Stem-cell therapy for cardiac disease

Heart failure is the leading cause of death worldwide, and current therapies only delay progression of the disease. Laboratory experiments and recent clinical trials suggest that cell-based therapies can improve cardiac function, and the implications of this for cardiac regeneration are causing great excitement. Bone-marrow-derived progenitor cells and other progenitor cells can differentiate into vascular cell types, restoring blood flow. More recently, resident cardiac stem cells have been shown to differentiate into multiple cell types present in the heart, including cardiac muscle cells, indicating that the heart is not terminally differentiated. These new findings have stimulated optimism that the progression of heart failure can be prevented or even reversed with cell-based therapy.     

诱导多能干细胞与心脏再生

诱导多能干细胞(induced pluripotent stem cells, iPSCs)研究的快速发展为心血管转化医学研究领域提供了新的策略. 诱导多能干细胞不仅具有与胚胎干细胞类似的多能性, 且巧妙地回避了胚胎干细胞面临的伦理学问题和免疫排斥反应. 心肌细胞等成体心血管细胞在发生心血管疾病后增殖能力有限, 而iPSCs 来源的心血管细胞在心脏再生治疗中颇具应用前景,是理想的细胞来源, 因此在基础医学和转化医学研究领域受到广泛关注. 就iPSCs 的发展过程及其在心脏再生中的应用作一综述, 并探讨目前iPSCs 在心脏再生临床转化中亟待解决的问题.     

Myocyte renewal and ventricular remodelling.

Remaining young at heart is a desirable but elusive goal. Unbeknown to us, however, myocyte regeneration may accomplish just that. Continuous cell renewal in the adult myocardium was thought to be impossible, but multipotent cardiac stem cells may be able to renew the myocardium and, under certain circumstances, can be coaxed to repair the broken heart after infarction.     

用于“治疗性克隆”人胚胎干细胞研究面临的问题与可能的解决办法

利用培育的干细胞(SC)来实现组织再生和器官修复对于许多重大疾病如糖尿病、心脏疾病、老年性痴呆(AD)、帕金森病(PD)、神经损伤等的治疗具有重要意义,同时也是新药研发的重要工具.使用体细胞核转移技术(SCNT)克隆人类早期胚胎和提取干细胞,即所谓的"治疗性克隆"(Therapeutic cloning)技术,是目前进行干细胞个性化治疗的重要手段,具有广泛的临床应用前景.通过这种方法获得人胚胎干细胞的研究尚处于基础阶段,仍面临着许多有待解决的科学问题和技术挑战.在此主要就用于"治疗性克隆"人胚胎干细胞的研究进展做了简要综述,着重探讨了在该研究领域面临的主要困难,特别是在获得人成熟卵细胞方面,并提出了可能的解决办法.     

心力衰竭对QT间期变异性的影响

探讨QT间期变异性在心力衰竭中的意义。对17例心力衰竭患者、22例无心力衰竭者进行动态心电图检查，并进行QT间期动态分析。结果显示，心力衰竭组的QT间期变异性（QTV）明显大于无心力衰竭组，心力衰竭影响QT间期变异性。     

Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts

The mammalian heart has a very limited regenerative capacity and, hence, heals by scar formation. Recent reports suggest that haematopoietic stem cells can transdifferentiate into unexpected phenotypes such as skeletal muscle, hepatocytes, epithelial cells, neurons, endothelial cells and cardiomyocytes, in response to tissue injury or placement in a new environment. Furthermore, transplanted human hearts contain myocytes derived from extra-cardiac progenitor cells, which may have originated from bone marrow. Although most studies suggest that transdifferentiation is extremely rare under physiological conditions, extensive regeneration of myocardial infarcts was reported recently after direct stem cell injection, prompting several clinical trials. Here, we used both cardiomyocyte-restricted and ubiquitously expressed reporter transgenes to track the fate of haematopoietic stem cells after 145 transplants into normal and injured adult mouse hearts. No transdifferentiation into cardiomyocytes was detectable when using these genetic techniques to follow cell fate, and stem-cell-engrafted hearts showed no overt increase in cardiomyocytes compared to sham-engrafted hearts. These results indicate that haematopoietic stem cells do not readily acquire a cardiac phenotype, and raise a cautionary note for clinical studies of infarct repair.     

Germ-layer and lineage-restricted stem/progenitors regenerate the mouse digit tip

The regrowth of amputated limbs and the distal tips of digits represent models of tissue regeneration in amphibians, fish and mice. For decades it had been assumed that limb regeneration derived from the blastema, an undifferentiated pluripotent cell population thought to be derived from mature cells via dedifferentiation. Here we show that a wide range of tissue stem/progenitor cells contribute towards the restoration of the mouse distal digit. Genetic fate mapping and clonal analysis of individual cells revealed that these stem cells are lineage restricted, mimicking digit growth during development. Transplantation of cyan-fluorescent-protein-expressing haematopoietic stem cells, and parabiosis between genetically marked mice, confirmed that the stem/progenitor cells are tissue resident, including the cells involved in angiogenesis. These results, combined with those from appendage regeneration in other vertebrate subphyla, collectively demonstrate that tissue stem cells rather than pluripotent blastema cells are an evolutionarily conserved cellular mode for limb regeneration after amputation.     

Live imaging of stem cell and progeny behaviour in physiological hair-follicle regeneration

Tissue development and regeneration depend on cell-cell interactions and signals that target stem cells and their immediate progeny. However, the cellular behaviours that lead to a properly regenerated tissue are not well understood. Using a new, non-invasive, intravital two-photon imaging approach we study physiological hair-follicle regeneration over time in live mice. By these means we have monitored the behaviour of epithelial stem cells and their progeny during physiological hair regeneration and addressed how the mesenchyme influences their behaviour. Consistent with earlier studies, stem cells are quiescent during the initial stages of hair regeneration, whereas the progeny are more actively dividing. Moreover, stem cell progeny divisions are spatially organized within follicles. In addition to cell divisions, coordinated cell movements of the progeny allow the rapid expansion of the hair follicle. Finally, we show the requirement of the mesenchyme for hair regeneration through targeted cell ablation and long-term tracking of live hair follicles. Thus, we have established an in vivo approach that has led to the direct observation of cellular mechanisms of growth regulation within the hair follicle and that has enabled us to precisely investigate functional requirements of hair-follicle components during the process of physiological regeneration.     

缺血性心脏病和扩张型心肌病患者心肺运动负荷研究

 缺血性心脏病是心力衰竭的常见病因,峰运动VO2已经广泛用于心力衰竭患者心脏储备能力的评估。本研究通过心肺运动试验（Cardiopulmonary Exercise Test,CPET）心脏储备指数、通气效能指数来评价缺血性心脏病和扩张型心肌病的心衰患者运动心肺储备功能变化。选择170例心力衰竭病人（包括100 例缺血性心脏病、70例扩张型心肌病患者）及75例正常人,进行症状限制性CPET。于运动前、运动高峰和运动后,分别测定心率和血压、峰氧耗量（Peak VO2）和VO2与预测最大VO2比例、无氧代谢阀、VE/VCO2斜率（通气效能指数）。结果显示,缺血性心脏病和扩张型心肌病患者左室射血分数相似,血压和静态心率无明显差异, 运动心率明显下降,峰氧摄取量、无氧阈值、VE/VCO2斜率与扩张型心肌病患者相比有显著差别（P＜0.05）,峰心率明显低于扩张性心肌病。但峰氧耗量/预测峰氧耗量比例无明显差别。45例病人运动心率未达到标准。研究表明,缺血性心脏病患者心肺运动负荷测定的运动高峰VO2、无氧阀值及VE/VCO2斜率提示缺血性心脏病患者运动时通气效能和运动耐力下降比扩张型心肌病患者更为显著。     

Tackling heart failure in the twenty-first century

Heart failure, or congestive heart failure, is a condition in which the heart cannot supply the body's tissues with enough blood. The result is a cascade of changes that lead to severe fatigue, breathlessness and, ultimately, death. In the past quarter century, much progress has been made in understanding the molecular and cellular processes that contribute to heart failure, leading to the development of effective therapies. Despite this, chronic heart failure remains a major cause of illness and death. And because the condition becomes more common with increasing age, the number of affected individuals is rising with the rapidly ageing global population. New treatments that target disease mechanisms at the cellular and whole-organ level are needed to halt and reverse the devastating consequences of this disease.     

Stem-cell ageing modified by the cyclin-dependent kinase inhibitor p16INK4a

Stem-cell ageing is thought to contribute to altered tissue maintenance and repair. Older humans experience increased bone marrow failure and poorer haematologic tolerance of cytotoxic injury. Haematopoietic stem cells (HSCs) in older mice have decreased per-cell repopulating activity, self-renewal and homing abilities, myeloid skewing of differentiation, and increased apoptosis with stress. Here we report that the cyclin-dependent kinase inhibitor p16INK4a, the level of which was previously noted to increase in other cell types with age, accumulates and modulates specific age-associated HSC functions. Notably, in the absence of p16INK4a, HSC repopulating defects and apoptosis were mitigated, improving the stress tolerance of cells and the survival of animals in successive transplants, a stem-cell-autonomous tissue regeneration model. Inhibition of p16INK4a may ameliorate the physiological impact of ageing on stem cells and thereby improve injury repair in aged tissue.     

杂交狼尾草不同外植体材料组织培养实验

选用杂交狼尾草的茎节(带侧芽)、茎段、心叶和嫩叶作为实验材料,通过对其在组织培养中愈伤组织诱导和植株再生的情况进行比较研究,从而筛选出较合适的组培外植体材料.结果表明:杂交狼尾草不同外植体状态在愈伤组织诱导和植株再生上有较大的差异.茎节和心叶的愈伤组织诱导率明显高于茎段;茎段和嫩叶的愈伤组织诱导率没明显差异.茎节的植株再生率最高,为最佳的杂交狼尾草组培外植体材料.     

涡虫成体干细胞研究进展

干细胞研究是当代生命科学研究的重点和热点之一,涡虫因具有结构简单、再生速度快、基因与脊椎动物同源性高等特点而成为研究再生的良好动物模型.涡虫的这种再生能力与其体内具有被称为neoblasts的多能干细胞群有关.文中结合近几年的研究成果从neoblasts与涡虫的再生关系、neoblasts的分子标记及研究方法3个方面进行综述,以促进neoblasts的研究.     

甲亢性心脏病(附37例报告)

37例甲亢性心脏病的临床表现,心脏增大者17例(45.9％),ST-T变化11例(29.7％),心力衰竭3例(8.1％),心律失常3例(8.1％),心脏杂音2例(5.4％),心绞痛1例(2.7％)。40岁以上发生甲亢性心脏病比40岁以下多1.64倍。由于临床表现多样又无特异性,易与其他心脏病混淆(本组有2例误诊)。介绍一例心绞痛患者,其心跳骤停可能与服用I~(131)有关。本文还简要讨论了甲亢性心脏病与甲亢关系以及甲亢性心脏病心绞痛的特点。     

干细胞与心肌再生

由于成年心肌细胞通常不能再生,严重的心肌损伤会导致心肌不可逆的重构坏死, 从而发生心功能失调. 干细胞再生治疗为心肌再生提供了很好的策略. 为了寻找合适的干细胞类型, 促进心肌再生, 有效改善心功能, 需要更好地了解心肌修复和再生的分子基础. 已有研究发现多种干细胞可促进心肌再生. 描述了骨髓干细胞的促血管新生及心肌分化的能力在心梗治疗中的作用, 还讨论了心脏侧群干细胞以及诱导型多能干细胞在心肌再生中的作用和分子机制. 所阐述的最新数据有利于拓展干细胞治疗的有效潜能及临床影响.     

Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium

Under conditions of tissue injury, myocardial replication and regeneration have been reported. A growing number of investigators have implicated adult bone marrow (BM) in this process, suggesting that marrow serves as a reservoir for cardiac precursor cells. It remains unclear which BM cell(s) can contribute to myocardium, and whether they do so by transdifferentiation or cell fusion. Here, we studied the ability of c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells to regenerate myocardium in an infarct model. Cells were isolated from transgenic mice expressing green fluorescent protein (GFP) and injected directly into ischaemic myocardium of wild-type mice. Abundant GFP+ cells were detected in the myocardium after 10 days, but by 30 days, few cells were detectable. These GFP+ cells did not express cardiac tissue-specific markers, but rather, most of them expressed the haematopoietic marker CD45 and myeloid marker Gr-1. We also studied the role of circulating cells in the repair of ischaemic myocardium using GFP+-GFP- parabiotic mice. Again, we found no evidence of myocardial regeneration from blood-borne partner-derived cells. Our data suggest that even in the microenvironment of the injured heart, c-kit-enriched BM cells, Lin- c-kit+ BM cells and c-kit+ Thy1.1(lo) Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.     

利用内源性干细胞原位再生晶状体治疗婴幼儿白内障

 利用内源性干细胞进行组织器官的修复和再生是再生医学研究的最终目标。婴幼儿白内障是幼儿致盲性眼病的首要病因,目前尚无有效治疗手段。本研究组从哺乳动物内成功分离并获得了晶状体上皮干细胞,证明Pax6和Bmi1是维持其分化和自我更新的关键因子,并以保留内源性干细胞为目标,设计了全新的白内障术式。相较于传统术式,新术式最大程度地保留了内源性干细胞、基底膜和微环境,在新西兰兔、食蟹猴和先天性白内障患儿内实现了功能性晶状体的再生。研究结果为白内障提供了全新的治疗策略并为组织再生及内源性干细胞的应用提供了全新的范例。     

Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair

Heart disease is a leading cause of death in newborn children and in adults. Efforts to promote cardiac repair through the use of stem cells hold promise but typically involve isolation and introduction of progenitor cells. Here, we show that the G-actin sequestering peptide thymosin beta4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta4. We found that thymosin beta4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt (also known as protein kinase B). After coronary artery ligation in mice, thymosin beta4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte migration, survival and repair and the pathway it regulates may be a new therapeutic target in the setting of acute myocardial damage.     

Human embryonic stem cells-derived endothelial cell therapy facilitates kidney regeneration by stimulating renal resident stem cell proliferation in acute kidney injury

Endothelial cell therapy has been implicated to enhance tissue regeneration and vascularization in ischemic kidney. However, no published study has yet examined direct effects of endothelial cell treatment in kidney recovery. This study investigated the therapeutic efficacy of endothelial cells in a mouse model with acute kidney injury (AKI). Thus, human embryonic stem cells-derived endothelial cells (hESC-ECs) labeled with a reporter system encoding a double fusion reporter gene for firefly luciferase (Fluc) and green fluorescent protein (GFP) were characterized by Fluc imaging and immunofluoresence staining. Cultured hESC-ECs (1×106) were injected into ischemic kidney shortly after AKI. Survival of the transplanted hESC-ECs was monitored in vivo from day 1 to 14 after endothelial cell transplantation and potential impact of hESC-EC treatment on renal regeneration was assessed by histological analyses. We report that a substantial level of bioluminescence activity was detected 24 h after hESC-EC injection followed by a gradual decline from 1 to 14 d. Human ESC-ECs markedly accelerated kidney cell proliferation in response to ischaemia-induced damage, indicated by an elevated number of BrdU+ cells. Co-expression of Sca-1, a kidney stem cell proliferation marker, and BrdU further suggested that the observed stimulation in renal cell regeneration was, at least in part, due to increased proliferation of renal resident stem cells especially within the medullary cords and arteriole. Differentiation of hESC-ECs to smooth muscle cells was also observed at an early stage of kidney recovery. In summary, our results suggest that endothelial cell therapy facilitates kidney recovery by promoting vascularization, trans-differentiation and endogenous renal stem cell proliferation in AKI.