造血干细胞微环境中的相互调节

目的 对造血干细胞（hematopoietic stem cell）微环境的研究现状作一综述。方法阅读近年国内、外相关文献，对造血干细胞微环境的组成，以及参与调控造血干细胞的相关细胞因子及相关细胞信号通路的研究进展进行总结。结果造血干细胞的活动通过与周围细胞构成的微环境（即干细胞微环境）来控制的，其调控不可能通过一种信号通路来完成，当然也不可能仅仅通过成骨细胞来单独完成对造血干细胞自我更新和分化调节。结论微环境对造血干细胞的调节通过多环节起作用，随着对其研究的深入可以使我们对干细胞的性质有更全面的了解，并且对以干细胞为基础的治疗提供更广阔的空间。     

成骨生长肽的研究进展

成骨生长肽(osteogenic growth peptide,OGP)的作用及其机制是国内外研究的热点.研究主要集中在两个方面:OGP的促成骨作用和促进造血作用.细胞和动物实验研究发现,在骨折愈合过程中,OGP能够促进骨密度增加,加速骨折愈合;对于体外培养的成骨细胞,能够促进体外培养的大鼠成骨细胞增殖和分化,Cbfal,I型胶原mRNA表达水平,增加胶原合成;对于体外培养骨髓间充质干细胞,能够上调成骨性标志物的表达,促进其向成骨方向分化.OGP还可以改善骨髓造血微环境,对各种类型的造血细胞都有刺激增殖作用,对其他种类的干细胞也有类似作用.对于OGP的作用机制仍缺乏了解,尤其是受体作用机制.目前有三种观点解释:OGP作用于MSCs,促进其向成骨方向转化,抑制其向脂肪细胞方向转化;作用于TGF-β系统;通过影响HO-1发挥作用.涉及信号通路有MAP激酶、Src及RhoA三条.OGP I临床可用于治疗骨折、骨移植、骨质疏松等疾病;另一方面,OGP作为一种有丝分裂原对成骨细胞、骨髓造血干细胞、骨髓间充质干细胞具有促分裂增殖作用,为临床中治疗血液系统疾病、缓解骨髓抑制提供了新思路.本文对近几年来OGP的作用及其机制的研究进展作一简要综述.     

破骨细胞非溶骨功能研究进展

目的综述破骨细胞除骨吸收之外的功能研究进展。方法查阅近年来与破骨细胞功能研究相关的文献,排除与骨吸收有关的文献,并进行分析总结。结果破骨细胞从骨基质调节因子、双向信号和细胞因子3个方面调节骨形成,参与造血微环境的形成,造血干细胞动员及其数量、功能的维持,以及血管生成过程。结论目前对破骨细胞调节造血作用的确切机制仍缺乏深入了解;此外,破骨细胞耦联因子作用于成骨细胞分化的哪一过程、诱导的血管生成参与哪些生理或病理过程等关键问题也有待解决;揭示其内在机制有助于为治疗多种破骨细胞相关性疾病提供科学的策略。     

肾细胞癌的异基因造血干细胞移植治疗进展

近年来研究发现,异基因造血干细胞移植后可以产生抗肿瘤作用,这种作用对耐细胞因子的肾细胞癌也有很好的疗效,为肾细胞癌的治疗提供了一种新的方法。本文就异基因造血干细胞移植治疗肾细胞癌的研究进展作一综述。     

部分细胞因子在原发性骨质疏松症发病机理中的作用

随着社会老龄化进程 ,骨质疏松成为日益突出的公共健康问题。骨质疏松的发病机理仍不清楚 ,其中细胞因子通过自分泌与旁分泌和细胞粘附的方式在骨重建中起重要作用。本文就近年来细胞因子在原发性骨质疏松症发病机制中的作用的研究进展作一综述。1　细胞因子在骨重建过程中的作用破骨细胞来源于骨髓的造血干细胞 ,通过血循环运输到骨组织 ,融合成为成熟的多核破骨细胞。成骨细胞来源于骨髓中的多能基质干细胞 ,和基质细胞一样可以分泌细胞因子 ,调节破骨细胞的形成。骨重建的过程即是骨吸收以及随之而来的骨形成的偶联。在骨组织内 ,成熟的…     

骨髓脂肪细胞与骨质疏松症

近年来，随着细胞分子生物学研究进展，骨髓基质干细胞（bone marrow stromall cell，BMS）分化方向，及其调控机制在原发性、继发性骨质疏松症发生机理中的意义引起高度关注。各种原因通过某种机制导致成骨细胞分化减少，脂肪细胞分化增加，脂肪细胞进一步刺激更多的造血干细胞，分化为破骨细胞，进而引起成骨细胞——破骨细胞的偶联失衡，最终导致骨丢失和骨质疏松。因此，骨髓脂肪细胞生成及其调控机制的阐明，对骨质疏松症的预防和治疗具有重要意义。     

骨髓间充质干细胞在软骨组织工程化组织构建中的应用

人骨髓中所含的细胞可以分为造血类细胞和非造血类细胞。前者中含有的干细胞主要为造血干细胞,而后者中含有间充质类干细胞（mesenchymal sten cell）能够分化为骨、软骨、肌腱、脂肪、皮肤和其他类型的细胞。骨髓中含有多向分化潜能的细胞,这类细胞的共同特征是具有成纤维细胞的形态,能黏附塑料培养皿,并能形成细胞克隆,但无吞噬功能。     

自噬相关miRNAs、lncRNAs、circRNAs在骨质疏松症中的作用

骨质疏松症由骨吸收增加和骨形成减少引起,是一种常见代谢性骨疾病,其发生发展的详细分子机制尚不清晰。自噬作为一种应激反应性分解代谢过程,在维持细胞和组织稳态中起着关键作用。非编码RNAs,如微小RNAs、长链非编码RNAs和环状RNAs,通过作为调节因子对基因表达进行转录后调控,在包括自噬在内的许多细胞过程中发挥重要作用。研究表明,部分自噬相关ncRNAs通过调节骨髓间充质干细胞、成骨细胞、骨细胞和破骨细胞生理和发育过程参与维持骨稳态。基于此,本文综述了影响骨微环境的自噬相关微小RNAs、长链非编码RNAs和环状RNAs参与调控骨质疏松发生发展的最新研究进展,为探索骨质疏松症发病机制和确定临床治疗潜在靶点提供理论基础。     

骨相关细胞中钙敏感受体研究进展

钙平衡对机体的正常生理功能至关重要.骨组织是人体最重要的钙库,维持骨组织的动态平衡有利于机体的钙平衡.钙敏感受体在多种细胞中都有表达.研究发现在成骨细胞中,钙敏感受体促进细胞增殖、分化以及矿化作用;而在破骨细胞中,钙敏感受体介导高浓度钙离子引起细胞分化和凋亡.此外,钙敏感受体还能协助造血干细胞的准确定位.而肿瘤细胞中钙敏感受体的高度表达,提示该肿瘤细胞具有骨转移的倾向.笔者综述了钙敏感受体在成骨细胞、破骨细胞、造血干细胞、肿瘤骨转移中的研究进展.     

骨髓干细胞向肝细胞分化的研究进展

骨髓中存在多种具有很强的自我更新和多向分化能力的干细胞。研究表明,骨髓干细胞在体外可通过肝细胞生长因子等的诱导作用转化成肝样细胞,在体内利用特定微环境的作用也可转化为肝前体细胞和成熟的肝细胞,并明显改善肝功能。骨髓干细胞有望成为肝细胞移植或生物人工肝的新型种子细胞。本文就近年来对骨髓干细胞向肝细胞的转化研究进行综述。     

Role of osteoclasts in regulating hematopoietic stem and progenitor cells

Bone marrow (BM) cavities are utilized for hematopoiesis and to maintain hematopoietic stem cells (HSCs). HSCs have the ability to self-renew as well as to differentiate into multiple different hematopoietic lineage cells. HSCs produce their daughter cells throughout the lifespan of individuals and thus, maintaining HSCs is crucial for individual life. BM cavities provide a specialized microenvironment termed “niche” to support HSCs. Niches are composed of various types of cells such as osteoblasts, endothelial cells and reticular cells. Osteoclasts are unique cells which resorb bones and are required for BM cavity formation. Loss of osteoclast function or differentiation results in inhibition of BM cavity formation, an osteopetrotic phenotype. Osteoclasts are also reportedly required for hematopoietic stem and progenitor cell (HSPC) mobilization to the periphery from BM cavities. Thus, lack of osteoclasts likely results in inhibition of HSC maintenance and HSPC mobilization. However, we found that osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization by using three independent osteoclast-less animal models. In this review, I will discuss the roles of osteoclasts in hematopoietic stem cell maintenance and mobilization.     

Stem Cell Interactions in a Bone Marrow Niche

Stem cells differ from other cells of the body in their potential for multilineage differentiation and their continued proliferation without substantial loss of potential (so-called self-renewal). These properties are maintained and regulated by a specific microenvironment referred to as “niche.” This term has been used to indicate the specific location of stem cells within tissues, as well as the cellular and molecular components that critically determine stem cell behavior. Whereas other, perhaps less complex, stem cell niches (e.g., Drosophila germarium) have been more clearly dissected in the 30 years that have passed since these observations, the hematopoietic stem cell (HSC) niche has proven challenging due to the difficulty to detect HSCs under normal conditions and the dynamism of HSCs and other cells of the bone marrow that influence HSC behavior. This article reviews the recent development of the HSC niche field with emphasis on prospective integrative mechanisms within bone marrow homeostasis and multisystem physiology. For that purpose, we will first highlight anatomical and histological features of the bone marrow of relevance for HSC behavior; then, we will summarize the principal findings concerning different cell types and potential mechanisms by which they critically regulate HSC function.     

Cellular Complexity of the Bone Marrow Hematopoietic Stem Cell Niche

The skeleton serves as the principal site for hematopoiesis in adult terrestrial vertebrates. The function of the hematopoietic system is to maintain homeostatic levels of all circulating blood cells, including myeloid cells, lymphoid cells, red blood cells, and platelets. This action requires the daily production of more than 500 billion blood cells. The vast majority of these cells are synthesized in the bone marrow, where they arise from a limited number of hematopoietic stem cells (HSCs) that are multipotent and capable of extensive self-renewal. These attributes of HSCs are best demonstrated by marrow transplantation, where even a single HSC can repopulate the entire hematopoietic system. HSCs are therefore adult stem cells capable of multilineage repopulation, poised between cell fate choices which include quiescence, self-renewal, differentiation, and apoptosis. While HSC fate choices are in part determined by multiple stochastic fluctuations of cell autonomous processes, according to the niche hypothesis, signals from the microenvironment are also likely to determine stem cell fate. While it had long been postulated that signals within the bone marrow could provide regulation of hematopoietic cells, it is only in the past decade that advances in flow cytometry and genetic models have allowed for a deeper understanding of the microenvironmental regulation of HSCs. In this review, we will highlight the cellular regulatory components of the HSC niche.     

HSCT联合不同剂量内皮祖细胞输注对小鼠造血重建的影响

目的 探讨异基因造血干细胞移植联合不同剂量内皮祖细胞(EPC)输注对移植后造血重建的影响.方法 以C57BL/6小鼠为供鼠,Balb/c小鼠为受鼠,进行HSCT,输注骨髓单个核细胞数量为5×106个/只.仅进行HSCT者为单纯骨髓细胞移植组;行HSCT的同时经尾静脉输注供者骨髓单个核细胞诱导培养的EPC的受鼠为EPC联合移植组,EPC的输注量分别为5×104、1×105、5× 105和1×106个/只.另设正常对照组和致死量照射组.观察小鼠的存活率、造血重建情况及骨髓微环境的变化.结果 各EPC联合移植组小鼠存活时间长于单纯骨髓移植组,5×105 EPC联合移植组至观察结束时存活率为100％,高于其他各组(P＜0.05).移植后10和15 d,5×105 EPC联合移植组外周血白细胞数量高于其他组(P＜0.05).移植后15 d,5×105 EPC联合移植组外周血血小板数量高于其他组(P＜0.05).5×105 EPC联合移植组造血组织增生程度也好于其他组.5×105 EPC联合移植组骨髓内HSC比例为(1.06±0.03)％,高于其他各组(P＜0.05).结论 小鼠异基因骨髓移植中联合输注5×105 EPC能够有效促进造血重建,提高小鼠存活率.     

The prostate cancer bone marrow niche: more than just ‘fertile soil'

The hematopoietic stem cell (HSC) niche in the bone marrow has been studied extensively over the past few decades, yet the bone marrow microenvironment that supports the growth of metastatic prostate cancer (PCa) has only been recently considered to be a specialized ‘niche'' as well. New evidence supports the fact that disseminated tumor cells (DTCs) of PCa actually target the HSC niche, displace the occupant HSCs and take up residence in the pre-existing niche space. This review describes some of the evidence and mechanisms by which DTCs act as molecular parasites of the HSC niche. Furthermore, the interactions between DTCs, HSCs and the niche may provide new targets for niche-directed therapy, as well as insight into the perplexing clinical manifestations of metastatic PCa disease.     

Consequences of irradiation on bone and marrow phenotypes,and its relation to disruption of hematopoietic precursors

The rising levels of radiation exposure, specifically for medical treatments and accidental exposures, have added great concern for the long term risks of bone fractures. Both the bone marrow and bone architecture are devastated following radiation exposure. Even sub-lethal doses cause a deficit to the bone marrow microenvironment, including a decline in hematopoietic cells, and this deficit occurs in a dose dependent fashion. Certain cell phenotypes though are more susceptible to radiation damage, with mesenchymal stem cells being more resilient than the hematopoietic stem cells. The decline in total bone marrow hematopoietic cells is accompanied with elevated adipocytes into the marrow cavity, thereby inhibiting hematopoiesis and recovery of the bone marrow microenvironment. Poor bone marrow is also associated with a decline in bone architectural quality. Therefore, the ability to maintain the bone marrow microenvironment would hinder much of the trabecular bone loss caused by radiation exposure, ultimately decreasing some comorbidities in patients exposed to radiation.     

骨质疏松视野下骨脂代谢相关调控网络的研究

骨髓间充质干细胞作为多能干细胞的一种,在骨髓微环境中可主要分化为成骨细胞、脂肪细胞等,而这种成骨和成脂分化之间的相互制约和交互关系可被归纳为骨脂平衡,并且这种动态平衡对骨稳态的维持起着至关重要的作用。在骨脂交互作用的过程中,骨髓脂肪组织是沟通其信号的重要载体和关键途径,并介导着骨髓微环境中的多种代谢调控过程。近年来,随着研究人员对骨脂代谢方面研究的深入,其防治骨质疏松的相关调控网络逐渐得到揭示,但是目前对于在生理病理条件下骨脂分化状态及其分子机制仍缺少系统阐释。因此,本文拟通过总结相关文献并结合我们的研究,在明确骨髓微环境视野下骨脂平衡相关概念的基础上,深入剖析其分子机制,以便为骨质疏松症的防治提供新思路。     

The influence of parathyroid hormone on the adult hematopoietic stem cell niche

Adult hematopoietic stem cells (HSCs) reside in the bone marrow in stable microenvironments known as the stem cell niche. One key component of the stem cell niche is cells of the osteoblastic lineage. Factors that are known to affect osteoblast activity, such as parathyroid hormone (PTH), have also been shown to affect the HSCs. Treatment of mice with PTH has led to beneficial effects on the HSC pool, which have led to clinical trials of PTH treatment to enhance HSC-based therapies.     

Transplantation of the bone marrow microenvironment leads to hematopoietic chimerism without cytoreductive conditioning

BACKGROUND: It has been hypothesized that regimens to induce transplantation tolerance and long-term hematopoietic chimerism require recipient conditioning with whole body irradiation or a cytoablative regimen to create space within the marrow microenvironment to permit pluripotent stem cell engraftment. The purpose of this study was to determine if transplantation of an intact bone marrow microenvironment in the form of a bone graft would permit stable hematopoietic stem cell engraftment, shape the repertoire of developing T cells, and induce donor-specific unresponsiveness in the absence of a conditioning regimen. METHODS: Fragments of femur were transplanted under the kidney capsule of recipient mice. At defined time points after bone graft transplantation recipients were assayed for chimerism, bone graft viability, and responses to donor and third party alloantigens in vitro and in vivo. RESULTS: In the absence of an immunological barrier, bone graft transplantation resulted in long-term multi-lineage hematopoietic chimerism in the peripheral blood. Nude bone graft transplantation into SCID recipients resulted in development of donor- derived T cells that underwent negative selection on bone graft derived I-E+ cells within the thymus. Across a fully allogeneic barrier in immunocompetent recipients treated with combined blockade of the CD40 and CD28 pathways bone graft transplantation resulted in long-term donor-specific hyporesponsiveness in vitro and acceptance of donor specific skin grafts. CONCLUSIONS: Transplantation of bone marrow in the form of a bone graft may facilitate the production of hematopoietic chimerism and lead to long-term donor-specific hyporesponsiveness in the absence of a cytoreductive conditioning regimen.     

Extracellular matrix made by bone marrow cells facilitates expansion of marrow-derived mesenchymal progenitor cells and prevents their differentiation into osteoblasts.

We cultured MSCs on an ECM made by bone marrow cells to attempt to reconstitute the MSC niche. This ECM promoted replication of mesenchymal progenitors and retention of their multipotentiality. We conclude that the marrow ECM facilitates expansion of mesenchymal progenitors and hypothesize that it plays an important role in the maintenance of MSC stemness. INTRODUCTION: Mesenchymal colony-forming cells of the bone marrow comprise mesenchymal stem cells (MSCs) and their transit amplifying progeny, which we term mesenchymal colony-forming units (MCFUs). These progenitors undergo self-renewal and can differentiate into many different cell types including osteoblasts. However, they lose their unique properties when cultured on tissue culture plastic. This indicates that a critical feature of the marrow microenvironment that facilitates retention of stem cell properties is missing in such culture systems. In other tissues, the extracellular matrix (ECM) forms part of the specialized niche that controls stem cell behavior. Therefore, we examined whether a marrow cell-derived ECM promotes retention of the stem cell characteristics of MCFUs in vitro. MATERIALS AND METHODS: A cell-free ECM was prepared from cultured murine marrow adherent cells. The replication and multipotentiality of murine MCFUs maintained on this marrow cell-derived ECM were examined in vitro and in vivo and compared with the behavior of MCFUs maintained on plastic. RESULTS: The marrow cell-derived ECM was made up of collagen types I, III, and V, syndecan-1, perlecan, fibronectin, laminin, biglycan, and decorin, similar to the composition of the marrow ECM. This ECM preparation promoted MCFU replication, restrained their "spontaneous" differentiation toward the osteoblast lineage, and preserved their ability to differentiate into osteoblasts or adipocytes. Moreover, transplantation of MCFUs expanded on the marrow cell-derived ECM into immunocompromised mice generated five times more bone and eight times more hematopoietic marrow compared with MCFUs expanded on plastic. CONCLUSIONS: The marrow ECM facilitates expansion of MCFUs in vitro while preserving their stem cell properties. We hypothesize that the ECM made by bone marrow cells plays an important role in the maintenance of MSC function.