力学刺激诱导骨髓间充质干细胞选择分化的研究进展

机体细胞／组织处于复杂的力学环境中，力学刺激对细胞的形态、发育和功能起着重要的调节作用。骨髓间充质干细胞的增殖、选择分化受多种力学因素的影响，而且力学刺激的大小、方式以及作用时间对骨髓间充质干细胞定向分化的调节作用不尽相同。作者就力学因素对骨髓间充质干细胞选择分化的调节作用进行简要的综述。     

影响骨髓间充质干细胞成骨分化的力学信号传导机制研究进展

骨髓间充质干细胞(bone marrow stem cell,BMSC)是一种具有多向分化潜能的成体干细胞,适量的力学刺激能促进BMSC向成骨细胞分化。近几年来,一些学者利用力学刺激作用于体外培养的BMSC,促进其向成骨细胞分化,并且对其诱导分化的机制进行了大量研究。尽管这一机制目前尚不十分清楚,但是已有的研究表明,多条信号通路参与了该力学信号传导。本文就国内外近几年来关于力学信号影响BMSC成骨分化的信号转导机制研究进展做一综述。     

Inflammatory signals regulate hematopoietic stem cells

Hematopoietic stem cells (HSCs) are the progenitors of all blood and immune cells, yet their role in immunity is not well understood. Most studies have focused on the ability of committed lymphoid and myeloid precursors to replenish immune cells during infection. Recent studies, however, have indicated that HSCs also proliferate in response to systemic infection and replenish effector immune cells. Inflammatory signaling molecules including interferons, tumor necrosis factor-α and Toll-like receptors are essential to the HSC response. Observing the biology of HSCs through the lens of infection and inflammation has led to the discovery of an array of immune-mediators that serve crucial roles in HSC regulation and function.     

Modulation Effects of the 3D Strain Microenvironment on Characteristics of Mesenchymal Stem Cell-Derived Exosomes

It is necessary to investigate the characteristics of Mesenchymal stem cells(MSCs)derived exosomes,and especially their application in tissue regeneration.Previous studies have shown that inflammatory stimulation enhanced the secretion of MSC-derived exosomes with stronger anti-inflammatory protein,cytokine profiles,and functional RNA via altering COX2/PGE2 pathway.Recently,accumulating evidence has also revealed that biophysical cues(especially biomechanical cues)in cell microenvironment have significant effects not only on cells but also on their exosomes.It has been reported that applying bi-axial strain to MSCs induces formation of a stiffer cytoskeleton through mTORC2 signaling,which biases against adipogenic differentiation and toward osteoblastogenesis.At the same time,For example,dimensionality,composition and stiffness of the extracellular matrix(ECM)has been proved to affect the size and composition of exosomes secreted by cancer cells.However,the effects of biomechanical cues in the three-dimensional(3D)microenvironment on stem cell-derived exosomes remains to be unveiled.Therefore,it is important to understand the roles of 3D cell mechanical microenvironment in regulating the characteristics of stem cell-derived exosomes and develop more efficient approaches to enhance their functions.This study aimed to explore the changes in characteristics of exosomes secreted by MSCs in periodontium in response to the matrix strain in 3D.Periodontal ligament stem cells(PDLSCs)were cultured in a 3D strain microenvironment engineered with microscale magnetically stretched collagen hydrogels.The morphology,particle distribution,marker protein expression of PDLSC-derived exosomes were analyzed.Then the pro-osteogenic property of exosomes was evaluated by assessing cell viability,proliferation,migration and osteogenic differentiation of target cells,for instance human bone marrow mesenchymal stem cells(hBMSCs).Detailed characterizations revealed that PDLSC-derived exosomes in the 3D strain mi-croenvironment were with similar morphology,particle distribution and surface markers.Notably,Exosomes secreted by PDLSCs in strain microenvironment were more endocytosed by hBMSCs and were more potent in improving proliferation and migration of hBMSCs,comparing with PDLSCs in non-strain environment.Alizarin red staining and molecular biology experiments confirmed that treatment of exosomes secreted by PDLSCs under mechanical stimulation led to a significant increase in osteogenic differentiation of hBMSCs in vitro.Meanwhile,in vivo study also indicated that PDLSC-derived exosomes obtained from the 3D strain microenvironment could obviously promote new bone formation.Our findings revealed that mechanical cues profoundly affected the characteristics of PDLSC-derived exosomes,especially for their bio-activity,providing a foundation for using the 3D mechanical microenvironment to enhance the osteo-inductive functions of stem cell-derived exosomes in cell-free therapy for bone regeneration.     

A neural network model for cell classification based on single-cell biomechanical properties

The potential success of tissue engineering or other cell-based therapies is dependent on factors such as the purity and homogeneity of the source cell populations. The ability to enrich cell harvests for specific phenotypes can have significant effects on the overall success of such therapies. While most techniques for cell sorting or enrichment have relied on cell surface markers, recent studies have shown that single-cell mechanical properties can serve as identifying markers of phenotype. In this study, a neural network modeling approach was developed to classify mesenchymal-derived primary and stem cells based on their biomechanical properties. Cell sorting was simulated using previously published data characterizing the mechanical properties of several different cell types as measured by atomic force microscopy. Neural networks were trained using combined data sets, with the resultant groupings analyzed for their purity, efficiency, and enrichment. Heterogeneous populations of zonal chondrocytes, chondrosarcoma cells, and mesenchymal-lineage cells, respectively, could all be classified into enriched subpopulations. Additionally, adult stem cells (adipose-derived or bone marrow-derived) separated disproportionately into nodes associated with the three primary mesenchymal lineages examined. These findings suggest that mathematical approaches such as neural network modeling, in combination with novel measures of cell properties, may provide a means of classifying and eventually sorting mixed populations of cells that are otherwise difficult to identify using more established techniques. In this respect, the identification of biomechanically based cell properties that increase the percentage of stem cells capable of differentiating into predictable lineages may improve the overall success of cell-based therapies.     

微环境通过细胞骨架张力对骨髓间充质干细胞成骨分化的影响

细胞外基质（extracellular matrix，ECM）是微环境中为细胞提供力学线索的主要元件。干细胞对基质力学信号改变的响应主要通过细胞骨架实现。细胞外基质性能改变后，力学信号经信号复合体传递，细胞骨架作为贯穿细胞整体的网状支架结构，在分子马达的作用下纤维重组产生张力，该力学信号可以转导为化学信号或直接传递至细胞核骨架，产生一系列对干细胞干性、增殖、分化以及凋亡的影响。骨髓间充质干细胞（bone mesenchymal stem cells, BMSCs）对于骨改建和治疗具有重要的意义。总结微环境改变后细胞骨架张力在BMSCs成骨分化过程中的影响及力信号响应机制。     

动静态不同牵张条件下大鼠骨髓间充质干细胞的增殖与分化

背景：在体外和体内关于细胞对于不同的机械牵张反应的大量研究表明,牵张能够刺激成骨。然而鲜有文献报道不同的牵张方式对于同种细胞的影响有何不同。 目的：比较不同机械牵张方式对大鼠骨髓间充质干细胞的影响。 方法：分离培养大鼠骨髓间充质干细胞,应用自行研制的牵张装置对骨髓间充质干细胞分别施加动态、静态和模拟临床的混合牵张牵张刺激,分别检测3种刺激方式下骨髓间充质干细胞的增殖能力、碱性磷酸酶活性及Runx2基因的mRNA表达,并测量细胞骨钙素的分泌情况。 结果与结论：静态牵张组与对照组相比,细胞增殖能力提高18.67%,碱性磷酸酶活性、Runx2表达及骨钙素分泌无明显差异;动态牵张组相对于对照组,细胞碱性磷酸酶活性提高60.33%, Runx2表达上升49.67%,细胞外骨钙素的分泌提高了48%,然而细胞增殖则受到了抑制;混合牵张组相对于对照组,细胞增殖能力稍有上升但无统计学差异,其对碱性磷酸酶活性、Runx2表达以及骨钙素的分泌有一定的促进作用,但没有动态牵张组明显。结果提示,静态牵张能够显著刺激骨髓间充质干细胞的增殖,而动态牵张对于刺激骨髓间充质干细胞成骨向分化作用更为明显,混合牵张方式对于细胞增殖及成骨分化均有一定的促进作用。     

Muscle stem cells in development, regeneration, and disease

Somatic stem cell populations participate in the development and regeneration of their host tissues. Skeletal muscle is capable of complete regeneration due to stem cells that reside in skeletal muscle and nonmuscle stem cell populations. However, in severe myopathic diseases such as Duchenne Muscular Dystrophy, this regenerative capacity is exhausted. In the present review, studies will be examined that focus on the origin, gene expression, and coordinated regulation of stem cell populations to highlight the regenerative capacity of skeletal muscle and emphasize the challenges for this field. Intense interest has focused on cell-based therapies for chronic, debilitating myopathic diseases. Future studies that enhance our understanding of stem cell biology and repair mechanisms will provide a platform for therapeutic applications directed toward these chronic, life-threatening diseases.     

Epigenetic regulation of mammalian stem cells

Two critical properties of stem cells are self-renewal and multipotency. The maintenance of their "stemness" state and commitment to differentiation are therefore tightly controlled by intricate molecular networks. Epigenetic mechanisms, including DNA methylation, chromatin remodeling and the noncoding RNA-mediated process, have profound regulatory roles in mammalian gene expression. Recent studies have shown that epigenetic regulators are key players in stem cell biology and their dysfunction can result in human diseases such as cancer and neurodevelopmental disorders. Here, we review the recent evidences that advance our knowledge in epigenetic regulations of mammalian stem cells, with focus on embryonic stem cells and neural stem cells.     

牙周膜干细胞与牙周膜细胞甲状旁腺激素受体表达的比较

背景：牙周膜干细胞是牙周膜细胞中一类具有自我更新及多向分化潜能的间充质干细胞,经诱导可分化为成骨样细胞或脂肪样细胞。关于牙周膜干细胞是否表达甲状旁腺激素受体以及受体表达量对牙周膜干细胞成骨能力的影响等,目前尚未见相关报道。 目的：检测并比较牙周膜干细胞与牙周膜细胞中甲状旁腺激素受体表达的差异,并探讨甲状旁腺激素受体在成骨过程中的作用机制。 方法：应用免疫磁珠法筛选分离牙周膜干细胞及牙周膜细胞。通过细胞免疫荧光染色、荧光定量PCR等方法检测并比较牙周膜干细胞与牙周膜细胞中甲状旁腺激素受体的表达差异。应用荧光定量PCR、碱性磷酸酶活性检测及矿化能力分析等方法评价甲状旁腺激素受体对两者成骨能力的影响。 结果与结论：应用免疫磁珠法筛选的STRO-1阳性细胞,经细胞免疫荧光染色鉴定STRO-1、CD146、Vimentin等间充质干细胞表面表型均呈阳性,证明为牙周膜干细胞。细胞免疫荧光染色证明,牙周膜干细胞表达甲状旁腺激素受体,其主要分布于细胞膜与胞浆内,与牙周膜细胞及人成骨肉瘤MG63细胞系相似。荧光定量PCR结果表明,牙周膜干细胞甲状旁腺激素受体的表达量约为牙周膜细胞的3.7倍,与MG63细胞相近。经10^-7 mol/L甲状旁腺激素处理30 min后,牙周膜干细胞的甲状旁腺激素受体表达量明显增加。经成骨诱导后,牙周膜干细胞的甲状旁腺激素受体表达量、成骨相关基因表达量、碱性磷酸酶活性及矿化能力均高于牙周膜细胞。上述实验结果证明,牙周膜干细胞能表达甲状旁腺激素受体,且主要分布于细胞膜和细胞浆内。牙周膜干细胞甲状旁腺激素受体的表达量明显高于牙周膜细胞,而且甲状旁腺激素受体表达量与细胞的成骨能力相关,说明牙周膜干细胞比牙周膜细胞具有更强的成骨能力,是口腔组织工程学中具有广阔应用前景的种子细胞。 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Concise review: putting a finger on stem cell biology: zinc finger nuclease-driven targeted genetic editing in human pluripotent stem cells

Human pluripotent stem cells (hPSCs) encompassing human embryonic stem cells and human induced pluripotent stem cells (hiPSCs) have a wide appeal for numerous basic biology studies and for therapeutic applications because of their potential to give rise to almost any cell type in the human body and immense ability to self-renew. Much attention in the stem cell field is focused toward the study of gene-based anomalies relating to the causative affects of human disease and their correction with the potential for patient-specific therapies using gene corrected hiPSCs. Therefore, the genetic manipulation of stem cells is clearly important for the development of future medicine. Although successful targeted genetic engineering in hPSCs has been reported, these cases are surprisingly few because of inherent technical limitations with the methods used. The development of more robust and efficient means by which to achieve specific genomic modifications in hPSCs has far reaching implications for stem cell research and its applications. Recent proof-of-principle reports have shown that genetic alterations with minimal toxicity are now possible through the use of zinc finger nucleases (ZFNs) and the inherent DNA repair mechanisms within the cell. In light of recent comprehensive reviews that highlight the applications, methodologies, and prospects of ZFNs, this article focuses on the application of ZFNs to stem cell biology, discussing the published work to date, potential problems, and future uses for this technology both experimentally and therapeutically.     

Therapeutic Application of Adipose Derived Stem Cells in Acute Myocardial Infarction: Lessons from Animal Models

The majority of patients survive an acute myocardial infarction (AMI). Their outcome is negatively influenced by post-AMI events, such as loss of viable cardiomyocytes due to a post-AMI inflammatory response, eventually resulting in heart failure and/or death. Recent pre-clinical animal studies indicate that mesenchymal stem cells derived from adipose tissue (ASC) are new promising candidates that may facilitate cardiovascular regeneration in the infarcted myocardium. In this review we have compared all animal studies in which ASC were used as a therapy post-AMI and have focused on aspects that might be important for future successful clinical application of ASC.     

Role of Gap Junctions in Embryonic and Somatic Stem Cells

Stem cells provide an invaluable tool to develop cell replacement therapies for a range of serious disorders caused by cell damage or degeneration. Much research in the field is focused on the identification of signals that either maintain stem cell pluripotency or direct their differentiation. Understanding how stem cells communicate within their microenvironment is essential to achieve their therapeutic potentials. Gap junctional intercellular communication (GJIC) has been described in embryonic stem cells (ES cells) and various somatic stem cells. GJIC has been implicated in regulating different biological events in many stem cells, including cell proliferation, differentiation and apoptosis. This review summarizes the current understanding of gap junctions in both embryonic and somatic stem cells, as well as their potential role in growth control and cellular differentiation.     

聚羟基乙酸-犬牙髓干细胞复合体修复犬牙周组织缺损

文题释义：牙髓干细胞：是牙髓组织中高度增殖、具有自我更新能力和多向分化潜能的一类成体干细胞,来源丰富、获取方便、不涉及伦理问题,在牙齿、骨和神经的修复、再生及组织工程相关研究中具有重要作用。 牙周组织缺损：包括牙周韧带、牙骨质和牙槽骨的破坏,牙周组织缺损或丧失常见于牙周病和牙周创伤。牙周组织缺损最理想的愈合是达到牙槽骨、牙骨质和牙周膜的完全功能性再生,从而获得牙周新附着。 背景：前期研究构建了聚羟基乙酸-人牙髓干细胞复合物,发现力学刺激该复合体可有效构建组织工程化肌腱韧带样组织。 目的：假设聚羟基乙酸与犬牙髓干细胞构建的肌腱/韧带组织工程复合物可以促进牙周组织缺损,验证其修复犬一壁牙周缺损的效果。方法：制备6只比格犬急性一壁牙周缺损模型,随机分为2组：实验组植入聚羟基乙酸-犬牙髓干细胞复合物,对照组不做任何填充处理。移植12周后,通过苏木精-伊红染色、AZAN组织学染色观察牙周再生情况。动物实验获得南京军区福州总医院实验动物福利与伦理委员会批准。结果与结论：①苏木精-伊红染色：实验组牙周缺损处可见较多的新骨生成,离根面缺损的远端处新生骨结构与正常骨组织结构仍存在差别,上方纤维结缔组织较厚;对照组缺损处只有少量新骨形成,牙龈与根面并没有结合形成长结合上皮结构;②AZAN染色：实验组牙周缺损处可见致密的新骨生成、牙周膜再生及较薄的牙骨质层形成,新生牙周膜与正常牙周膜组织接近;对照组缺损处只有少量新骨形成,几乎没有新生牙周膜,上方为牙龈结缔组织,牙龈与根面并没有结合形成长结合上皮结构;③组织学定量分析结果显示,实验组结合上皮长度、新生牙骨质、新生牙周膜、新生骨高度、新生骨面积均多于对照组(P < 0.05);④结果表明,犬牙髓干细胞复合聚羟基乙酸可以促进牙周组织再生。ORCID: 0000-0003-2093-7549(周鹏飞) 中国组织工程研究杂志出版内容重点：生物材料;骨生物材料; 口腔生物材料; 纳米材料; 缓释材料; 材料相容性;组织工程     

Engineering the cell-material interface for controlling stem cell adhesion, migration, and differentiation

The effective utilization of stem cells in regenerative medicine critically relies upon our understanding of the intricate interactions between cells and their extracellular environment. While bulk mechanical and chemical properties of the matrix have been shown to influence various cellular functions, the role of matrix interfacial properties on stem cell behavior is unclear. Here, we report the striking effect of matrix interfacial hydrophobicity on stem cell adhesion, motility, cytoskeletal organization, and differentiation. This is achieved through the development of tunable, synthetic matrices with control over their hydrophobicity without altering the chemical and mechanical properties of the matrix. The observed cellular responses are explained in terms of hydrophobicity-driven conformational changes of the pendant side chains at the interface leading to differential binding of proteins. These results demonstrate that the hydrophobicity of the extracellular matrix could play a considerably larger role in dictating cellular behaviors than previously anticipated. Additionally, these tunable matrices, which introduce a new control feature for regulating various cellular functions offer a platform for studying proliferation and differentiation of stem cells in a controlled manner and would have applications in regenerative medicine.     

A New Chapter for Mesenchymal Stem Cells: Decellularized Extracellular Matrices

From orthopedic to neurological disorders, stem cells are used as platforms to understand disease mechanisms and considered as novel and promising treatment options, especially when the valid therapeutic approaches are unavailable or ineffective. There are different stem cell types in the literature, however the spindle-shaped, colony forming and multilineage-differentiating cells, also known as mesenchymal stem cells (MSC) are very popular, as MSC can be isolated from different tissues with minimal ethical concerns and without tumor formations, which make them easily accessible and widely used in vitro and in vivo studies. In the literature, MSC have been shown to have therapeutic effects and orchestrate the healing process via their mobilization, migration, differentiation capacities, immunomodulation properties and/or secretion of bioactive factors. Nowadays, MSC derived extracellular matrices (ECM), which are part of the secreted/produced bioactive molecules from MSC; draw attention of researchers due to their key roles in cell biology. Several groups have isolated ECM from in vitro cultured MSC using different methods of decellularization techniques for tissue-engineering approaches. According to current knowledge, decellularized ECM (dECM) influence growth, adhesion, differentiation, migration, apoptosis, proliferation, and phenotype of cells, covering almost all cellular events. In this comprehensive review we focused on MSC and the isolation methods and effects of MSC derived dECM (MSC-dECM).     

The influence of substrate creep on mesenchymal stem cell behaviour and phenotype

Human mesenchymal stem cells (hMSCs) are capable of probing and responding to the mechanical properties of their substrate. Although most biological and synthetic matrices are viscoelastic materials, previous studies have primarily focused upon substrate compressive modulus (rigidity), neglecting the relative contributions that the storage (elastic) and loss (viscous) moduli make to the summed compressive modulus. In this study we aimed to isolate and identify the effects of the viscous component of a substrate on hMSC behaviour. Using a polyacrlyamide gel system with constant compressive modulus and varying loss modulus we determined that changes to substrate loss modulus substantially affected hMSC morphology, proliferation and differentiation potential. In addition, we showed that the effect of substrate loss modulus on hMSC behaviour is due to a reduction in both passive and actively generated isometric cytoskeletal tension caused by the inherent creep of substrates with a high loss modulus. These findings highlight substrate creep, or more explicitly substrate loss modulus, as an important mechanical property of a biomaterial system that can be tailored to encourage the growth and differentiation of specific cell types.     

Pre-transplantation Specification of Stem Cells to Cardiac Lineage for Regeneration of Cardiac Tissue

Myocardial infarction (MI) is a lead cause of mortality in the Western world. Treatment of acute MI is focused on restoration of antegrade flow which inhibits further tissue loss, but does not restore function to damaged tissue. Chronic therapy for injured myocardial tissue involves medical therapy that attempts to minimize pathologic remodeling of the heart. End stage therapy for chronic heart failure (CHF) involves inotropic therapy to increase surviving cardiac myocyte function or mechanical augmentation of cardiac performance. Not until the point of heart transplantation, a limited resource at best, does therapy focus on the fundamental problem of needing to replace injured tissue with new contractile tissue. In this setting, the potential for stem cell therapy has garnered significant interest for its potential to regenerate or create new contractile cardiac tissue. While to date adult stem cell therapy in clinical trials has suggested potential benefit, there is waning belief that the approaches used to date lead to regeneration of cardiac tissue. As the literature has better defined the pathways involved in cardiac differentiation, preclinical studies have suggested that stem cell pretreatment to direct stem cell differentiation prior to stem cell transplantation may be a more efficacious strategy for inducing cardiac regeneration. Here we review the available literature on pre-transplantation conditioning of stem cells in an attempt to better understand stem cell behavior and their readiness in cell-based therapy for myocardial regeneration.     

细胞力学机械刺激对牙髓干细胞的影响

文题释义：牙髓干细胞：通过GRONTHOS等对牙髓细胞的研究,发现一种具有与间充质干细胞相似免疫表型和形成矿化结节能力的细胞,称为牙髓干细胞,具有自我更新、多向分化和较强的克隆能力。细胞力学：研究细胞在力学载荷作用下细胞膜和细胞骨架的变形、弹性常数、黏弹性、黏附力等力学性质,以及机械因素对细胞生长、发育、成熟、增殖、分化、衰老和死亡等的影响及其机制研究,是生物力学的一个前沿领域,也是组织工程学的一个重要组成部分。  摘要背景：力学刺激对于机体内很多器官、组织的发育和损伤修复发挥重要的调控作用。除生物化学因素外,细胞力学等机械因素越来越被认为是影响牙髓干细胞行为和功能的关键调节因素。目的：综述细胞力学刺激对牙髓干细胞生物学行为的作用及影响。方法：通过检索PubMed、Embase、Medline、CNKI数据库,分别以“牙髓干细胞,机械压力,机械张力,剪切力,压应力,细胞增殖,成骨分化”为中文检索词和“human dental pulp stem cells(hDPSCs),mechanical strain,mechanical stretch,mechanical tension,shear stress,cell proliferation,osteogenesis differentiation”为英文检索词进行检索,选取与细胞力学机械刺激参与影响牙髓干细胞增殖、分化的56篇文献进行综述。结果与结论：细胞力学机械刺激是影响细胞增殖、分化、蛋白表达和凋亡的重要生物学因素。牙髓干细胞是牙髓组织中的间充质干细胞,其生物学行为也受到细胞力学机械刺激的影响。细胞力学刺激参与牙髓干细胞的增殖、成牙/成骨分化,并且当牙本质受到流体流动力作用时,会激活其机械感受器来调节并维持牙齿的完整性。介导牙髓干细胞生物学行为的信号通路包括MAPK、Wnt、Akt及BMP-7、Nrf2/HO-1等,通过调控这些信号通路进而对牙髓干细胞增殖及成牙/成骨分化发挥不同程度的促进及抑制作用。ORCID: 0000-0001-6191-6539(李峻青) 中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程     

In vitro marrow culture techniques in aplastic anaemia and related disorders.

In vitro studies of marrow growth from patients with AA have generally confirmed the hypothesis that the disease is due to stem cell injury. By studies of marrow growth from AA patients (when possible) and their relatives to detect altered sensitivity of marrow stem cells to drugs or toxins, it may be possible better to identify suspected aetiological agents, and study genetic susceptibility to toxic AA. Lack of adequate stimulation has not been shown to be aetiological in AA as both ESF and CSF levels are generally higher than normal. Serum from AA patients has not been shown to be toxic to marrow and recent data suggesting that lymphocytes mediate some cases of AA have been questioned. Further studies of committed stem cell growth and the interaction between lymphocytes and stem cells are indicated in attempting to understand the complex of diseases that result in marrow aplasia.