导读一
现在不少研究者发现骨髓干细胞可以分化成心肌细胞而修复心肌缺血或者梗死后的心肌,于是不少单位开始尝试向受损心肌注射BM细胞。本文对这个观点提出质疑并证实骨髓造血干细胞注入心脏后仍进行造血细胞的分化而不会分化成心肌细胞。
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+ Thy1.1lo 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+ Thy1.1lo Lin- Sca-1+ long-term reconstituting haematopoietic stem cells adopt only traditional haematopoietic fates.
造血干细胞在心肌缺血时经历成熟造血命运
在组织损伤时报道有心肌复制和再生。许多研究者发现成人骨髓(BM)参与了这个过程,说明骨髓可以作为心肌的前体细胞库存。骨髓细胞如何对心肌产生贡献的机制还不清楚,具体是通过转分化还是细胞融合来实现也不明了。作者研究了在心肌梗塞模型中富含c-kit的BM细胞-Lin- c-kit+ BM细胞和c-kit+ Thy1.1lo Lin- Sca-1+长久重建造血干细胞的再生心肌细胞的能力。从转基因小鼠中分离表达GFP的细胞并直接注射到野生型小鼠的缺血心肌中。10天以后在心肌中发现大量的GFP+细胞但是至30天时可以检测的细胞就很少了。这些GFP+ 细胞不表达心脏组织特异标记但是大多数却表达造血标记CD45和髓样标记Gr-1。作者还利用GFP+–GFP-联体共生小鼠研究了循环细胞在缺血心肌修复中的作用。依然没有发现来自伙伴血液传递的细胞使心肌再生。作者的数据暗示即使在受损心脏的微环境中,富含c-kit的BM细胞-Lin- c-kit+ BM细胞和c-kit+ Thy1.1lo Lin- Sca-1+长久重建造血干细胞只经历传统的造血命运。(生物谷原创)
导读二
同样的问题不同的方法还是证实造血干细胞不能转分化为心肌细胞,这里如火如荼开展的临床试验可能要叫停了。
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.
造血干细胞在心肌梗塞时不会转分化为心肌细胞
哺乳动物心脏的再生能力十分有限因此采用疤痕修复。最近不少研究指出造血干细胞在组织损伤反应或者安置在新环境中时可以转分化为料想不到的表型如骨骼肌,肝细胞,上皮细胞,神经元,内皮细胞和心肌细胞。此外,移植人类心脏包含有来源于可能起源于骨髓的心脏外的前体细胞。尽管在大多数研究中发现在生理条件下转分化十分罕见,但是最近在直接注射干细胞后发现广泛的心肌梗塞再生促进了不少这样类似的临床试验进行。作者采用局限于心肌细胞的和广泛表达的报告转基因来跟踪145例移植入成年小鼠正常和损伤心脏的造血干细胞的命运。使用这些基因技术跟踪细胞命运没有发现造血干细胞转分化为心肌细胞而且移植干细胞的心脏与未移植入干细胞的心脏相比在心肌细胞数目上没有明显增加。这些结果表明造血干细胞还不能迅速获得心肌表型并对临床的梗塞修复研究提出了警告。(生物谷原创)
导读三
本篇形态发育学论文发现了表皮中某一激酶在骨骼等组织发育中的作用,采用的是基因工程小鼠手段。但是这个分子具体的作用机制还不是很清楚。
IB kinase- acts in the epidermis to control skeletal and craniofacial morphogenesis
IB kinase- (IKK-) exhibits protein-kinase-dependent and -independent functions. Its kinase activity is required for lymphoid organogenesis and mammary gland development, whereas a kinase-independent activity is required for epidermal keratinocyte differentiation. In addition to failed epidermal differentiation, IKK--deficient mice exhibit abnormal skeletal and craniofacial morphogenesis. As similar defects are not exhibited by mice that experience systemic inhibition of NF-B, we postulated that the morphogenetic defects in IKK--deficient mice are not caused by reduced NF-B activity but instead are due to failed epidermal differentiation that disrupts proper epidermal–mesodermal interactions. We tested this hypothesis by introducing an epidermal-specific Ikka (also known as Chuk) transgene into IKK--deficient mice. Mice lacking IKK- in all cell types including bone and cartilage, but not in basal epidermal keratinocytes, exhibit normal epidermal differentiation and skeletal morphology. Thus, epidermal differentiation is required for proper morphogenesis of mesodermally derived skeletal elements. One way by which IKK- controls skeletal and craniofacial morphogenesis is by repressing expression of fibroblast growth factor (FGF) family members, such as FGF8, whose expression is specifically elevated in the limb bud ectoderm of IKK--deficient mice.
IB激酶在表皮中控制骨骼和颅面形态发生
IB激酶(IKK)表现出蛋白激酶依赖和非依赖的功能。其激酶活性对淋巴样器官发生和乳腺发育是必需的,但是在表皮角质细胞的分化需要非激酶依赖活性。IKK缺失小鼠除了不能表皮分化还表现出异常的骨骼和颅面形态发生。因为类似的缺陷没有出现在经历了全身NF-B抑制的小鼠,作者推断IKK缺失小鼠的形态发生缺陷不是由于NF-B活性降低引起而是因为可以破裂专属表皮-中胚层相互作用的表皮分化失败引起。作者通过引入一个表皮特异的Ikka(也称为Chuk)基因转入IKK缺失小鼠测试了该假说。除了在基底表皮角质细胞中,其余在包括骨骼和软骨的所有细胞类型缺失IKK的小鼠表现出了正常的表皮分化和骨骼形态发生。因此,表皮分化是中胚层来源的骨骼成分正确形态发生必需的。IKK控制骨骼和颅面形态发生的一个途径是抑制成纤维细胞生长因子(FGF)家族成员如FGF8的表达,后者的表达在IKK缺失小鼠肢芽外胚层中特异升高。(生物谷原创)
导读四
藻类是单细胞低等真核生物,通过对其基因组的研究可以探知许多进化的秘密。
Genome sequence of the ultrasmall unicellular red alga Cyanidioschyzon merolae 10D
超小单细胞Cyanidioschyzon merolae 10D红藻的基因组序列
超小单细胞红藻小而紧凑的基因组提供了基础和必要的基因信息以支持进行光合作用的包括高等植物的真核生物生存。作者报道了单细胞红藻Cyanidioschyzon merolae 10D的20个染色体共16,520,305个碱基对序列,这也是第一个完整的藻类基因组序列。作者确认了总共5331个基因,其中至少86.3%是表达的基因。其基因组结构的独特之处包括:除了26个基因以外都缺少内含子;只有三个拷贝的核糖体DNA单位保留了核仁;两个只参与线粒体和质体分离的dynamin基因。在该红藻和绿色植物中含有的卡尔文循环(光合碳还原环)酶的保守嵌合起源支持单一初级质体胞内共生的假说存在。肌球蛋白缺乏和不表达的肌动蛋白提示具有更简单细胞动力(胞质分离)系统。以上这些结果提示C. merolae基因组可以作为具有简单基因组成的模式系统来研究真核细胞的起源,发育和基本机制。
Small, compact genomes of ultrasmall unicellular algae provide information on the basic and essential genes that support the lives of photosynthetic eukaryotes, including higher plants. Here we report the 16,520,305-base-pair sequence of the 20 chromosomes of the unicellular red alga Cyanidioschyzon merolae 10D as the first complete algal genome. We identified 5,331 genes in total, of which at least 86.3% were expressed. Unique characteristics of this genomic structure include: a lack of introns in all but 26 genes; only three copies of ribosomal DNA units that maintain the nucleolus; and two dynamin genes that are involved only in the division of mitochondria and plastids. The conserved mosaic origin of Calvin cycle enzymes in this red alga and in green plants supports the hypothesis of the existence of single primary plastid endosymbiosis. The lack of a myosin gene, in addition to the unexpressed actin gene, suggests a simpler system of cytokinesis. These results indicate that the C. merolae genome provides a model system with a simple gene composition for studying the origin, evolution and fundamental mechanisms of eukaryotic cells.(生物谷原创)
导读五
酿酒酵母是很好的模式生物,这篇分子进化学文章揭示了酿酒酵母的来源。
Proof and evolutionary analysis of ancient genome duplication in the yeast Saccharomyces cerevisiae
Whole-genome duplication followed by massive gene loss and specialization has long been postulated as a powerful mechanism of evolutionary innovation. Recently, it has become possible to test this notion by searching complete genome sequence for signs of ancient duplication. Here, we show that the yeast Saccharomyces cerevisiae arose from ancient whole-genome duplication, by sequencing and analysing Kluyveromyces waltii, a related yeast species that diverged before the duplication. The two genomes are related by a 1:2 mapping, with each region of K. waltii corresponding to two regions of S. cerevisiae, as expected for whole-genome duplication. This resolves the long-standing controversy on the ancestry of the yeast genome, and makes it possible to study the fate of duplicated genes directly. Strikingly, 95% of cases of accelerated evolution involve only one member of a gene pair, providing strong support for a specific model of evolution, and allowing us to distinguish ancestral and derived functions.
酿酒酵母古老基因组重复的证据和进化分析
大量基因遗失和特化之后的全基因组复制长期以来被推断为进化更新的强有力机制。最近这个概念的证实已经通过在全基因组序列中搜索古老基因重复而变成可能。作者通过测序和分析克鲁维酵母waltii(一个在重复前分支出来的相关酵母属)表明酿酒酵母是由古老的基因组重复而产生的。两个基因组序列图为1:2的关系即K. waltii的每个区域对应S. cerevisiae的两个区域,这正与全基因组重复的情况相同。这个发现解决了长期以来关于酵母基因组起源的争议并使得对重复基因的直接研究成为可能。令人惊奇的是,95%的加速进化案例只涉及一个基因对成员,这为特异的进化模型提供强有力的支持并使我们可以区分祖先具有的功能和传得的功能。(生物谷原创)


