in CM/CSC co-cultures via HIF-1α/Jagged1/Notch signaling.

“Second-generation” stem cells for cardiac repair

Over the last years, stem cell therapy has emerged asan inspiring alternative to restore cardiac function after myocardial infarction. A large body of evidence has been obtained in this field but there is no conclusive data on the efficacy of these treatments. Preclinical studies and early reports in humans have been encouraging and have fostered a rapid clinical translation, but positive results have not been uniformly observed and when present, they have been modest. Several types of stem cells, manufacturing methods and delivery routes have been tested in different clinical settings but direct comparison between them is challenging and hinders further research. Despite enormous achievements, major barriers have been found and many fundamental issues remain to be resolved. A better knowledge of the molecular mechanisms implicated in cardiac development and myocardial regeneration is critically needed to overcome some of these hurdles. Genetic and pharmacological priming together with the discovery of new sources of cells have led to a "second generation" of cell products that holds an encouraging promise in cardiovascular regenerative medicine. In this report, we review recent advances in this field focusing on the new types of stem cells that are currently being tested in human beings and on the novel strategies employed to boost cell performance in order to improve cardiac function and outcomes after myocardial infarction.

Cardiac disease modeling using induced pluripotent stem cell-derived human cardiomyocytes

Causative mutations and variants associated with cardiac diseases have been found in genes encoding cardiac ion channels, accessory proteins, cytoskeletal components, junctional proteins, and signaling molecules. In most cases the functional evaluation of the genetic alterationhas been carried out by expressing the mutated proteins in in-vitro heterologous systems. While these studies have provided a wealth of functional details that have greatly enhanced the understanding of the pathological mechanisms, it has always been clear that heterologous expression of the mutant protein bears the intrinsic limitation of the lack of a proper intracellular environment and the lack of pathological remodeling. The results obtained from the application of the next generation sequencing technique to patients suffering from cardiac diseases have identified several loci, mostly in non-coding DNA regions, which still await functional analysis. The isolation and culture of human embryonic stem cells has initially provided a constant source of cells from which cardiomyocytes(CMs) can be obtained by differentiation. Furthermore, the possibility to reprogram cellular fate to a pluripotent state, has opened this process to the study of genetic diseases. Thus induced pluripotent stem cells(i PSCs) represent a completely new cellular model that overcomes the limitations of heterologous studies. Importantly, due to the possibility to keep spontaneously beating CMs in culture for several months, during which they show a certain degree of maturation/aging, this approach will also provide a system in which to address the effect of long-term expression of the mutated proteins or any other DNA mutation, in terms of electrophysiological remodeling. Moreover, since i PSC preserve the entire patients' genetic context, the system will help the physicians in identifying the most appropriate pharmacological intervention to correct the functional alteration. This article summarizes the current knowledge of cardiac genetic diseases modelled with i PSC.

Magnetic resonance imaging tracing of transplanted bone marrow mesenchymal stem cells in a rat model of cardiac arrest-induced global brain ischemia

BACKGROUND： Numerous studies have shown that magnetic resonance imaging （MRI） can detect survival and migration of super paramagnetic iron oxide-labeled stem cells in models of focal cerebral infarction. OBJECTIVE： To observe distribution of bone marrow mesenchymal stem cells （BMSCs） in a rat model of global brain ischemia following cardiac arrest and resuscitation, and to investigate the feasibility of tracing iron oxide-labeled BMSCs using non-invasive MRI. DESIGN, TIME AND SETTING： The randomized, controlled, molecular imaging study was performed at the Linbaixin Medical Research Center, Second Affiliated Hospital, Sun Yat-sen University, and the Institute of Cardiopulmonary Cerebral Resuscitation, Sun Yat-sen University, China from October 2006 to February 2009. MATERIALS： A total of 40 clean, Sprague Dawley rats, aged 6 weeks and of either gender, were supplied by the Experimental Animal Center, Sun Yat-sen University, China, for isolation of BMSCs. Feridex （iron oxide）, Gyroscan Inetra 1.5T MRI system, and cardiopulmonary resuscitation device were used in this study. METHODS： A total of 30 healthy, male Sprague Dawiey rats, aged 6 months, were used to induce ventricular fibrillation using alternating current. After 8 minutes, the rats underwent 6-minute chest compression and mechanical ventilation, followed by electric defibrillation, to establish rat models of global brain ischemia due to cardiac arrest and resuscitation. A total of 24 successful models were randomly assigned to Feridex-labeled and non-labeled groups （n = 12 for each group）. At 2 hours after resuscitation, 5 ×10^8 Feridex-labeled BMSCs, with protamine sulfate as a carrier, and 5 ×10^6 non-labeled BMSCs were respectively transplanted into both groups of rats through the right carotid artery （cells were harvested in 1 mL phosphate buffered saline）. MAIN OUTCOME MEASURES： Feridex-labeled BMSCs were observed by Prussian blue staining and electron microscopy. Signal intensity, celluar viability, and proliferative capacity of BMSCs were measured using MRI, Trypan blue test, and M-IT assay, respectively. Distribution of transplanted cells was observed in rats utilizing MRI and Prussian blue staining prior to and 1, 3, 7, and 14 days after transplantation. RESULTS： Prussian blue staining displayed many blue granules in the Feridex-labeled BMSCs. High density of iron granules was observed in the cytoplasm under electron microscopy. According to MRI results, and compared with the non-labeled group, the signal intensity was decreased in the Feridex-labeled group （P 〈 0.05）. The decrease was most significant in the 50 pg/mL Feridex-labeled group （P 〈 0.01）. There were no significant differences in celluar viability and proliferation of BMSCs between the Feridex-labeled and non-labeled groups after 1 week （P 〉 0.05）. Low-signal lesions were detected in the rat hippocampus and temporal cortex at 3 days after transplantation. The low-signal lesions were still detectable at 14 days, and positively stained cells were observed in the hippocampus and temporal cortex using Prussian blue staining. There were no significant differences in signal intensity in the non-labeled group. CONCLUSION： BMSC transplantation traversed the blood-brain barrier and distributed into vulnerable zones in a rat model of cardiac arrest-induced global brain ischemia. MRI provided a non-invasive method to in vivo dynamically and spatially trace Feridex-labeled BMSCs after transplantation.

In Vitro Study on Mesenchymal Stem Cells:Anti-apoptotic Effects on Cardiac Myocytes

Objectives To investigate the anti-apoptotic effects of mesenchymal stem cells （MSCs） on hypoxic injured cardiac myocytes in vitro. Methods MSCs were isolated from bone marrow of Sprague-Dawley （SD） rats, and cardiac myocytes from neonatal rats. The rat cardiac myocytes were co-cultured with MSCs or MSC-conditioned media in anoxia （95% N2 ±5% CO2） for 72 hours. Cell apoptosis was measured by Hoechst 33258 staining. The expression of Bcl-2 and Bax in cardiac myocytes was tested by Western Blot. Results The apoptotic rate was 51.6% ± 2.4% when cardiac myocytes were cultured in continuous hypoxia and was significantly decreased when cardiac myocytes were cocultured with MSCs or MSC-conditioned media （ 15.1% ± 5.4% and 24. 0% ± 4.2% respectively, P 〈 0. 001 ）. The decreased expression of Bax in the cardiac myocytes was greatly related to the decreasing of apoptosis, but there was no difference in Bcl-2 expression among these groups. Conclusions Co-cultured MSCs showed significant anti-apoptotic effects on cardiac myocytes in continuous hypoxia. The mechanism may be the interact of cell to cell and paracrine of cytokines which effected the expression of Bax in the cardiac myocytes.

Pursuing meaningful end-points for stem cell therapy assessment in ischemic cardiac disease

Despite optimal interventional and medical therapy, ischemic heart disease is still an important cause of morbidity and mortality worldwide. Although not included in standard of care rehabilitation, stem cell therapy(SCT) could be a solution for prompting cardiac regeneration. Multiple studies have been published from the beginning of SCT until now, but overall no unanimous conclusion could be drawn in part due to the lack of appropriate endpoints. In order to appreciate the impact of SCT, multiple markers from different categories should be considered: Structural, biological, functional, physiological, but also major adverse cardiac events or quality of life. Imaging end-points are among the most used-especially left ventricle ejection fraction(LVEF) measured through different methods. Other imaging parameters are infarct size, myocardial viability and perfusion. The impact of SCT on all of the aforementioned end-points is controversial and debatable. 2 D-echocardiography is widely exploited, but new approaches such as tissue Doppler, strain/strain rate or 3 D-echocardiography are more accurate, especially since the latter one is comparable with the MRI gold standard estimation of LVEF. Apart from the objective parameters, there are also patient-centered evaluations to reveal the benefits of SCT, such as quality of life and performance status, the most valuable from the patient point of view. Emerging parameters investigating molecular pathways such as non-coding RNAs or inflammation cytokines have a high potential as prognostic factors. Due to the disadvantages of current techniques, new imaging methods with labelled cells tracked along their lifetime seem promising, but until now only pre-clinical trials have been conducted in humans. Overall, SCT is characterized by high heterogeneity not only in preparation, administration and type of cells, but also in quantification of therapy effects.

Intravenously Injected Mesenchymal Stem Cells Home to Infarcted Myocardium Without Altering Cardiac Function

Background:Systemic delivery of mesenchymal stem cells (MSCs) to the infarcted myocardium is an attractive noninvasive strategy, but therapeutic effect of this strategy remain highly controversial. Methods: Myocardial infarction was induced in female Sprague-Dawley rats by transient ligation of the left anterior descending coronary artery for 60 min. Either 2.5×106 DiI-labeled MSCs or equivalent saline was injected into the tail vein at 24 h after infarction.Results: Three days later, MSCs localized predominantly in the infarct region of heart rather than in the remote region. MSCs were also observed in spleen, lung and liver. At 4 weeks after infarction, echocardiographic parameters, including ejection fraction, fractional shortening, left ventricular end-diastolic and end-systolic diameters, were not significantly different between MSCs and saline groups. Hemodynamic examination showed that ±dp/dtmax were similar between MSCs and saline-treated animals. Histological evaluation revealed that infarct size and vessel density were not significantly changed by MSCs infusion.Conclusion: Intravenously injected MSCs can home to infarcted myocardium, but plays a limited role in cardiac repair following myocardial infarction.

The therapeutic potential of stem cell therapy for myocardial infraction

It has been researched that myocardial infarction(MI)has drastically affected patients all over the world.The current guidelines of the medical treatments including PTCA or CABG just improve the condition and reduce damage to an extent.In the new studies and recent updates on myocardial stem cells,it has been researched that myocardial stem cells have regenerative capacity.Stem cell therapy used in cardiac disease management shows a promising and novel approach for cardiac tissues,cardiac muscle repair,and regeneration.Furthermore,it’s been observed that the stem cell-derived paracrine factors help in regulating and remodeling the coronary artery inflammation and cardiac tissue generation in the MI region.Here,we highlight recent findings and discuss how they use stem cell therapy during MI and heart disease.

How do resident stem cells repair the damaged myocardium?

It has been a decade since the monumental discovery of resident stem cells in the mammalian heart, and the following studies witnessed the continuous turnover of cardiomyocytes and vascular cells, maintaining the homeostasis of the organ. Recently, the autologous administration of c-kit-positive cardiac stem cells in patients with ischemic heart failure has led to an incredible outcome; the left ventricular ejection fraction of the celltreated group improved from 30% at the baseline to 38% after one year and to 42% after two years of cell injection. The potential underlying mechanisms, before and after cell infusion, are explored and discussed in this article. Some of them are related to the intrinsic property of the resident stem cells, such as direct differentiation, paracrine action, and immunomodulatory function, whereas others involve environmental factors, leading to cellular reverse remodeling and to the natural selection of "juvenile" cells. It has now been demonstrated that cardiac stem cells for therapeutic purposes can be prepared from tiny biopsied specimens of the failing heart as well as from frozen tissues, which may remarkably expand the repertoire of the strategy against various cardiovascular disorders, including non-ischemic cardiomyopathy and congenital heart diseases. Further translational investigations are needed to explore these possibilities.

Stem cell-derived exosomes-an emerging tool for myocardial regeneration

Cardiovascular diseases(CVDs) continue to represent the number one cause of death and disability in industrialized countries. The most severe form of CVD is acute myocardial infarction(AMI), a devastating disease associated with high mortality and disability. In a substantial proportion of patients who survive AMI, loss of functional cardiomyocytes as a result of ischaemic injury leads to ventricular failure, resulting in significant alteration to quality of life and increased mortality. Therefore, many attempts have been made in recent years to identify new tools for the regeneration of functional cardiomyocytes. Regenerative therapy currently represents the ultimate goal for restoring the function of damaged myocardium by stimulating the regeneration of the infarcted tissue or by providing cellsthat can generate new myocardial tissue to replace the damaged tissue. Stem cells(SCs) have been proposed as a viable therapy option in these cases. However, despite the great enthusiasm at the beginning of the SC era, justified by promising initial results, this therapy has failed to demonstrate a significant benefit in large clinical trials. One interesting finding of SC studies is that exosomes released by mesenchymal SCs(MSCs) are able to enhance the viability of cardiomyocytes after ischaemia/reperfusion injury, suggesting that the beneficial effects of MSCs in the recovery of functional myocardium could be related to their capacity to secrete exosomes. Ten years ago, it was discovered that exosomes have the unique property of transferring miRNA between cells, acting as miRNA nanocarriers. Therefore, exosomebased therapy has recently been proposed as an emerging tool for cardiac regeneration as an alternative to SC therapy in the post-infarction period. This review aims to discuss the emerging role of exosomes in developing innovative therapies for cardiac regeneration as well as their potential role as candidate biomarkers or for developing new diagnostic tools.

5-Azacytidine induces changes in electrophysiological properties of human mesenchymal stem cells

以前，导出髓的干细胞(MSC ) 与不确定的脱氧核糖核酸甲基转移酶禁止者 5-azacytidine 对待的老鼠骨头被报导区分 intocardiomyocytes。现在的学习的目的是在从健康骨髓施主获得的人的单音的原子房间调查类似的区别策略的效率。After1-3 段落，文化为 24 h 暴露于到 6 星期进一步的文化跟随的 5-azacytidine (3 mciroM ) 。药处理没导致 myogenic 标记 MyoD 或心脏的 markersNkx2.5 和 GATA-4 的表示并且没在后续期间产出跳动的房间。在补丁夹钳实验，近似 10-15% 对待，未经治疗的房间展出了 L 类型 Ca (2+) 水流。几乎所有房间表面地出现了修正快速或慢的激活动力学的 K (+) 水流。在与匹配时间的控制相比在 6 星期处理以后加倍的 +60 mV 意味着当前的振幅。对待的房间的 Membranecapacitance 比在在处理以后的 controls2 星期内显著地大并且在 6 个星期以后仍然保持高。为 K (+) 隧道 Kv1.1， Kv1.5， Kv2.1， Kv4.3 和 KCNMA1 并且为 Ca (2+) 隧道 Ca (v) 的 mRNAs 的表示层次 1.2 没被 5-azacytidine 影响。在以前显示出禁止 hMSC 的快速或慢慢地激活的 K (+) 水流的集中的 Treatmentwith 钾隧道块 ers tetraethylammonium 和 clofilium 禁止了这些房间的增长。我们的结果建议尽管有进 cardiomyocytes 的 hMSC 的区别的缺席，有 5-azacytidine 的处理在当前的密度引起了深刻变化。

Cardiogenic differentiation of mesenchymal stem cells on elastomeric poly (glycerol sebacate)/collagen core/shell fibers

AIM: To facilitate engineering of suitable biomaterials to meet the challenges associated with myocardial infarction. METHODS: Poly (glycerol sebacate)/collagen (PGS/ collagen) core/shell fibers were fabricated by core/ shell electrospinning technique, with core as PGS and shell as collagen polymer; and the scaffolds were characterized by scanning electron microscope (SEM), fourier transform infrared spectroscopy (FTIR), contact angle and tensile testing for cardiac tissue engineering. Collagen nanofibers were also fabricated by electrospinning for comparison with core/shell fibers. Studies on cell-scaffold interaction were carriedout using cardiac cells and mesenchymal stem cells (MSCs) co-culture system with cardiac cells and MSCs separately serving as positive and negative controls respectively. The co-culture system was characterized for cell proliferation and differentiation of MSCs into cardiomyogenic lineage in the co-culture environment using dual immunocytochemistry. The co-culture cells were stained with cardiac specific marker proteins like actinin and troponin and MSC specific marker protein CD 105 for proving the cardiogenic differentiation of MSCs. Further the morphology of cells was analyzed using SEM.RESULTS: PGS/collagen core/shell fibers, core is PGS polymer having an elastic modulus related to that of cardiac fibers and shell as collagen, providing natural environment for cellular activities like cell adhesion, proliferation and differentiation. SEM micrographs of electrospun fibrous scaffolds revealed porous, beadless, uniform fibers with a fiber diameter in the range of 380 ± 77 nm and 1192 ± 277 nm for collagen fibers and PGS/collagen core/shell fibers respectively. The obtained PGS/collagen core/shell fibrous scaffolds were hydrophilic having a water contact angle of 17.9 ± 4.6° compared to collagen nanofibers which had a contact angle value of 30 ± 3.2°. The PGS/collagen core/shell fibers had mechanical properties comparable to that of native heart muscle with a young's modulus of 4.24 ± 0.7 MPa, while that of collagen nanofibers was comparatively higher around 30.11 ± 1.68 MPa. FTIR spectrum was performed to confirm the functional groups present in the electrospun scaffolds. Amide Ⅰ and amide Ⅱ of collagen were detected at 1638.95 cm -1 and 1551.64 cm -1 in the electrospun collagen fibers and at 1646.22 cm -1 and 1540.73 cm -1 for PGS/collagen core/shell fibers respectively. Cell culture studies performed using MSCs and cardiac cells co-culture environment, indicated that the cellproliferation significantly increased on PGS/collagen core/shell scaffolds compared to collagen fibers and the cardiac marker proteins actinin and troponin were expressed more on PGS/collagen core/shell scaffolds compared to collagen fibers alone. Dual immunofluorescent staining was performed to further confirm the cardiogenic differentiation of MSCs by employing MSC specific marker protein, CD 105 and cardiac specific marker protein, actinin. SEM observations of cardiac cells showed normal morphology on PGS/collagen fibers and providing adequate tensile strength for the regeneration of myocardial infarction. CONCLUSION: Combination of PGS/collagen fibers and cardiac cells/MSCs co-culture system providing natural microenvironments to improve cell survival and differentiation, could bring cardiac tissue engineering to clinical application.

Transdifferentiation of Fetal Liver-delivered Mesenchymal Stem Cells into Cardiomyocyte-like Cells

Objectives To explore the possibility to induce mesenchymal stem cells from human fetal livers （FMSCs） to differentiate along cardiac lineage and the way to obtain high rate of differentiation. Methods Cells from passage 6-9 were plated at the density of 1.5 × 10^4/cm^2 and were treated with the combination of 5-azacytine（5-aza）, retinoitic acid（RA） and Dimethylsulfoxide （DMSO） in different doses when near confluence. 24 hours later, the treatment was removed by changing into normal medium without inducers. Different culture conditions were tried, including temperature, oxygen content and medium. Results When FMSCs were treated with highdose combination （ 5-aza 50 μM ＋RA 10-1 μM ＋ DMSO 1%） and modified combination（5-aza 50 μM ＋RA 10-3 μM ＋ DMSO 0.8 %） in cardiac differentiation medium （CDM）, at 37℃ and 20% 02, the cardiac differentiation was induced. When near confluence, cells became round and tended to gather together to form ball-like structures. 3 weeks after treatment, the cells were harvested and stained with anti-desmin and cardiac troponin I antibodies, and about 40% of the cells were positively stained. No beating cells observed during observation. Conclusions FMSCs cardiac have lineage the potential to differentiate along , and the stimulus for the cardiac differentiation is different from those for MSCs from different species.

Cardiotrophin-1 promotes cardiomyocyte differentiation from mouse induced pluripotent stem cells via JAK2/STAT3/Pim-1 signaling pathway

BackgroundThe 导致了 pluripotent 干细胞(iPSC ) 在心肌的梗塞(MI ) 的细胞的治疗显示出大潜力，当它的申请被 cardiomyocyte 区别的低效率妨碍时。现在的学习被设计从老鼠在 cardiomyocyte 区别上调查 cardiotrophin-1 ( CT-1 )的效果导致的 pluripotent 干细胞( miPSCs )和内在的机制 involved.MethodsThe 为从 miPSCs 的 cardiomyocyte 区别的最佳的治疗状况与理想的集中( 10 ng/mL )和持续时间被建立(从到白天的白天 3 14 ) CT-1 管理。说明了胚胎的 cardiogenesis 的心脏的特定的基因的起来调整的表示被量的 RT-PCR 观察。 &#x003b1 的提高的数量；肌浆球蛋白重链( &#x003b1 ；-MHC)和心脏的 troponin 我( cTn 我)积极房间被 immunofluorescence 在显微镜的分析揭示了的 CT-1 group.ResultsTransmission 电子染色和流动 cytometry 分析检测与 CT-1 对待的房间更好出现了，这组织了 sacromeric 结构和更多线粒体，它是成熟 cardiomyocytes 的词法特征。当与控制 group.ConclusionsThese 相比调查结果建议 CT-1 能提高 cardiomyocyte 区别以及导致的 pluripotent 干细胞导出的老鼠的成熟，西方的污点证明 CT-1 经由 JAK2/STAT3/Pim-1 小径部分从 miPSCs 支持 cardiomyocyte 区别由调整 JAK2/STAT3/Pim-1signaling 的 cardiomyocytes 小径。

Safety and effect of umbilical cord blood -derived mesenchymal stem cells on apoptosis of human cardiomyocytes

学习脐的绳索血(UCB ) 的安全和效果的目的在人的 cardiomyocytes (HCM ) 的 apoptosis 上导出间充质的干细胞(MSC ) 。方法 UCB 在交货的时候被收集，知情同意从 10donors .The 获得了 导出UCB 的 MSC 与 5-azaserube ( 5-AZA )被对待并且进一步被导致区分活动进 cardiomyocytes.Telomerase ， chromosomal karyotypes 的 乐队G 模式，在裸体老鼠的肿瘤形成， RT-PCR ，并且禁止 HCM 的 apoptosis 的效果被调查。从 UCB 导出的结果 MSC 在 vitro 被区分进 cardiomyocytes ，它在 5-AZA 正式就职以后拥有了 telomerase 活动，并且没有反常 chromosomal karyotypes 是 p53 的 observed.Expression ， cyclin A ， cdk2 ，在 5-AZA treatment.There 不是在裸体老鼠的肿瘤形成前后，在 导出UCB 的 导出MSCs.UCB 的 MSC 的注射显著地禁止了 HCM 的 apoptosis 以后， -actin,C-fos,h-TERT 和 c-myc 在 MSC 是类似的。结论导出 UCB 的 MSC 是房间移植处理的珍贵、安全、有效的来源。