膝关节内干细胞/祖细胞在软骨再生中作用研究进展

关节软骨(AC)由于缺乏血管、神经和淋巴,一旦损伤无法自我修复.虽然以外源性细胞为基础的治疗策略在一定程度上能够再生关节软骨,但仍然存在手术间隔长、供体有限、细胞体外培养易去分化和病原体传播等风险.成人膝关节存在许多类型干细胞/祖细胞(SCPCs),当软骨损伤时,就会被动员,迁移到损伤部位,参与再生修复.因此,基于趋化...     

Programmed cell death in stem cell-based therapy: Mechanisms and clinical applications

Stem cell-based therapy raises hopes for a better approach to promoting tissue repair and functional recovery. However, transplanted stem cells show a high death percentage, creating challenges to successful transplantation and prognosis. Thus, it is necessary to investigate the mechanisms underlying stem cell death, such as apoptotic cascade activation, excessive autophagy, inflammatory response, reactive oxygen species, excitotoxicity, and ischemia/hypoxia. Targeting the molecular pathways involved may be an efficient strategy to enhance stem cell viability and maximize transplantation success. Notably, a more complex network of cell death receives more attention than one crucial pathway in determining stem cell fate, highlighting the challenges in exploring mechanisms and therapeutic targets. In this review, we focus on programmed cell death in transplanted stem cells. We also discuss some promising strategies and challenges in promoting survival for further study.     

Stem cell therapies in cardiac diseases: Current status and future possibilities

Cardiovascular diseases represent the world’s leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.     

Mechanisms of DNA damage repair in adult stem cells and implications for cancer formation

Maintenance of genomic integrity in tissue-specific stem cells is critical for tissue homeostasis and the prevention of deleterious diseases such as cancer. Stem cells are subject to DNA damage induced by endogenous replication mishaps or exposure to exogenous agents. The type of DNA lesion and the cell cycle stage will invoke different DNA repair mechanisms depending on the intrinsic DNA repair machinery of a cell. Inappropriate DNA repair in stem cells can lead to cell death, or to the formation and accumulation of genetic alterations that can be transmitted to daughter cells and so is linked to cancer formation. DNA mutational signatures that are associated with DNA repair deficiencies or exposure to carcinogenic agents have been described in cancer. Here we review the most recent findings on DNA repair pathways activated in epithelial tissue stem and progenitor cells and their implications for cancer mutational signatures. We discuss how deep knowledge of early molecular events leading to carcinogenesis provides insights into DNA repair mechanisms operating in tumours and how these could be exploited therapeutically.     

Stem cell self-renewal in intestinal crypt

As a rapidly cycling tissue capable of fast repair and regeneration, the intestinal epithelium has emerged as a favored model system to explore the principles of adult stem cell biology. However, until recently, the identity and characteristics of the stem cell population in both the small intestine and colon has remained the subject of debate. Recent studies based on targeted lineage tracing strategies, combined with the development of an organotypic culture system, have identified the crypt base columnar cell as the intestinal stem cell, and have unveiled the strategy by which the balance between proliferation and differentiation is maintained. These results show that intestinal stem cells operate in a dynamic environment in which frequent and stochastic stem cell loss is compensated by the proliferation of neighboring stem cells. We review the basis of these experimental findings and the insights they offer into the mechanisms of homeostatic stem cell regulation.     

Telomere dysfunction and stem cell ageing

Ageing is characterized by a decline in organ maintenance and repair. Adult stem cells contribute to tissue repair and organ maintenance. Thus it is conceivable that ageing is partly due to a decline of stem cell function. At molecular level, ageing is associated with an accumulation of damage affecting DNA, proteins, membranes, and organelles, as well as the formation of insoluble protein aggregates. Telomere shortening represents a cell intrinsic mechanism, which contributes to the accumulation of DNA damage during cellular ageing. Telomere dysfunction in response to critical telomere shortening induces DNA damage checkpoints that lead to cell cycle arrest and/or cell death. Checkpoint responses induced by telomere dysfunction have mostly been studied in somatic cells but there are emerging data on cell intrinsic checkpoints that impair the maintenance and function of adult stem cell in response to telomere dysfunction. Moreover, telomere dysfunction induces alterations in the stem cell environment that limit the function of adult stem cells. In this review we summarize our current knowledge on the role of telomere dysfunction in adult stem cell ageing.     

TWEAK/Fn14信号调控干细胞增殖与分化的作用与机制

肿瘤坏死因子样弱凋亡诱导蛋白(TWEAK)是肿瘤坏死因子(TNF)超家族成员,通过作用于唯一受体成纤维细胞生长因子14(Fn14)调控细胞的增殖、分化和迁移等多种生命活动。近来研究表明,TWEAK/Fn14信号可以作用于多种干细胞,如肝干细胞、神经干细胞和间充质干细胞等,通过影响其增殖与分化的能力,干预组织的修复与再生。对该领域的研究进行综述,将有助于揭示TWEAK/Fn14信号调控干细胞增殖与分化的作用与机制,并为干细胞在疾病发生机制等基础研究、细胞治疗和组织工程等临床医学研究提供新的方向。     

Mechanotransduction of stem cells for tendon repair

Tendon is a mechanosensitive tissue that transmits force from muscle to bone. Physiological loading contributes to maintaining the homeostasis and adaptation of tendon, but aberrant loading may lead to injury or failed repair. It is shown that stem cells respond to mechanical loading and play an essential role in both acute and chronic injuries, as well as in tendon repair. In the process of mechanotransduction, mechanical loading is detected by mechanosensors that regulate cell differentiation and proliferation via several signaling pathways. In order to better understand the stem-cell response to mechanical stimulation and the potential mechanism of the tendon repair process, in this review, we summarize the source and role of endogenous and exogenous stem cells active in tendon repair, describe the mechanical response of stem cells, and finally, highlight the mechanotransduction process and underlying signaling pathways.     

Regeneration of the retina: toward stem cell therapy for degenerative retinal diseases

Degenerative retinal diseases affect millions of people worldwide, which can lead to the loss of vision. However, therapeutic approaches that can reverse this process are limited. Recent efforts have allowed the possibility of the stem cell-based regeneration of retinal cells and repair of injured retinal tissues. Although the direct differentiation of pluripotent stem cells into terminally differentiated photoreceptor cells comprises one approach, a series of studies revealed the intrinsic regenerative potential of the retina using endogenous retinal stem cells. Muller glial cells, ciliary pigment epithelial cells, and retinal pigment epithelial cells are candidates for such retinal stem cells that can differentiate into multiple types of retinal cells and be integrated into injured or developing retina. In this review, we explore our current understanding of the cellular identity of these candidate retinal stem cells and their therapeutic potential for cell therapy against degenerative retinal diseases. [BMB Reports 2015; 48(4): 193-199]     

Mesenchymal stem cells as anti-inflammatories: Implications for treatment of Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal X-linked musculodegenerative condition consisting of an underlying genetic defect whose manifestation is augmented by inflammatory mechanisms. Previous treatment approaches using gene replacement, exon-skipping or allogeneic cell therapy have been relatively unsuccessful. The only intervention to mediate improvement in survival, albeit minor, is glucocorticoid treatment. Given this modality appears to function via suppression of underlying inflammation; we focus this review on the inflammatory response as a target for mesenchymal stem cell (MSC) therapy. In contrast to other cell based therapies attempted in DMD, MSC have the advantages of (a) ability to fuse with and genetically complement dystrophic muscle; (b) possess anti-inflammatory activities; and (c) produce trophic factors that may augment activity of endogenous repair cells. We conclude by describing one practical scenario of stem cell therapy for DMD.     

How stem cells remember their past

Somatic stem cells are required for tissue development, homeostasis, and repair. Recent data suggested that previous biographical experiences of individual stem cells influence their behavior in the context of tissue formation and govern stem cell responses to external stimuli. Here we provide a concise review how a cell's biography, for example, previous rounds of cell divisions or the age-dependent accumulation of cellular damage, is remembered in stem cells and how previous experiences affect the segregation of cellular components, thus guiding cellular behavior in vertebrate stem cells. Further, we suggest future directions of research that may help to unravel the molecular underpinnings of how past experiences guide future cellular behavior.     

Stem cell therapies in tendon-bone healing

Tendon-bone insertion injuries such as rotator cuff and anterior cruciate ligament injuries are currently highly common and severe. The key method of treating this kind of injury is the reconstruction operation. The success of this reconstructive process depends on the ability of the graft to incorporate into the bone. Recently, there has been substantial discussion about how to enhance the integration of tendon and bone through biological methods. Stem cells like bone marrow mesenchymal stem cells (MSCs), tendon stem/progenitor cells, synovium-derived MSCs, adipose-derived stem cells, or periosteum-derived periosteal stem cells can self-regenerate and potentially differentiate into different cell types, which have been widely used in tissue repair and regeneration. Thus, we concentrate in this review on the current circumstances of tendon-bone healing using stem cell therapy.     

Therapeutic Use of Stem Cell Transplantation for Cell Replacement or Cytoprotective Effect of Microvesicle Released from Mesenchymal Stem Cell

Idiopathic pulmonary fibrosis (IPF) is the most common and severe type of idiopathic interstitial pneumonias (IIP), and which is currently no method was developed to restore normal structure and function. There are several reports on therapeutic effects of adult stem cell transplantations in animal models of pulmonary fibrosis. However, little is known about how mesenchymal stem cell (MSC) can repair the IPF. In this study, we try to provide the evidence to show that transplanted mesenchymal stem cells directly replace fibrosis with normal lung cells using IPF model mice. As results, transplanted MSC successfully integrated and differentiated into type II lung cell which express surfactant protein. In the other hand, we examine the therapeutic effects of microvesicle treatment, which were released from mesenchymal stem cells. Though the therapeutic effects of MV treatment is less than that of MSC treatment, MV treat-ment meaningfully reduced the symptom of IPF, such as collagen deposition and inflammation. These data suggest that stem cell transplantation may be an effective strategy for the treatment of pulmonary fibrosis via replacement and cytoprotective effect of microvesicle released from MSCs.     

Regulating the fate of stem cells for regenerating the intervertebral disc degeneration

Lower back pain is a leading cause of disability and is one of the reasons for the substantial socioeconomic burden. The etiology of intervertebral disc (IVD) degeneration is complicated, and its mechanism is still not completely understood. Factors such as aging, systemic inflammation, biochemical mediators, toxic environmental factors, physical injuries, and genetic factors are involved in the progression of its pathophysiology. Currently, no therapy for restoring degenerated IVD is available except pain management, reduced physical activities, and surgical intervention. Therefore, it is imperative to establish regenerative medicine-based approaches to heal and repair the injured disc, repopulate the cell types to retain water content, synthesize extracellular matrix, and strengthen the disc to restore normal spine flexion. Cellular therapy has gained attention for IVD management as an alternative therapeutic option. In this review, we present an overview of the anatomical and molecular structure and the surrounding pathophysiology of the IVD. Modern therapeutic approaches, including proteins and growth factors, cellular and gene therapy, and cell fate regulators are reviewed. Similarly, small molecules that modulate the fate of stem cells for their differentiation into chondrocytes and notochordal cell types are highlighted.     

Microfluidic three-dimensional cell culture of stem cells for high-throughput analysis

Although the recent advances in stem cell engineering have gained a great deal of attention due to their high potential in clinical research, the applicability of stem cells for preclinical screening in the drug discovery process is still challenging due to difficulties in controlling the stem cell microenvironment and the limited availability of high-throughput systems. Recently, researchers have been actively developing and evaluating three-dimensional (3D) cell culture-based platforms using microfluidic technologies, such as organ-on-a-chip and organoid-on-a-chip platforms, and they have achieved promising breakthroughs in stem cell engineering. In this review, we start with a comprehensive discussion on the importance of microfluidic 3D cell culture techniques in stem cell research and their technical strategies in the field of drug discovery. In a subsequent section, we discuss microfluidic 3D cell culture techniques for high-throughput analysis for use in stem cell research. In addition, some potential and practical applications of organ-on-a-chip or organoid-on-a-chip platforms using stem cells as drug screening and disease models are highlighted.     

The use of adipose-derived stem cells as sheets for wound healing

Cellular therapies have shown immense promise in the treatment of nonhealing wounds. Cell sheets are an emerging strategy in tissue engineering, and these cell sheets are promising as a delivery method of mesenchymal stem cells to the wound bed. Cell sheet technology utilizes temperature dependent polymers to allow for lifting of cultured cells and extracellular matrix without the use of digestive enzymes. While mesenchymal stem cells (MSCs) have shown success in cell sheets for myocardial repair, examination of cell sheets in the field of wound healing has been limited. We previously developed a novel cell sheet composed of human adipose-derived stem cells (ASCs). Both single and triple layer cell sheets were examined in a full-thickness murine wound model. The treatment cell sheets were compared with untreated controls and analyzed at timepoints of 7, 14, 18 and 21 d. The ASC cell sheets showed increased healing at 7, 14 and 18 d, and this effect was increased in the triple layer cell sheet group. Future development of these cell sheets will focus on increasing angiogenesis in the wound bed, utilizing multiple cell types, and examining allogeneic cell sheets. Here we review our experiment, expand upon our future directions and discuss the potential of an off-the-shelf cell sheet. In the field of wound healing, such a cell sheet is both clinically and scientifically exciting.     

Multiplexed targeting of microRNA in stem cell-derived extracellular vesicles for regenerative medicine

Regenerative medicine is a research field that develops methods to restore damaged cell or tissue function by regeneration, repair or replacement. Stem cells are the raw material of the body that is ultimately used from the point of view of regenerative medicine, and stem cell therapy uses cells themselves or their derivatives to promote responses to diseases and dysfunctions, the ultimate goal of regenerative medicine. Stem cell-derived extracellular vesicles (EVs) are recognized as an attractive source because they can enrich exogenous microRNAs (miRNAs) by targeting pathological recipient cells for disease therapy and can overcome the obstacles faced by current cell therapy agents. However, there are some limitations that need to be addressed before using miRNA-enriched EVs derived from stem cells for multiplexed therapeutic targeting in many diseases. Here, we review various roles on miRNA-based stem cell EVs that can induce effective and stable functional improvement of stem cell-derived EVs. In addition, we introduce and review the implications of several miRNA-enriched EV therapies improved by multiplexed targeting in diseases involving the circulatory system and nervous system. This systemic review may offer potential roles for stem cell-derived therapeutics with multiplexed targeting.     

Microenvironment at tissue injury, a key focus for efficient stem cell therapy: A discussion of mesenchymal stem cells

Stem cell therapy is not a new field, as indicated by the success of hematopoietic stem cell reconstitution for various hematological malignancies and immune-mediated disorders. In the case of tissue repair, the major issue is whether stem cells should be implanted, regardless of the type and degree of injury. Mesenchymal stem cells have thus far shown evidence of safety, based on numerous clinical trials, particularly for immune-mediated disorders. The premise behind these trials is to regulate the stimulatory immune responses negatively. To apply stem cells for other disorders, such as acute injuries caused by insults from surgical trauma and myocardial infarction, would require other scientific considerations. This does not imply that such injuries are not accompanied by immune responses. Indeed, acute injuries could accompany infiltration of immune cells to the sites of injuries. The implantation of stem cells within a milieu of inflammation will establish an immediate crosstalk among the stem cells, microenvironmental molecules, and resident and infiltrating immune cells. The responses at the microenvironment of tissue injury could affect distant and nearby organs. This editorial argues that the microenvironment of any tissue injury is a key consideration for effective stem cell therapy.