稳态及衰老情况下骨髓微环境对造血干细胞的调控作用

稳态下,骨髓微环境(bone marrow microenvironment)被证实能通过多种信号通路和细胞因子调控造血干细胞(hematopoietic stem cells,HSCs)的自我更新、增殖、分化和迁移能力以维持造血系统的稳定。在衰老过程中,HSCs功能受损会导致造血系统功能的退化以及年龄相关的免疫应答的改变,增加机体对贫血、自身免疫性和骨髓增生性疾病的易感性。HSCs的衰老最初被认为是一种细胞内在调控机制,但近年来,随着对骨髓造血微环境研究的深入,人们发现骨髓微环境不但能在稳态下调控HSCs的功能,而且在HSCs衰老的过程中也发挥着重要作用。该文将对稳态及衰老情况下骨髓微环境对HSCs的调控作用作一综述。     

间充质干细胞衰老基础的研究进展

间充质干细胞(mesenchymal stem cells, MSCs)是再生医学领域和组织工程领域研究应用最广泛的成体干细胞。MSCs不仅随着机体的衰老而衰老，而且MSCs的衰老也被认为是引起机体衰老的主要原因，是许多衰老相关退行性疾病的重要诱因。干细胞治疗的发展为衰老相关疾病的治疗带来了新的方向，然而体外扩增过程中供体细胞容易出现衰老，影响治疗效果，制约临床发展与应用。因此，该文针对MSCs衰老基础研究进行综述，为加快MSCs临床转化提供参考。     

精原干细胞与睾丸生殖衰老的研究进展

雄性睾丸内精子的生成及其质量随年龄增长逐渐降低。精原干细胞是精子生成的起点,其数量和质量决定了精子的生成,而精原干细胞niche是调节精原干细胞自我更新与分化的重要因素。在衰老过程中,干细胞微环境退化,精原干细胞自我更新和分化失衡,被认为是衰老导致睾丸生殖功能衰退的的主要因素。本文将综述衰老引起的精原干细胞与niche变化及其对生殖的影响相关研究进展。     

间充质干细胞来源的细胞外囊泡在机体修复及疾病治疗中的应用研究

间充质干细胞(mesenchymal stem cells, MSCs)作为一种成体干细胞,不仅具有干细胞固有的增殖分化能力,而且还拥有强大的免疫调节功能,所以在机体修复及炎症疾病的治疗中显示出广阔的应用前景.在近几年的研究中,越来越多的证据表明, MSCs的作用机制主要是通过其细胞旁分泌分泌出的细胞外囊泡(extracellular vesicles,EVs)而实现的. MSCs所分泌的EVs具有其亲本细胞的生物学特性,并且在许多疾病模型中有显著的治疗效果.研究表明, MSCs所分泌的EVs存在大量microRNA的富集,而microRNA的富集与血管生成、细胞凋亡和生长等功能有密切的关联.此外, EVs中还包含有源自MSCs的mRNA、细胞因子、趋化因子、免疫调节因子等生物活性分子,这些因素都在机体组织损伤修复和疾病治疗方面发挥着重要作用.本文总结了最新的关于MSCs-EVs的应用与研究进展,为深入讨论MSCs-EVs的作用机制及临床应用前景提供了综合信息.     

自噬与间充质干细胞衰老的关系研究进展

间充质干细胞(mesenchymal stem cells,MSCs)具备多向分化、免疫调控和靶向迁移的能力,在再生医学领域一直备受关注。但是,随着供体年龄的增长和体外培养时间的延长,MSCs通常表现出衰老特征。MSCs衰老以及功能衰退被认为是机体衰老和相关退行性疾病发展的重要诱发因素,同时也制约着MSCs在再生医学领域中的应用。自噬是溶酶体依赖途径介导细胞内物质的降解和再循环过程,是真核细胞的非核(细胞质)部分得以更新的有效途径,对维持细胞稳态至关重要,是调节MSCs衰老的潜在调控靶标。对MSCs衰老的表型特征、功能变化和分子机制,以及自噬与衰老之间的关系进行综述,为促进MSCs临床应用提供理论基础。     

微环境调控间充质干细胞复制性衰老的研究进展

间充质干细胞(mesenchymal stem cells, MSCs)是一类能自我更新和分化的多能细胞。越来越多的证据表明,MSCs在再生医学和组织工程等领域具有重要的作用。但是值得注意的是,与很多细胞一样,MSCs在长期体外扩增过程中会逐渐衰老,出现迁徙能力减弱、增殖速度减慢和分化潜能下降等干性减退的现象,这极大地阻碍了MSCs的应用。目前公认的引起MSCs复制性衰老的因素之一就是细胞生长的微环境。新近研究显示,外源性给药、氧浓度调节、细胞外基质(extracellular matrix, ECM)构建等最新技术都可以通过模拟或者调控微环境来改善干细胞的行为,延缓干细胞复制性衰老。本文首先综述了近年来关于MSCs复制性衰老特征和分子机制方面的研究进展,然后总结了通过改变微环境来保持MSCs干性的技术和方法,旨在为未来MSCs制剂大规模应用于组织工程和临床研究提供参考。     

衰老个体中的组织干细胞

组织干细胞是组织器官稳态维持和损伤修复或再生的结构基础。伴随着年龄的增加,组织干细胞的数量、增殖和分化等功能及其所处微环境发生改变,从而使得老年个体再生修复功能降低或异常。此外,组织干细胞的衰老与老年个体衰老相关疾病的发生有着密切的关系。该文拟介绍几种目前比较明确的组织干细胞在老年个体中发生改变的基本特征及其发生机制,旨在为正确理解老年组织机能低下提供重要的理论基础,并希望能够建立有效可行的延缓或逆转组织干细胞衰老的途径以提高老年人群的生活质量。     

利用多能干细胞技术研究和治疗衰老相关疾病

人类衰老是复杂的生物学过程,主要表现为组织、器官的功能性衰退以及衰老相关疾病风险的增加。多能性干细胞(PSC)是指具有多向分化潜能的细胞,主要包括胚胎干细胞(ESC)和诱导多能干细胞(iPSC)。多能干细胞技术的飞速发展和广泛应用为衰老及老年性疾病的科学研究和药物筛选提供了重要的平台。同时,日新月异的基因靶向编辑技术为衰老及相关疾病的干预及治疗提供了可行性。基于人类干细胞和基因编辑技术的衰老基础研究及应用具有重要的科学意义和社会价值。     

维生素D介导肿瘤微环境调控的研究进展

肿瘤微环境(tumor microenvironment,TME)与肿瘤发生、转移、耐药等息息相关,研究肿瘤微环境的调控机制能为肿瘤治疗提供新的线索。维生素D作为机体代谢性物质,广泛分布在细胞微环境中,能够参与肿瘤微环境的调控并发挥抑制肿瘤的功能。本文总结了维生素D的代谢以及作用机制,并综述了维生素D在肿瘤微环境中影响肿瘤细胞、肿瘤干细胞、肿瘤相关成纤维细胞等研究进展,为维生素D及其类似物在肿瘤治疗中的基础研究和临床应用研究等方面奠定基础。     

间充质干细胞影响肿瘤细胞增殖及其分子机理

间充质干细胞MSCs(mesenchymal stem cells)与肿瘤细胞间的相互作用是近年来肿瘤领域的研究热点之一.MSCs是一种多能干细胞,具有分化为成骨细胞、软骨细胞、脂肪细胞、纤维母细胞或肌肉细胞等多种间充质细胞的能力.MSCs在肿瘤细胞中表现出的归巢和转移能力为其成为潜在的抗肿瘤工具奠定了基础,MSCs转移到肿瘤细胞后参与重塑肿瘤微环境,并对其增殖、侵袭和转移等生物学行为产生重要影响.MSCs重塑肿瘤微环境后对肿瘤细胞的增殖究竟是促进还是抑制,相关文献报道有很大的争议.基于相关研究近况,主要综述骨髓间充质干细胞BMSCs(bone marrow derived mesenchymal stem cells)参与重塑肿瘤微环境对肿瘤细胞增殖的影响,并就已知的分子机理做一简要介绍.     

Senescent cells: A new Achilles’ heel to exploit for cancer medicine?

Cellular senescence is a typical tumor‐suppressive mechanism that restricts the proliferation of premalignant cells. However, mounting evidence suggests that senescent cells, which also persist in vivo, can promote the incidence of aging‐related disorders principally via the senescence‐associated secretory phenotype (SASP), among which cancer is particularly devastating. Despite the beneficial effects of the SASP on certain physiological events such as wound healing and tissue repair, more studies have demonstrated that senescent cells can substantially contribute to pathological conditions and accelerate disease exacerbation, particularly cancer resistance, relapse and metastasis. To limit the detrimental properties while retaining the beneficial aspects of senescent cells, research advancements that support screening, design and optimization of anti‐aging therapeutic agents are in rapid progress in the setting of prospective development of clinical strategies, which together represent a new wave of efforts to control human malignancies or mitigate degenerative complications.     

Emerging roles of extracellular vesicles in cellular senescence and aging

Cellular senescence is a cellular program that prevents the proliferation of cells at risk of neoplastic transformation. On the other hand, age‐related accumulation of senescent cells promotes aging at least partially due to the senescence‐associated secretory phenotype, whereby cells secrete high levels of inflammatory cytokines, chemokines, and matrix metalloproteinases. Emerging evidence, however, indicates that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Senescent cells secrete more EphA2 and DNA via EVs, which can promote cancer cell proliferation and inflammation, respectively. Extracellular vesicles secreted from DNA‐damaged cells can also affect telomere regulation. Furthermore, it has now become clear that EVs actually play important roles in many aspects of aging. This review is intended to summarize these recent progresses, with emphasis on relationships between cellular senescence and EVs.     

清除衰老细胞在衰老与老龄化相关疾病中的研究进展

衰老是一个新兴的重要研究领域,随着该领域相关知识的积累和技术的进步,人们逐渐意识到衰老本身可以被针对性地干预,实现延长寿命并且延缓衰老相关疾病的发生发展,具有重要的科学和现实意义.引起个体衰老的众多因素中,衰老细胞的积累被认为是导致器官衰老发生退行性变,最终引起衰老相关疾病的重要原因.近年来,多项研究表明,清除体内衰老细胞可以延缓多种衰老相关疾病的发生,直接证明了衰老细胞是导致衰老相关疾病的重要原因之一,为治疗衰老相关疾病提供了新靶点.细胞衰老是由于损伤积累诱发了细胞周期抑制通路的激活,细胞永久地退出细胞增殖周期.衰老细胞会发生细胞形态、转录谱、蛋白质稳态、表观遗传以及代谢等系列特征的改变,同时衰老细胞对凋亡发生抵抗从而在体内多器官组织积累.衰老细胞会激活炎症因子分泌通路,导致组织局部非感染性炎症微环境,进而导致器官退行性变及多种衰老相关疾病的发生发展.因此针对衰老细胞对凋亡抵抗的特性,多个研究小组通过筛选小分子化合物库,发现某些化合物能够选择性清除衰老细胞,这些小分子化合物被称为"senolytics",意为"衰老细胞杀伤性化合物".衰老细胞杀伤性化合物在多种衰老相关疾病动物模型中能够延缓疾病的发展并延长哺乳动物寿命.因此,靶向杀伤衰老细胞对多种衰老相关疾病的治疗从而提高健康寿命具有重要的临床应用前景.除靶向杀伤衰老细胞策略以外,干细胞移植、基因编辑、异体共生等策略在抗衰老研究发展中也具有重要意义,具有启发性.本文通过汇总近期衰老细胞清除领域的重要进展和多种抗衰老策略,将细胞衰老研究发展史做简要梳理,就细胞衰老与衰老相关疾病的关系作一综述,重点讨论衰老细胞在多种衰老相关疾病中作为治疗靶点的应用潜力,并就其局限性和进一步的研究方向进行探讨.     

From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes

Cellular senescence is a process by which cells enter a state of permanent cell cycle arrest. It is commonly believed to underlie organismal aging and age-associated diseases. However, the mechanism by which cellular senescence contributes to aging and age-associated pathologies remains unclear. Recent studies showed that senescent cells exert detrimental effects on the tissue microenvironment, generating pathological facilitators or aggravators. The most significant environmental effector resulting from senescent cells is the senescence-associated secretory phenotype (SASP), which is constituted by a strikingly increased expression and secretion of diverse pro-inflammatory cytokines. Careful investigation into the components of SASPs and their mechanism of action, may improve our understanding of the pathological backgrounds of age-associated diseases. In this review, we focus on the differential expression of SASP-related genes, in addition to SASP components, during the progress of senescence. We also provide a perspective on the possible action mechanisms of SASP components, and potential contributions of SASP-expressing senescent cells, to age-associated pathologies. [BMB Reports 2015; 48(10): 549-558]     

Aged‐senescent cells contribute to impaired heart regeneration

Aging leads to increased cellular senescence and is associated with decreased potency of tissue‐specific stem/progenitor cells. Here, we have done an extensive analysis of cardiac progenitor cells (CPCs) isolated from human subjects with cardiovascular disease, aged 32–86 years. In aged subjects (>70 years old), over half of CPCs are senescent (p16^INK4A, SA‐β‐gal, DNA damage γH2AX, telomere length, senescence‐associated secretory phenotype [SASP]), unable to replicate, differentiate, regenerate or restore cardiac function following transplantation into the infarcted heart. SASP factors secreted by senescent CPCs renders otherwise healthy CPCs to senescence. Elimination of senescent CPCs using senolytics abrogates the SASP and its debilitative effect in vitro. Global elimination of senescent cells in aged mice (INK‐ATTAC or wild‐type mice treated with D + Q senolytics) in vivo activates resident CPCs and increased the number of small Ki67‐, EdU‐positive cardiomyocytes. Therapeutic approaches that eliminate senescent cells may alleviate cardiac deterioration with aging and restore the regenerative capacity of the heart.     

Mesenchymal stem cell‐derived extracellular vesicles reduce senescence and extend health span in mouse models of aging

Aging drives progressive loss of the ability of tissues to recover from stress, partly through loss of somatic stem cell function and increased senescent burden. We demonstrate that bone marrow‐derived mesenchymal stem cells (BM‐MSCs) rapidly senescence and become dysfunctional in culture. Injection of BM‐MSCs from young mice prolonged life span and health span, and conditioned media (CM) from young BM‐MSCs rescued the function of aged stem cells and senescent fibroblasts. Extracellular vesicles (EVs) from young BM‐MSC CM extended life span of Ercc1 ^−/− mice similarly to injection of young BM‐MSCs. Finally, treatment with EVs from MSCs generated from human ES cells reduced senescence in culture and in vivo, and improved health span. Thus, MSC EVs represent an effective and safe approach for conferring the therapeutic effects of adult stem cells, avoiding the risks of tumor development and donor cell rejection. These results demonstrate that MSC‐derived EVs are highly effective senotherapeutics, slowing the progression of aging, and diseases driven by cellular senescence.     

Placenta Stem/Stromal Cell–Derived Extracellular Vesicles for Potential Use in Lung Repair

Many acute and chronic lung injuries are incurable and rank as the fourth leading cause of death globally. While stem cell treatment for lung injuries is a promising approach, there is growing evidence that the therapeutic efficacy of stem cells originates from secreted extracellular vesicles (EVs). Consequently, EVs are emerging as next‐generation therapeutics. While EVs are extensively researched for diagnostic applications, their therapeutic potential to promote tissue repair is not fully elucidated. By housing and delivering tissue‐repairing cargo, EVs refine the cellular microenvironment, modulate inflammation, and ultimately repair injury. Here, the potential use of EVs derived from two placental mesenchymal stem/stromal cell (MSC) lines is presented; a chorionic MSC line (CMSC29) and a decidual MSC cell line (DMSC23) for applications in lung diseases. Functional analyses using in vitro models of injury demonstrate that these EVs have a role in ameliorating injuries caused to lung cells. It is also shown that EVs promote repair of lung epithelial cells. This study is fundamental to advancing the field of EVs and to unlock the full potential of EVs in regenerative medicine.     

Senescent cells and macrophages: key players for regeneration?

Over the last decade, our understanding of the physiological role of senescent cells has drastically evolved, from merely indicators of cellular stress and ageing to having a central role in regeneration and repair. Increasingly, studies have identified senescent cells and the senescence-associated secretory phenotype (SASP) as being critical in the regenerative process following injury; however, the timing and context at which the senescence programme is activated can lead to distinct outcomes. For example, a transient induction of senescent cells followed by rapid clearance at the early stages following injury promotes repair, while the long-term accumulation of senescent cells impairs tissue function and can lead to organ failure. A key role of the SASP is the recruitment of immune cells to the site of injury and the subsequent elimination of senescent cells. Among these cell types are macrophages, which have well-documented regulatory roles in all stages of regeneration and repair. However, while the role of senescent cells and macrophages in this process is starting to be explored, the specific interactions between these cell types and how these are important in the different stages of injury/reparative response still require further investigation. In this review, we consider the current literature regarding the interaction of these cell types, how their cooperation is important for regeneration and repair, and what questions remain to be answered to advance the field.     

Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin

ERCC1 (excision repair cross complementing‐group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross‐link repair. Ercc1^?/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1^?/Δ mice display combined features of human progeroid and cancer‐prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1^?/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1^?/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1^?/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence‐associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor‐suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1‐deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1^?/Δ mouse skin, where the apoptotic cells are localized, compared to age‐matched wild‐type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1‐depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health‐ or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.