Primer and interviews: The dynamic stem cell niche

A stem cell niche is a microenvironment that supports self‐renewal of a population of stem cells, and their production of differentiated cells. While the definition evokes images of a stem cell Shangri‐La—where a serene stem cell pool nestles within a niche that shelters and sustains it—the reality is much more tumultuous. Niches are subject to an ever‐changing maelstrom of environmental factors, the ravages of old age, and the sly tactics of disease. Presented here is a basic overview of the different ways in which stem cell niches respond to local and systemic environments, and their impact on stem cell behavior. The primer culminates with a discussion of the topic with stem cell and niche biologists D. Leanne Jones, Ph.D., and Tudorita Tumbar, Ph.D. Developmental Dynamics 240:737–743, 2011. © 2011 Wiley‐Liss, Inc.     

The establishment of the plasma cell survival niche in the bone marrow

Antibodies continuously secreted by plasma cells play a central role in humoral immune protection of the organism. These plasma cells are generated during the germinal center reaction, and it is likely that they here acquire the potential to develop into long-lived cells. To achieve longevity, these cells require factors provided by the microenvironment. Indeed, only a few of the plasmablasts arising during an immune response will differentiate into mature plasma cells, which may survive for decades in specialized survival niches in the bone marrow. Here, we discuss how the survival niche in the bone marrow is established and what is known about the cell–cell interactions needed to support the long-term survival of plasma cells. A particular emphasis is put on the role of eosinophils, which have been shown to be key providers of plasma cell survival factors. The data suggest that the reticulum of bone marrow stromal cells supports a dynamic survival niche, in which long-lived plasma cells are provided with essential factors by a continuously turning over population of eosinophils and other cells.     

骨髓造血干细胞龛

造血干细胞(hematopoietic stem cell,HSC)位于骨髓的造血微环境即龛(niche)中,它们与龛内特定的细胞相互作用以调节其自我更新和定向分化。研究发现,骨髓中的成骨细胞和内皮细胞与造血干细胞关系密切,分别构成了HSC龛中的成骨龛和血管龛,其中成骨龛维持静态的HSC微环境,而血管龛调控HSC的增殖、分化和动员等行为。对骨髓HSC龛的研究为将来临床治疗血液系统相关疾病提供了新的思路。     

Revealing the glioma cancer stem cell interactome,one niche at a time

Glioblastoma (GBM) cancer stem cells (CSCs) are insidious. They extensively infiltrate brain tissue, resist radiotherapy and chemotherapy, and are thought to represent the ultimate drivers of disease progression. New research has identified CD109, a GPI‐anchored protein, on a population of perivascular CSCs. Investigation of primary human tumour tissue suggests a role for CD109‐expressing CSCs in the progression from low‐grade to high‐grade glioma, and animal modelling reveals a critical role for CD109 in the maintenance of the GBM CSC phenotype. Furthermore, CD109‐expressing CSCs appear to drive the proliferation of adjacent non‐stem tumour cells (NSTCs) in a rare example of CSC–NSTC cooperative interaction. With this Commentary, we highlight the newly revealed biology of CD109, and offer a synthesis of the published information on glioma CSCs in a variety of anatomical growth zones. We also discuss the landscape of interacting cells within GBM tumours, emphasizing the few reported examples of pro‐tumourigenic, interactive tumour cell partnerships, as well as a variety of tumour cell–non‐transformed neural cell interactions. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The gastrointestinal tract stem cell niche

The gastrointestinal epithelium is unique in that cell proliferation, differentiation, and apoptosis occur in an orderly fashion along the crypt-villus axis. The intestinal crypt is mainly a proliferative compartment, is monoclonal and is maintained by stem cells. The villus represents the differentiated compartment, and is polyclonal as it receives cells from multiple crypts. In the small intestine, cell migration begins near the base of the crypt, and cells migrate from here emerging onto the villi. The basal crypt cells at position 5 are candidate stem cells. As the function of stem cells is to maintain the integrity of the intestinal epithelium, it must self-renew, proliferate, and differentiate within a protective niche. This niche is made up of proliferating and differentiating epithelial cells and surrounding mesenchymal cells. These mesenchymal cells promote the epithelial-mesenchymal crosstalk required to maintain the niche. A stochastic model of cell division has been proposed to explain how a single common ancestral stem cell exists from which all stem cells in a niche are descended. Our group has argued that these crypts then clonally expand by crypt fission, forming two daughters’ crypts, and that this is the mechanism by which mutated stem cells or even cancer stem cell clones expand in the colon and in the entire gastrointestinal tract. Until recently, the differentiation potential of stem cells into adult tissues has been thought to be limited to cell lineages in the organ from which they were derived. Bone marrow cells are rare among adult stem cells regarding their abundance and role in the continuous, lifelong, physiological replenishment of circulating cells. In human and mice experiments, we have shown that bone marrow can contribute to the regeneration of intestinal myofibroblasts and thereby after epithelium following damage, through replacing the cells, which maintain the stem cells niche. Little is known about the markers characterizing the stem and transit amplifying populations of the gastrointestinal tract, although musashi-1 and hairy and enhancer of split homolog-1 have been proposed. As the mammalian gastrointestinal tract develops from the embryonic gut, it is made up of an endodermally-derived epithelium surrounded by cells of mesoderm origin. Cell signaling between these two tissue layers plays a critical role in coordinating patterning and organogenesis of the gut and its derivatives. Many lines of evidence have revealed that Wnt signaling is the most dominant force in controlling cell proliferation, differentiation, and apoptosis along the crypt-villus axis. We have found Wnt messenger RNAs expression in intestinal subepithelial myofibroblasts and frizzled messenger RNAs expression in both myofibroblasts and crypt epithelium. Moreover, there are many other factors, for example, bone morphogenetic protein, homeobox, forkhead, hedgehog, homeodomain, and platelet-derived growth factor that are also important to stem cell signaling in the gastrointestinal tract.     

One cell one niche: hematopoietic microenvironments constructed by bone marrow stromal cells with fibroblastic and histiocytic features

Hematopoietic microenvironments have been extensively studied, especially focusing on regulation of hematopoietic stem cells (HSCs) in HSC niche following progress of molecular biology in resent years. Based on prior morphological achievements from 1970s, the characteristics of cellular compartments and bone marrow stromal cells (BMSCs) were studied ultrastructurally in human and mice bone marrow in the present study. The samples, human bone marrow granules, were collected from bone marrow aspirations (BMAs) of 20 patients with hematocytopenia and isolated BMSCs were found undesignedly in nucleated cells of BMAs of the patients. Femoral bone marrow samples were collected from 6-week-old three sacrificed mice. Detailed images illustrated maturing hematopoietic cells harbored individually in honeycomb-like microenvironment constituted by BMSCs that shared of fibroblastic and histiocytic characteristics in hematopoietic microenvironments of human and mice bone marrow.     

The realized niche of adult neural stem cells

This review gives an overview of current issues concerning the application of the concept of the stem cell niche to the adult mammalian brain. It describes how the niche manifests itself at different structural levels as well as the main applications that are influenced by this concept. Finally, special regard is given to what is known for the adult human brain and how far the findings from lower animals can be applied in harnessing the regenerative potential of stem cells for therapy.     

Neural stem and progenitor cells in the aged subependyma are activated by the young niche

Previous studies have demonstrated an age related decline in the size of the neural stem cell (NSC) pool and a decrease in neural progenitor cell proliferation, however, the mechanisms underlying these changes are unclear. In contrast to previous reports, we report that the numbers of NSCs is unchanged in the old age subependyma and the apparent loss is because of reduced proliferative potential in the aged stem cell niche. Transplantation studies reveal that the proliferation kinetics and migratory behavior of neural precursor cells are dependent on the age of the host animal and independent of the age of the donor cells suggesting that young and old age neural precursors are not intrinsically different. Factors from the young stem cell niche rescue the numbers of NSC colonies derived from old age subependyma and enhance progenitor cell proliferation in vivo in old age mice. Finally, we report a loss of Wnt signaling in the old age stem cell niche that underlies the lack of expansion of the NSC pool after stroke.     

Ovarian Stem Cell Niche and Follicular Renewal in Mammals

Stem cell niche consists of perivascular compartment, which connects the stem cells to the immune and vascular systems. During embryonic period, extragonadal primordial germ cells colonize coelomic epithelium of developing gonads. Subsequently, ovarian stem cells (OSC) produce secondary germ cells under the influence of OSC niche, including immune system‐related cells and hormonal signaling. The OSC in fetal and adult human ovaries serve as a source of germ and granulosa cells. Lack of either granulosa or germ cell niche will result in premature ovarian failure in spite of the presence of OSC. During perinatal period, the OSC transdifferentiate into fibroblast‐like cells forming the ovarian tunica albuginea resistant to environmental threats. They represent mesenchymal precursors of epithelial OSC during adulthood. The follicular renewal during the prime reproductive period (PRP) ensures that there are fresh eggs available for a healthy progeny. End of PRP is followed by exponentially growing fetal genetic abnormalities. The OSC are present in adult, aging, and postmenopausal ovaries, and differentiate in vitro into new oocytes. During in vitro development of large isolated oocytes reaching 200 μm in diameter, an ancestral mechanism of premeiotic nurse cells, which operates during oogenesis in developing ovaries from invertebrates to mammalian species, is utilized. In vitro developed eggs could be used for autologous IVF treatment of premature ovarian failure. Such eggs are also capable to produce parthenogenetic embryos like some cultured follicular oocytes. The parthenotes produce embryonic stem cells derived from inner cell mass, and these cells can serve as autologous pluripotent stem cells. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Rejuvenation of chondrogenic potential in a young stem cell microenvironment

Autologous cells suffer from limited cell number and senescence during ex vivo expansion for cartilage repair. Here we found that expansion on extracellular matrix (ECM) deposited by fetal synovium-derived stem cells (SDSCs) (FE) was superior to ECM deposited by adult SDSCs (AE) in promoting cell proliferation and chondrogenic potential. Unique proteins in FE might be responsible for the rejuvenation effect of FE while advantageous proteins in AE might contribute to differentiation more than to proliferation. Compared to AE, the lower elasticity of FE yielded expanded adult SDSCs with lower elasticity which could be responsible for the enhancement of chondrogenic and adipogenic differentiation. MAPK and noncanonical Wnt signals were actively involved in ECM-mediated adult SDSC rejuvenation.     

The effects of microenvironment and internal programming on plasma cell survival

Two populations of plasma cells (PCs) are formed after immunization. A short-lived population in the spleen and lymph nodes provides rapid protection. A long-lived population, mainly in the bone marrow, provides lasting immunity. The mechanisms responsible for the differences in PCs life span remain largely unknown. The goal of the current study was to compare the intrinsic survival capacity of isolated short-lived (spleen) versus long-lived (bone marrow) PCs. We approached this question by using a previously established in vitro model that measures PC survival in a supportive stromal environment. Regardless of the tissue source or isolation time point after immunization, the two PC populations showed similar intrinsic ability to survive in vitro. To test differences in the stromal microenvironments, stromal cells from marrow, spleen or lymph nodes were evaluated for ability to support PCs survival. Survival of isolated PC was always greater when co-cultured with marrow stromal cells compared with those from spleen (or lymph node) despite the finding that IL-6, necessary for PC survival in culture, was secreted by all three stromal cell sources. Additionally, low expression of B-cell-activating factor belonging to the tumor necrosis factor-family was detected in all three stromal isolates. In contrast, marrow stromal cells were distinguished by cell-surface phenotype and CXC chemokine ligand (CXCL)12, IL-7 and stem cell factor expression. Although CXCL12 has been suggested as a possible survival factor for PC, addition or neutralization of CXCL12 had minimal effect on PC survival. We conclude the mechanisms regulating PC longevity appear extrinsically driven and marrow favored, but the factors that give marrow stromal cells a unique advantage remain unknown.     

Extracellular matrix regulation in the muscle satellite cell niche

Abstract

Increasing evidence points to extracellular matrix (ECM) components playing integral roles in regulating the muscle satellite cell (SC) niche. Even small alterations to the niche ECM can have profound effects on SC localization, activation, self-renewal, proliferation and differentiation. This review will focus on the ECM components that comprise the niche, how they are modulated in health and disease and how these changes are thought to affect SC function. Particular emphasis will be placed on the pathological niche and interventions that aim to restore healthy structure and function, as a better understanding of the interplay between the SC and its environment will drive more targeted and effective therapies.     

干细胞和心血管疾病

随着人们生活方式的改变,心血管疾病逐渐成为人类的头号杀手。干细胞是一类具有自我更新和分化潜能的细胞。干细胞的异常,可能是心血管疾病发病的细胞学基础。最近几年,由于干细胞技术的发展更使细胞治疗在心脏疾病中的应用达到了一个新的高潮,但目前还存在如何进一步优化移植方法和筛选最佳细胞类型和数量等问题。     

Asymmetry of stem cell fate and the potential impact of the niche

Asymmetric cell division is a common concept to explain the capability of stem cells to simultaneously produce a continuous output of differentiated cells and to maintain their own population of undifferentiated cells. Whereas for some stem cell systems, an asymmetry in the division process has explicitly been demonstrated, no evidence for such a functional asymmetry has been shown for hematopoietic stem cells (HSC) so far. This raises the question regarding whether asymmetry of cell division is a prerequisite to explain obvious heterogeneity in the cellular fate of HSC. Through the application of a mathematical model based on self-organizing principles, we demonstrate that the assumption of asymmetric stem cell division is not necessary to provide a consistent account for experimentally observed asymmetries in the development of HSC. Our simulation results show that asymmetric cell fate can alternatively be explained by a reversible expression of functional stem cell potentials, controlled by changing cell-cell and cell-microenvironment interactions. The proposed view on stem cell organization is pointing to the potential role of stem cell niches as specific signaling environments, which induce developmental asymmetries and therefore, generate cell fate heterogeneity. The self-organizing concept is fully consistent with the functional definition of tissue stem cells. It naturally includes plasticity phenomena without contradicting a hierarchical appearance of the stem cell population. The concept implies that stem cell fate is only predictable in a probabilistic sense and that retrospective categorization of stem cell potential, based on individual cellular fates, provides an incomplete picture.     

体外诱导兔骨髓间充质干细胞分化为类许旺细胞的初步研究

目的：探索将兔骨髓间充质干细胞（Mesenchymal Stem Cells，MSCs）在体外定向诱导分化为类许旺细胞（Schwann Cells，SC）有效的诱导方法。方法：（1）中国白兔5只，穿刺抽取股骨大转子骨髓3mL，用密度为1．073g／mL的percoll淋巴分离液行密度梯度分离，吸取中间白色膜状细胞层，接种在加有10％FCS的DMEM培养液的塑料培养瓶中，观察细胞形态并传代。（2）MSCs传至第3代，实验组加入加有0．5mmol β-巯基乙醇、20ng／mL全反式黄酸、2．5μmol Forskolin、5ng／mL bFGF、20ng／mL PDGF、100ng／mL HRG的培养液培养24h，然后换用10％FBS的DMEM培养液培养24h，同样方法再诱导一次。对照组不加诱导剂，用10％FCS的DMEM培养液培养。观察两组MSCs的细胞形态，7d后用抗S-100、GFAP和P75抗体做免疫组织化学染色来鉴定诱导后MSCs。结果：MSCs在体外培养以梭形细胞为主，细胞平行排列或旋涡状生长，胞浆丰富，核大，核染色质细，有些核仁明显。细胞经多次传代后，呈长梭型。加入诱导剂后有少量细胞死亡，诱导后的细胞免疫组化阳性。诱导后细胞S-100、GFAP、P75免疫组化染色阳性率分别为74.9％、83％、70％。结论：兔MSCs可以在体外培养、增殖，并经β-巯基乙醇、全反式黄酸、Forskolin、bFGF、PDGF、HRG联合诱导分化为类SC。     

c-Myc controls the balance between hematopoietic stem cell self-renewal and differentiation

The activity of adult stem cells is essential to replenish mature cells constantly lost due to normal tissue turnover. By a poorly understood mechanism, stem cells are maintained through self-renewal while concomitantly producing differentiated progeny. Here, we provide genetic evidence for an unexpected function of the c-Myc protein in the homeostasis of hematopoietic stem cells (HSCs). Conditional elimination of c-Myc activity in the bone marrow (BM) results in severe cytopenia and accumulation of HSCs in situ. Mutant HSCs self-renew and accumulate due to their failure to initiate normal stem cell differentiation. Impaired differentiation of c-Myc-deficient HSCs is linked to their localization in the differentiation preventative BM niche environment, and correlates with up-regulation of N-cadherin and a number of adhesion receptors, suggesting that release of HSCs from the stem cell niche requires c-Myc activity. Accordingly, enforced c-Myc expression in HSCs represses N-cadherin and integrins leading to loss of self-renewal activity at the expense of differentiation. Endogenous c-Myc is differentially expressed and induced upon differentiation of long-term HSCs. Collectively, our data indicate that c-Myc controls the balance between stem cell self-renewal and differentiation, presumably by regulating the interaction between HSCs and their niche.     

Genomic Profiling of Mesenchymal Stem Cells

Mesenchymal stem/stromal cells (MSC) are an accessible source of precursor cells that can be expanded in vitro and used for tissue regeneration for different clinical applications. The advent of microarray technology has enabled the monitoring of individual and global gene expression patterns across multiple cell populations. Thus, genomic profiling has fundamentally changed our capacity to characterize MSCs, identify potential biomarkers and determined key molecules regulating biological processes involved in stem cell survival, growth and development. Numerous studies have now examined the genomic profiles of MSCs derived from different tissues that exhibit varying levels of differentiation and proliferation potentials. The knowledge gained from these studies will help improve our understanding of the cellular signalling pathways involved in MSC growth, survival and differentiation, and may aid in the development of strategies to improve the tissue regeneration potential of MSCs for different clinical indications. The present review summarizes studies characterizing the gene expression profile of MSCs.     

微环境对心肌干细胞动员和分化的影响

在成体心脏和骨髓中存在多能性心肌干细胞(cardiac stem cell,CSC)。当心肌发生缺血坏死时,心肌局部微环境发生改变,在粒细胞集落刺激因子、基质细胞衍生因子、骨形态发生蛋白-2和胰岛素样生长因子-Ⅰ等各类因子的作用下,CSC可被动员至心肌缺血区,向心肌细胞、内皮细胞等定向分化,从而修复缺血坏死的心肌。因此,尝试改善心肌局部微环境对于CSC动员或移植治疗缺血性心脏病将具有重要意义。     

干细胞移植与肺缺血再灌注损伤

肺移植是治疗终末期肺疾病的唯一有效手段,但目前全球对于肺移植的治疗效果仍不能达到理想的要求,其中主要因素是供体肺组织由于缺血再灌注而导致的器官损伤,从而影响了移植物功能,但目前尚无有效的治疗措施,国际上对于肺缺血再灌注的治疗多以常规手段为主,但治疗效果难以突破完全修复损伤的技术瓶颈.将干细胞治疗引入到缺血再灌注损伤的治疗当中会带来新的希望,明确干细胞中的各个细胞亚群所起到的作用及其间的相互协调及辅助作用,会为临床治疗找到新的方向.