巨核细胞生成与调控的研究进展

巨核细胞由骨髓造血干细胞分化为巨核系祖细胞,再经过渡细胞的增殖分化,成熟后生成血小板。这一过程受到巨核细胞集落刺激因子和血小板生成素的特异性刺激,白细胞介素３,粒单系集落刺激因子,白细胞介素６和红细胞生成素等细胞因子的非特异性刺激,及血小板蛋白因子、β转化生长因子和干扰素的抑制,以及辅助骨髓细胞的调控。     

microRNA调控血小板生成及功能

microRNA（miRNA）是一类长约22nt（19～23nt）在进化上非常保守的非编码RNA,其能够通过降解mRNA或抑制mRNA翻译来调控蛋白表达。研究证实miRNAs在包括胚胎干细胞分化、单核细胞和巨核细胞生成等血细胞形成过程中扮演重要的角色。而由巨核细胞生成的血小板内同样存在miRNAs,并且被证实参与到血小板活化和血小板生理病理状态改变等过程中。对miRNA调控血小板生成及功能的深入研究将有利于早期诊断治疗血液系统相关疾病。     

iPSCs诱导的造血干细胞对内皮细胞血管生成作用的影响及相关作用机制研究

目的 体外实验探讨诱导多能干细胞(iPSCs)诱导的造血干细胞(HSCs)对内皮细胞血管生成作用的影响,及其相关的作用机制.方法 将iPSCs经体外诱导分化,形成造血干细胞(iPS-HSCs).实验分为两组,分别为单纯人脐静脉内皮细胞(HUVECs)组和iPS-HSC+HUVEC组(iPS-HSCs与HUVEC进行共培...     

重组红细胞生成素对小鼠巨核细胞后期成熟及血小板生成的影响

本文应用血小板生成液体培养体系,检测了重组人红细胞生成素(r-EPO)对巨核细胞成熟及血小板生成的影响。r-EPO 能在1U 至6~U/ml 浓度范围内增加体系血小板数,r-EPO剂量与血小板数之间呈线性关系。r-EPO 还能促进巨核细胞 DNA 合成,并使 Ⅱ、Ⅳ 期巨核细胞比例增加,Ⅰ、Ⅱ 期巨核细胞比例减少。结果表明:r-EPO 可以促进巨核细胞成熟,并作为一种主要刺激因子,以增加血小板数的方式促进血小板生成。     

人胚胎干细胞高效分化为巨核细胞模型的建立

人胚胎干细胞具有无限增殖潜能,且能够分化为包括巨核细胞在内的大多数的成熟血细胞。因此,为解决临床治疗血小板来源不足而建立一种由人胚胎干细胞高效分化获得成熟巨核细胞的分化模型具有重要应用前景。该文利用人胚胎干细胞与m AGM-S3基质细胞系共培养进行早期造血前体细胞的定向分化,并在分化第14 d获得大量"卵石样"造血前体细胞(CD43+细胞、CD45+细胞)。将"卵石样"造血前体细胞分离后,用无血清培养基分阶段添加SCF、TPO、IL-6、IL-3、FLt-3、IL-11等细胞因子进行巨核细胞定向诱导分化。结果显示,在分化的第3 d,CD41a+细胞比例可高达48.5%,CD42b+细胞比例可高达30.0%。对分化第6 d的细胞进行Wright-Giemsa染色,可见形态典型的巨核细胞。综上所述,该研究初步建立了一种人胚胎干细胞高效分化为巨核细胞的模型,为体外获得大量巨核细胞奠定了基础。     

造血干细胞向红系发育的分子调控机制

造血干细胞(hematopoietic stem cell,HSC)向红细胞(red blood cell,RBC)的分化是一个精确又复杂的过程,从谱系决定到终末分化以及去核、去细胞器的过程都受到了严格的调控.红细胞生成障碍会导致各种疾病,治疗这些疾病的关键是阐明红系发育中的调控机制.该综述主要总结了近年来在分子水平上...     

造血干细胞自我更新调控及wnt信号在其中的作用

干细胞生物学最为重要的问题之一就是干细胞自我更新的调控机制.造血干细胞具有自我更新和分化为各血细胞世系的能力,但目前对其自我更新的调控机制尚未明确.大量的研究表明,造血干细胞的自我更新受到来自其所处微环境和自身内在基因的共同调控.经典的发育调控通路——wnt信号通路在造血干细胞自我更新调控中起着至关重要的作用.就造血干细胞自我更新及其调控,特别是wnt信号通路在其中的作用作一综述,并对其应用前景和今后的研究方向作了展望.     

MicroRNA对干细胞调控作用的研究进展

干细胞是具有自我复制及更新能力的原始不成熟细胞,可向不同组织及器官分化,在胚胎和成体组织中都有存在.干细胞的应用作为组织修复和重建的一种新策略,近几年来受到了医学界和生物学界的广泛关注,而microRNA(miRNA)作为一种长约21～23个核苷酸的内源性非编码RNA的分子,其通过与靶mRNA结合,发挥负向基因转录调控作用的功能已在研究中被证实,其对细胞乃至生物体的影响也渐渐成为研究的热点.但干细胞与miRNA两者之间是否存在联系,miRNA是否在干细胞的分化、增殖中也具一定有作用,已逐渐成为一项值得研究的课题.这不仅可以使我们更加全面的了解miRNA的作用,也为干细胞的应用提供了新的研究途径和理论依据.因此本文就miRNA及其对胚胎干细胞和成体干细胞的调控做一综述.     

非洲猪瘟病毒调控宿主细胞因子表达水平的研究进展

非洲猪瘟(African swine fever,ASF)是由非洲猪瘟病毒(African swine fever virus,ASFV)引起的一种猪的急性、热性、高度接触性传染病,给全球养猪业造成了巨大的经济损失.ASFV基因组庞大,结构复杂,至今无有效药物和疫苗,只能依靠生物安全对其防控.由于非洲猪瘟发病急的特点,发病后极易引发细胞因子风暴,加快病情发展.本文综述了当前已证实的猪感染ASFV后白介素、干扰素、肿瘤坏死因子等细胞因子的变化及其调控机制.了解细胞因子与ASFV感染的关系,以期对保护性免疫机制的探究奠定基础,为ASFV疫苗研发提供参考.     

Intercellular network structure and regulatory motifs in the human hematopoietic system

The hematopoietic system is a distributed tissue that consists of functionally distinct cell types continuously produced through hematopoietic stem cell (HSC) differentiation. Combining genomic and phenotypic data with high‐content experiments, we have built a directional cell–cell communication network between 12 cell types isolated from human umbilical cord blood. Network structure analysis revealed that ligand production is cell type dependent, whereas ligand binding is promiscuous. Consequently, additional control strategies such as cell frequency modulation and compartmentalization were needed to achieve specificity in HSC fate regulation. Incorporating the in vitro effects (quiescence, self‐renewal, proliferation, or differentiation) of 27 HSC binding ligands into the topology of the cell–cell communication network allowed coding of cell type‐dependent feedback regulation of HSC fate. Pathway enrichment analysis identified intracellular regulatory motifs enriched in these cell type‐ and ligand‐coupled responses. This study uncovers cellular mechanisms of hematopoietic cell feedback in HSC fate regulation, provides insight into the design principles of the human hematopoietic system, and serves as a foundation for the analysis of intercellular regulation in multicellular systems.     

Defining the hematopoietic stem cell niche: the chicken and the egg conundrum

Understanding the in vivo regulation of hematopoietic stem cells (HSCs) will be critical to identifying key factors involved in the regulation of HSC self‐renewal and differentiation. The niche (microenvironment) in which HSCs reside has recently regained attention accompanied by a dramatic increase in the understanding of the cellular constituents of the bone marrow HSC niche. The use of sophisticated genetic models allowing modulation of specific lineages has demonstrated roles for mesenchymal‐derived elements such as osteoblasts and adipocytes, vasculature, nerves, and a range of hematopoietic progeny of the HSC as being participants in the regulation of the bone marrow microenvironment. Whilst providing significant insight into the cellular composition of the niche, is it possible to manipulate any given cell lineage in vivo without impacting, knowingly or unknowingly, on those that remain? J. Cell. Biochem. 112: 1486–1490, 2011. © 2011 Wiley‐Liss, Inc.     

Differentiation of hematopoietic stem cell and myeloid populations by ATP is modulated by cytokines

Extracellular nucleotides are emerging as important regulators of inflammation, cell proliferation and differentiation in a variety of tissues, including the hematopoietic system. In this study, the role of ATP was investigated during murine hematopoiesis. ATP was able to reduce the percentage of hematopoietic stem cells (HSCs), common myeloid progenitors and granulocyte–macrophage progenitors (GMPs), whereas differentiation into megakaryocyte–erythroid progenitors was not affected. In addition, in vivo administration of ATP to mice reduced the number of GMPs, but increased the number of Gr-1⁺Mac-1⁺ myeloid cells. ATP also induced an increased proliferation rate and reduced Notch expression in HSCs and impaired HSC-mediated bone marrow reconstitution in sublethally irradiated mice. Moreover, the effects elicited by ATP were inhibited by suramin, a P2 receptor antagonist, and BAPTA, an intracellular Ca²⁺ chelator. We further investigated whether the presence of cytokines might modulate the observed ATP-induced differentiation. Treatment of cells with cytokines (stem cell factor, interleukin-3 and granulocyte–monocyte colony stimulator factor) before ATP stimulation led to reduced ATP-dependent differentiation in long-term bone marrow cultures, thereby restoring the ability of HSCs to reconstitute hematopoiesis. Thus, our data suggest that ATP induces the differentiation of murine HSCs into the myeloid lineage and that this effect can be modulated by cytokines.     

Lineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches

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干细胞巢研究进展

干细胞巢即干细胞周围的微环境构成,一般包括干细胞的相邻细胞、粘附分子及基质等,但不同的干细胞有不同的巢结构。干细胞巢通过不同信号途径调控着干细胞的行为,使干细胞的自我更新和分化处于平衡状态。根据近年来有关干细胞巢的研究,本文从果蝇生殖系干细胞巢、哺乳动物造血干细胞巢、肠干细胞巢、毛囊表皮干细胞巢和神经干细胞巢等五个系统分别综述了干细胞巢的构成及其对干细胞的调节作用,探讨了干细胞巢作用于干细胞的内在机制。     

Stem cell exhaustion and leukemogenesis

Cancer is the result of a combination of genetic alterations, which aid transformation of cells. However, oncogenic alterations also simultaneously induce some detrimental effects on the cells such as apoptosis, senescence, and differentiation. Such negative effects caused by certain oncogenic events are overcome by other cooperating genetic hits. We propose stem cell exhaustion as a novel detrimental effect that is caused by a wide variety of oncogenic alterations. Interestingly, in most cases, the stem cell exhaustion due to oncogenic alterations is preceded by an abnormal expansion of stem/progenitor cells. This preceding stem/progenitor cell expansion may be a key feature that still promotes cancer development, along with cooperating hits that rescue stem cell exhaustion. This review summarizes current knowledge about hematopoietic stem cell exhaustion and the mechanisms to overcome stem cell exhaustion in cancer development. J. Cell. Biochem. 107: 393–399, 2009. © 2009 Wiley‐Liss, Inc.     

Young donor hematopoietic stem cells revitalize aged or damaged bone marrow niche by transdifferentiating into functional niche cells

The bone marrow niche maintains hematopoietic stem cell (HSC) homeostasis and declines in function in the physiologically aging population and in patients with hematological malignancies. A fundamental question is now whether and how HSCs are able to renew or repair their niche. Here, we show that disabling HSCs based on disrupting autophagy accelerated niche aging in mice, whereas transplantation of young, but not aged or impaired, donor HSCs normalized niche cell populations and restored niche factors in host mice carrying an artificially harassed niche and in physiologically aged host mice, as well as in leukemia patients. Mechanistically, HSCs, identified using a donor lineage fluorescence-tracing system, transdifferentiate in an autophagy-dependent manner into functional niche cells in the host that include mesenchymal stromal cells and endothelial cells, previously regarded as “nonhematopoietic” sources. Our findings thus identify young donor HSCs as a primary parental source of the niche, thereby suggesting a clinical solution to revitalizing aged or damaged bone marrow hematopoietic niche.     

Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells

Upon aging, hematopoietic stem cells (HSCs) undergo changes in function and structure, including skewing to myeloid lineages, lower reconstitution potential and loss of protein polarity. While stem cell intrinsic mechanisms are known to contribute to HSC aging, little is known on whether age-related changes in the bone marrow niche regulate HSC aging. Upon aging, the expression of osteopontin (OPN) in the murine bone marrow stroma is reduced. Exposure of young HSCs to an OPN knockout niche results in a decrease in engraftment, an increase in long-term HSC frequency and loss of stem cell polarity. Exposure of aged HSCs to thrombin-cleaved OPN attenuates aging of old HSCs, resulting in increased engraftment, decreased HSC frequency, increased stem cell polarity and a restored balance of lymphoid and myeloid cells in peripheral blood. Thus, our data suggest a critical role for reduced stroma-derived OPN for HSC aging and identify thrombin-cleaved OPN as a novel niche informed therapeutic approach for ameliorating HSC phenotypes associated with aging.     

Aging of hair follicle stem cells and their niches

Hair follicles in the skin undergo cyclic rounds of regeneration, degeneration, and rest throughout life. Stem cells residing in hair follicles play a pivotal role in maintaining tissue homeostasis and hair growth cycles. Research on hair follicle aging and age-related hair loss has demonstrated that a decline in hair follicle stem cell (HFSC) activity with aging can decrease the regeneration capacity of hair follicles. This review summarizes our understanding of how age-associated HFSC intrinsic and extrinsic mechanisms can induce HFSC aging and hair loss. In addition, we discuss approaches developed to attenuate age-associated changes in HFSCs and their niches, thereby promoting hair regrowth.