Lineage-Biased Hematopoietic Stem Cells Are Regulated by Distinct Niches

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Osteoblast lineage cells expressing high levels of Runx2 enhance hematopoietic progenitor cell proliferation and function

Although osteoblasts (OB) play a key role in the hematopoietic stem cell (HSC) niche, little is known as to which specific OB lineage cells are critical for the enhancement of stem and progenitor cell function. Unlike hematopoietic cells, OB cell surface phenotypic definitions are not well developed. Therefore, to determine which OB lineage cells are most important for hematopoietic progenitor cell (HPC) function, we characterized OB differentiation by gene expression and OB function, and determined whether associations existed between OB and HPC properties. OB were harvested from murine calvariae, used immediately (fresh OB) or cultured for 1, 2, or 3 weeks prior to their co‐culture with Lin^?Sca1⁺c‐kit⁺ (LSK) cells for 1 week. OB gene expression, alkaline phosphatase activity, calcium deposition, hematopoietic cell number fold increase, CFU fold increase, and fold increase of Lin^?Sca1⁺ cells were determined. As expected, HPC properties were enhanced when LSK cells were cultured with OB compared to being cultured alone. Initial alkaline phosphatase and calcium deposition levels were significantly and inversely associated with an increase in the number of LSK progeny. Final calcium deposition levels and OB culture duration were inversely associated with all HPC parameters, while Runx2 levels were positively associated with all HPC properties. Since calcium deposition is associated with OB maturation and high levels of Runx2 are associated with less mature OB lineage cells, these results suggest that less mature OB better promote HPC proliferation and function than do more mature OB. J. Cell. Biochem. 111: 284–294, 2010. © 2010 Wiley‐Liss, Inc.     

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.     

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。     

OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy

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The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage

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Ptpn21 Controls Hematopoietic Stem Cell Homeostasis and Biomechanics

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Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche

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造血干细胞移植条件对小鼠造血重建的影响

通过同种基因型小鼠构建造血干细胞移植模型,将预处理的全骨髓单个核细胞或c-Kit⁺造血干细胞移植至致死剂量照射的受体小鼠体内,动态监测移植2～16周后受体小鼠体内供体来源细胞造血重建以及嵌合情况,以期揭示不同群体的供体细胞以及预处理等因素对小鼠造血干细胞移植后造血重建的影响。实验结果显示,移植后早期(2周)全骨髓单个核细胞组髓系比例要高于c-Kit⁺细胞移植组,但全骨髓移植组受体小鼠呈现出较大的移植后不良反应,出现脱毛、食欲不振以及体重减轻的症状。c-Kit⁺细胞移植组在淋系重建上要早于全骨髓移植组,供体细胞的嵌合植入也早于全骨髓移植组,但两组实验组最终均能完成造血重建过程。实验结果表明c-Kit⁺细胞移植组在移植后能够较快地实现供体细胞植入,进而开始造血重建,且c-Kit⁺细胞移植组的不良反应要低于全骨髓移植组。结果说明在整体造血重建效果上c-Kit⁺细胞移植组要优于全骨髓移植组。     

Autophagy Promotes Tumor-like Stem Cell Niche Occupancy

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毛囊干细胞及其隆突微环境

毛囊隆突(bulge)是毛囊干细胞特定的微环境,它维持并调节干细胞的特性,使干细胞在静息态、自我更新和分化上保持平衡。现重点从毛囊隆突的物理结构上来简要揭示微环境对干细胞的调控。     

小鼠胚胎干细胞定向血管内皮和造血细胞分化体系的建立

目的:建立小鼠胚胎干细胞体外定向分化为血管内皮细胞和造血细胞的体系,并验证诱导后2种细胞的表面分子特征。方法:以小鼠胚胎成纤维细胞为饲养层,首先在无血清培养基StemPro中加入骨形态发生蛋白4(BMP4)、激活素A、碱性成纤维细胞生长因子(FGF-Basic)和血管内皮细胞生长因子(VEGF),诱导小鼠胚胎干细胞系R1/E 4 d后形成拟胚体;再将拟胚体消化后与OP9-DL1基质细胞共孵育,分别用干细胞因子(SCF)、VEGF和SCF、FLt3、白细胞介素3(IL-3)诱导向内皮和造血2个方向分化,并以CD31、CD45、CD144、Kit、CD201作为表面标志,流式检测诱导后细胞的表面分子特征和诱导效率;诱导10 d后免疫组化染色,进行内皮细胞的形态学鉴定。结果:诱导分化10 d后,免疫组化染色观察到多个内皮管状结构,流式检测CD31^+的内皮细胞比例为1.35%±0.05%,进一步分析CD31^+CD144^+CD45^-群体,有3.0%±0.2%的细胞表型为Kit^+CD201^+,提示该部分细胞可能是处于分化上游的内皮干祖细胞;CD45^+的造血细胞比例为35.0%±0.5%,其中0.35%±0.05%的细胞表达Kit和CD201,提示该部分细胞可能是处于分化上游的造血干祖细胞。结论:本研究将胚胎干细胞诱导为内皮细胞和造血细胞,并且能诱导出具有内皮、造血干祖细胞分子特征的细胞,可作为理想的体外诱导分化体系。     

Stem cell mechanobiology

Stem cells are undifferentiated cells that are capable of proliferation, self‐maintenance and differentiation towards specific cell phenotypes. These processes are controlled by a variety of cues including physicochemical factors associated with the specific mechanical environment in which the cells reside. The control of stem cell biology through mechanical factors remains poorly understood and is the focus of the developing field of mechanobiology. This review provides an insight into the current knowledge of the role of mechanical forces in the induction of differentiation of stem cells. While the details associated with individual studies are complex and typically associated with the stem cell type studied and model system adopted, certain key themes emerge. First, the differentiation process affects the mechanical properties of the cells and of specific subcellular components. Secondly, that stem cells are able to detect and respond to alterations in the stiffness of their surrounding microenvironment via induction of lineage‐specific differentiation. Finally, the application of external mechanical forces to stem cells, transduced through a variety of mechanisms, can initiate and drive differentiation processes. The coalescence of these three key concepts permit the introduction of a new theory for the maintenance of stem cells and alternatively their differentiation via the concept of a stem cell ‘mechano‐niche’, defined as a specific combination of cell mechanical properties, extracellular matrix stiffness and external mechanical cues conducive to the maintenance of the stem cell population. J. Cell. Biochem. 112: 1–9, 2011. © 2010 Wiley‐Liss, Inc.     

Transcription factor induction of vascular blood stem cell niches in vivo

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Immunohistochemical Detection of Neural Stem Cells and Glioblastoma Stem Cells in the Subventricular Zone of Glioblastoma Patients

Glioblastoma usually recurs after therapy consisting of surgery, radiotherapy, and chemotherapy. Recurrence is at least partly caused by glioblastoma stem cells (GSCs) that are maintained in intratumoral hypoxic peri-arteriolar microenvironments, or niches, in a slowly dividing state that renders GSCs resistant to radiotherapy and chemotherapy. Because the subventricular zone (SVZ) is a major niche for neural stem cells (NSCs) in the brain, we investigated whether GSCs are present in the SVZ at distance from the glioblastoma tumor. We characterized the SVZ of brains of seven glioblastoma patients using fluorescence immunohistochemistry and image analysis. NSCs were identified by CD133 and SOX2 but not CD9 expression, whereas GSCs were positive for all three biomarkers. NSCs were present in all seven samples and GSCs in six out of seven samples. The SVZ in all samples were hypoxic and expressed the same relevant chemokines and their receptors as GSC niches in glioblastoma tumors: stromal-derived factor-1α (SDF-1α), C-X-C receptor type 4 (CXCR4), osteopontin, and CD44. In conclusion, in glioblastoma patients, GSCs are present at distance from the glioblastoma tumor in the SVZ. These findings suggest that GSCs in the SVZ niche are protected against radiotherapy and chemotherapy and protected against surgical resection due to their distant localization and thus may contribute to tumor recurrence after therapy.     

A complex linkage in the developmental pathway of endothelial and hematopoietic cells

During normal vertebrate development, hematopoietic and endothelial cells form closely situated and interacting populations. Although the close proximity of cells to each other does not necessarily mean that they are relatives, accumulating evidence indicates that hematopoietic and endothelial cells are indeed close kin; they share common progenitors and each is able to become the other under certain circumstances. This article summarizes recent advances in the developmental relationship between hematopoietic and endothelial cells.     

Mesenchymal stem cell aging: Mechanisms and influences on skeletal and non-skeletal tissues

The aging population and the incidence of aging-related diseases such as osteoporosis are on the rise. Aging at the tissue and organ levels usually involves tissue stem cells. Human and animal model studies indicate that aging affects two aspects of mesenchymal stem cell (MSC): a decrease in the bone marrow MSC pool and biased differentiation into adipocyte at the cost of osteoblast, which underlie the etiology of osteoporosis. Aging of MSC cells is also detrimental to some non-skeletal tissues, in particular the hematopoietic system, where MSCs serve as a niche component. In addition, aging compromises the therapeutic potentials of MSC cells, including cells isolated from aged individuals or cells cultured for many passages. Here we discuss the recent progress on our understanding of MSC aging, with a focus on the effects of MSC aging on bone remodeling and hematopoiesis and the mechanisms of MSC aging.