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The uterine tube, belonging to the female internal reproductive organs, is the only tubular organ in the human body that has, under physiological conditions, a transport function occurring in two opposite directions. It transports the picked-up oocyte released during ovulation and early embryo towards the uterine cavity. At the same time, it can transport spermatozoa towards the abdominal opening of the fallopian tube. Moreover, the uterine tube has many other vital functions as sperm selection (one of the crucial factors preventing polyspermy) and the production of tubal fluid. This unique secretion is essential not only for the process of fertilization but also for sperm activation and the nourishment of the early embryo during its transport into the uterine cavity. The first part of our review is focused on the historical introduction to the topic in which the reader will become familiar with the views and understanding of these peculiar organs by famous anatomists of the 16th and 17th centuries, namely Gabriele Falloppio and Renier de Graaf. The following section will cover the overview of the latest anatomical, embryological, and histological knowledge, which are also crucial for a better understanding of pathological processes affecting the fallopian tube, such as tubal infertility or tubal pregnancy. Interestingly, recent years have been very fruitful regarding uterine tube morphology, e. g. the discovery of an unique mechanism of lymphatic flow within the uterine tube mucosa, the first description of immunologically-active intraepithelial suppressor T-lymphocytes, or the observation of pacemaker cell population – telocytes – in the muscle layer. Key words: fallopian tube – history – anatomy – histology – embryology – recent findings

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects the synovial joints and, if not treated properly, can lead to multiple progressive articular and extra-articular damage. Its pathogenesis is primarily associated with an inadequate immune response and dysregulated cytokine production. However, RA is also linked to disruption in oxygen metabolism, impaired redox signaling, acidosis and aberrant intercellular communication. Even though treatment modalities have made RA a manageable disease, a significant number of patients still do not respond satisfactorily or suffer considerably from the adverse events of conventional therapy. In recent years, cell-based strategies, especially the administration of the mesenchymal/medicinal stem/signaling cells (MSCs), have been proposed as a novel and very promising therapeutic approach. RA patients may benefit from the potent anti-inflammatory and immunomodulatory properties and tissue-repair potential of MSCs. Furthermore, the satisfactory safety profile of MSC therapy has been already demonstrated in several clinical studies. This review summarizes current understanding of the pathomechanism behind RA at the molecular and cellular level and focuses on MSC-based clinical research and applications of MSCs for RA treatment.

Recently, several scaffolds have been introduced for urethral tissue engineering. However, acellular human urethral scaffold harvested from deceased donors may provide significant advantages compared to synthetic, composite, or other biological scaffolds. This study aims to develop the protocol for decellularization of the human urethra that preserves substantial extracellular matrix (ECM) components, which are essential for subsequent recellularization mimicking the natural environment of the native ECM. A total of 12 human urethras were harvested from deceased donors. An equal part of every harvested urethra was used as a control sample for analyses. The protocol design was based on the enzyme-detergent-enzyme method. Trypsin and Triton X-100 were used to remove cells, followed by DNase treatment to remove DNA residues. Subsequently, the specimens were continually rinsed in deionized water for seven days. The efficiency of decellularization was determined by histochemistry, immunohistochemical staining, scanning electron microscopy (SEM), and DNA quantification. Histological analysis confirmed cell removal and preservation of urethral structure after decellularization. The preservation of collagen IV and fibronectin was confirmed by histologic examination and immunohistochemical staining. SEM confirmed the maintenance of the ultrastructural architecture of ECM and fibers. DNA content in decellularized urethra was significantly lower compared to the native sample ( P

Healing of articular cartilage defects presents a challenging issue, due to its regenerative shortcomings. Lacking vascularity and innervation of cartilage and low proliferative potential of chondrocytes are the main reasons for the limited healing potential of articular cartilage. Traditional reparative approaches are limited in their efficiency, hence there is a demand for novel reparative treatments. Mesenchymal stromal cells, preferred for clinical uses, can be readily derived from various sources and have been proven to have a therapeutic effect on cartilage and subchondral bone. Therefore, mesenchymal stromal cells, their derivates, and scaffolds have been utilized in research targeting osteochondral regeneration. The present review aims to comprehensively outline and discuss literature considering this topic published within last 5 years.

Oral and craniofacial bone defects caused by congenital disease or trauma are widespread. In the case of severe alveolar bone defect, autologous bone grafting has been considered a “gold standard”; however, the procedure has several disadvantages, including limited supply, resorption, donor site morbidity, deformity, infection, and bone graft rejection. In the last few decades, bone tissue engineering combined with stem cell-based therapy may represent a possible alternative to current bone augmentation techniques. The number of studies investigating different cell-based bone tissue engineering methods to reconstruct alveolar bone damage is rapidly rising. As an interdisciplinary field, bone tissue engineering combines the use of osteogenic cells (stem cells/progenitor cells), bioactive molecules, and biocompatible scaffolds, whereas stem cells play a pivotal role. Therefore, our work highlights the osteogenic potential of various dental tissue-derived stem cells and induced pluripotent stem cells (iPSCs), the progress in differentiation techniques of iPSCs into osteoprogenitor cells, and the efforts that have been made to fabricate the most suitable and biocompatible scaffold material with osteoinductive properties for successful bone graft generation. Moreover, we discuss the application of stem cell-derived exosomes as a compelling new form of “stem-cell free” therapy.

The regeneration of a diseased heart is one of the principal challenges of modern cardiovascular medicine. There has been ongoing research on stem-cell-based therapeutic approaches. A cell population called telocytes (TCs) described only 16 years ago largely contributed to the research area of cardiovascular regeneration. TCs are cells with small bodies and extremely long cytoplasmic projections called telopodes, described in all layers of the heart wall. Their functions include cell-to-cell signaling, stem-cell nursing, mechanical support, and immunoregulation, to name but a few. The functional derangement or quantitative loss of TCs has been implicated in the pathogenesis of myocardial infarction, heart failure, arrhythmias, and many other conditions. The exact pathomechanisms are still unknown, but the loss of regulative, integrative, and nursing functions of TCs may provide important clues. Therefore, a viable avenue in the future modern management of these conditions is TC-based cell therapy. TCs have been previously transplanted into a mouse model of myocardial infarction with promising results. Tandem transplantation with stem cells may provide additional benefit; however, many underresearched areas need to be addressed in future research before routine application of TC-based cell therapy in human subjects. These include the standardization of protocols for isolation, cultivation, and transplantation, quantitative optimization of TC transplants, cost-effectivity analysis, and many others.

Osteoarthritis (OA) belongs to chronic degenerative disorders and is often a leading cause of disability in elderly patients. Typically, OA is manifested by articular cartilage erosion, pain, stiffness, and crepitus. Currently, the treatment options are limited, relying mostly on pharmacological therapy, which is often related to numerous complications. The proper management of the disease is challenging because of the poor regenerative capacity of articular cartilage. During the last decade, cell-based approaches such as implantation of autologous chondrocytes or mesenchymal stem cells (MSCs) have shown promising results. However, the mentioned techniques face their hurdles (cell harvesting, low proliferation capacity). The invention of induced pluripotent stem cells (iPSCs) has created new opportunities to increase the efficacy of the cartilage healing process. iPSCs may represent an unlimited source of chondrocytes derived from a patient’s somatic cells, circumventing ethical and immunological issues. Aside from the regenerative potential of iPSCs, stem cell-derived cartilage tissue models could be a useful tool for studying the pathological process of OA. In our recent article, we reviewed the progress in chondrocyte differentiation techniques, disease modeling, and the current status of iPSC-based regenerative therapy of OA.

Huntington’s disease (HD) is an inherited, autosomal dominant, degenerative disease characterized by involuntary movements, cognitive decline, and behavioral impairment ending in death. HD is caused by an expansion in the number of CAG repeats in the huntingtin gene on chromosome 4. To date, no effective therapy for preventing the onset or progression of the disease has been found, and many symptoms do not respond to pharmacologic treatment. However, recent results of pre-clinical trials suggest a beneficial effect of stem-cell-based therapy. Induced pluripotent stem cells (iPSCs) represent an unlimited cell source and are the most suitable among the various types of autologous stem cells due to their patient specificity and ability to differentiate into a variety of cell types both in vitro and in vivo. Furthermore, the cultivation of iPSC-derived neural cells offers the possibility of studying the etiopathology of neurodegenerative diseases, such as HD. Moreover, differentiated neural cells can organize into three-dimensional (3D) organoids, mimicking the complex architecture of the brain. In this article, we present a comprehensive review of recent HD models, the methods for differentiating HD–iPSCs into the desired neural cell types, and the progress in gene editing techniques leading toward stem-cell-based therapy.

Diabetes type 1 (T1D) is a common autoimmune disease characterized by permanent destruction of the insulin-secreting β-cells in pancreatic islets, resulting in a deficiency of the glucose-lowering hormone insulin and persisting high blood glucose levels. Insulin has to be replaced by regular subcutaneous injections, and blood glucose level must be monitored due to the risk of hyperglycemia. Recently, transplantation of new pancreatic β-cells into T1D patients has come to be considered one of the most potentially effective treatments for this disease. Therefore, much effort has focused on understanding the regulation of β-cells. Induced pluripotent stem cells (iPSCs) represent a valuable source for T1D modelling and cell replacement therapy because of their ability to differentiate into all cell types in vitro. Recent advances in stem cell-based therapy and gene-editing tools have enabled the generation of functionally adult pancreatic β-cells derived from iPSCs. Although animal and human pancreatic development and β-cell physiology have significant differences, animal models represent an important tool in evaluating the therapeutic potential of iPSC-derived β-cells on type 1 diabetes treatment. This review outlines the recent progress in iPSC-derived β-cell differentiation methods, disease modelling, and future perspectives.

Regeneration of injuries occurring in the central nervous system, particularly spinal cord injuries (SCIs), is extremely difficult. The complex pathological events following a SCI often restrict regeneration of nervous tissue at the injury site and frequently lead to irreversible loss of motor and sensory function. Neural stem/progenitor cells (NSCs/NPCs) possess neuroregenerative and neuroprotective features, and transplantation of such cells into the site of damaged tissue is a promising stem cell-based therapy for SCI. However, NSC/NPCs have mostly been induced from embryonic stem cells or fetal tissue, leading to ethical concerns. The pioneering work of Yamanaka and colleagues gave rise to the technology to induce pluripotent stem cells (iPSCs) from somatic cells, overcoming these ethical issues. The advent of iPSCs technology has meant significant progress in the therapy of neurodegenerative disease and nerve tissue damage. A number of published studies have described the successful differentiation of NSCs/NPCs from iPSCs and their subsequent engraftment into SCI animal models, followed by functional recovery of injury. The aim of this present review is to summarize various iPSC- NPCs differentiation methods, SCI modelling, and the current status of possible iPSC- NPCs- based therapy of SCI.

Cartilage and bone disorders are a group of varied acute and chronic traumatic, degenerative, malignant or congenital conditions affecting the joints and bones. Recently, cell-based therapy appears...

A novel approach for stem cell generation is the attempt to induce conversion of the adult somatic cells into pluripotent stem cells so called induced pluripotent stem cells (iPSCs) by introducing specific transcription factors. iPSCs have two essential cell characteristics, they are pluripotent and posses long term cell-renewal capacity. Additionally, iPSCs can be derived from patient-specific somatic cells, thus bypassing ethical and immunological issues. The aim of our study was to reprogram long-term cryopreserved human neonatal fibroblasts by new method using lipid nano-particle technology (Lipofectamine 3000 reagent transfection system) in combination with Epi 5 reprogramming vectors. Obtained iPSCs were characterized by several sophisticated methods of molecular biology and microscopy. Distinct colonies of iPSCs started to appear by day 20 after reprogramming. The presence of iPSCs colonies was proved by alkaline phosphatase (AP) live staining. After manual picking the colonies and their subsequent passaging, they did not lose ability to form embryoid bodies, they were positive for AP, Tra-1-60, and SSEA-5. Moreover, obtained iPSCs expressed pluripotency markers Oct4, Sox2 and Nanog, and the expression levels of chondrogenic, osteogenic and adipogenic markers were significantly higher in comparison to control (p

Stem cells represent heterogeneous population of undifferentiated cells with unique characteristics of long term self renewal and plasticity. Moreover, they are capable of active migration to diseased tissues, secretion of different bioactive molecules, and they have immunosuppressive potential as well. They occur in all tissues through life and are involved in process of embryogenesis and regeneration. During last decades stem cells attracted significant attention in each field of medicine, including plastic and reconstructive surgery. The main goal of the present review article is to present and discuss the potential of stem cells and to provide information about their safe utilization in chronic wounds and fistulae healing, scar management, breast reconstruction, as well as in bone, tendon and peripheral nerve regeneration.

The lack of effective therapies for different neurodegenerative disorders has placed huge burdens on society. To overcome the restricted capacity of the central nervous system for regeneration, the promising alternative would be to use stem cells for more effective treatment of chronic degenerative and inflammatory neurological conditions and also of acute neuronal damage and from injuries or cerebrovascular diseases. The generation of induced pluripotent stem cells from somatic cells by the ectopic expression of specific transcription factors has provided the regenerative medicine field with a new tool for investigating and treating neurodegenerative diseases, including Alzheimer’s disease (AD). This technology provides an alternative to traditional approaches, such as nuclear transfer and somatic cell fusion using embryonic stem cells. However, due to a problem in standardization of certain reprogramming techniques and systems research, the induced pluripotent stem cell-based technology is still in its infancy. The present paper is aimed at a brief review of the current status in modeling and cell-based therapies for AD.

Unexpected toxicity in areas such as cardiotoxicity, hepatotoxicity, and neurotoxicity is a serious complication of clinical therapy and one of the key causes for failure of promising drug candidates in development. Animal studies have been widely used for toxicology research to provide preclinical security evaluation of various therapeutic agents under development. Species differences in drug penetration of the blood–brain barrier, drug metabolism, and related toxicity contribute to failure of drug trials from animal models to human. The existing system for drug discovery has relied on immortalized cell lines, animal models of human disease, and clinical trials in humans. Moreover, drug candidates that are passed as being safe in the preclinical stage often show toxic effects during the clinical stage. Only around 16% drugs are approved for human use. Research on induced pluripotent stem cells (iPSCs) promises to enhance drug discovery and development by providing simple, reproducible, and economically effective tools for drug toxicity screening under development and, on the other hand, for studying the disease mechanism and pathways. In this review, we provide an overview of basic information about iPSCs, and discuss efforts aimed at the use of iPSC-derived hepatocytes, cardiomyocytes, and neural cells in drug discovery and toxicity testing.

The main goal of this study was a comparison of biological properties of mesenchymal stromal cells (MSCs) obtained from bone marrow, adipose tissue and umbilical cord with respect to articular cartilage regeneration. MSCs were isolated and expanded in vitro up to the third passage. The kinetics of proliferation was analyzed by cell analyzer CEDEX XS and expression of selected markers was assessed by flow cytometry. The morphology was analyzed by inverted microscope and TEM. Pellet culture system and chondrogenic medium containing TGF-β1 was used to induce chondrogenic differentiation. Chondrogenesis was analyzed by real-time PCR; the expression of collagen type I and type II was compared. MSCs from all sources showed similar kinetics of proliferation and shared expression of CD73, CD90 and CD105; and were negative for CD14, CD20, CD34 and CD45. Observation under inverted microscope and TEM showed similar morphology of all analyzed MSCs. Cells from all sources underwent chondrogenic differentiation - they expressed collagen type II and acid mucopolysaccharides typical for hyaline cartilage. On the basis of obtained results it should be emphasized that MSCs from bone marrow, adipose tissue and umbilical cord share biological properties. They possess the chondrogenic potential and may be utilized in cartilage tissue engineering.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutation of the DMD gene which encodes the protein dystrophin. This dystrophin defect leads to the progressive degeneration of skeletal and cardiac muscles. Currently, there is no effective therapy for this disorder. However, the technology of cell reprogramming, with subsequent controlled differentiation to skeletal muscle cells or cardiomyocytes, may provide a unique tool for the study, modeling, and treatment of Duchenne muscular dystrophy. In the present review, we describe current methods of induced pluripotent stem cell generation and discuss their implications for the study, modeling, and development of cell-based therapies for Duchenne muscular dystrophy.

The ability of stem cells to self-renew and differentiate into cell types of different lineages forms the basis of regenerative medicine, which focuses on repairing or regenerating damaged or diseased tissues. This has a huge potential to revolutionize medicine. It is anticipated that in future, stem cell therapy will be able to restore function in all major organs. Intensive research has been on-going to bring stem cell therapy from bench to bedside as it holds promise of widespread applications in different areas of medicine. This is also applicable to orthopaedics, where stem cell transplantation could benefit complications like spinal cord injury, critical bone defects, cartilage repair or degenerative disc disorders. Stem cell therapy has a potential to change the field of orthopaedics from surgical replacements and reconstructions to a field of regeneration and prevention. This article summarizes advances in stem cell applications in orthopaedics as well as discussing regulation and ethical issues related to the use of stem cells.

Human Merkel cells (MCs) were first described by Friedrich S. Merkel in 1875 and named “Tastzellen” (touch cells). Merkel cells are primarily localized in the basal layer of the epidermis and concentrated in touch-sensitive areas. In our previous work, we reported on the distribution of MCs in the human esophagus, so therefore we chose other parts of the human body to study them. We selected the human vagina, because it has a similar epithelium as the esophagus and plays very important roles in reproduction and sexual pleasure. Due to the fact that there are very few research studies focusing on the innervation of this region, we decided to investigate the occurrence of MCs in the anterior wall of the vagina. The aim of our research was to identify MCs in the stratified squamous non-keratinized epithelium of the human vagina in 20 patients. For the identification of Merkel cells by light microscopy, we used antibodies against simple-epithelial cytokeratins (especially anti-cytokeratin 20). We also tried to identify them using transmission electron microscopy. Our investigation confirmed that 10 (50 %) of 20 patients had increased number of predominantly intraepithelial CK20 positive “Merkel-like” cells (MLCs) in the human vaginal epithelium. Subepithelial CK20 positive MLCs were observed in only one patient (5%). We tried to identify them also using transmission electron microscopy. Our investigation detected some unique cells that may be MCs. The purpose of vaginal innervation is still unclear. There are no data available concerning the distribution of MCs in the human vagina, so it would be interesting to study the role of MCs in the vaginal epithelium, in the context of innervation and epithelial biology.

The groundbreaking discovery, that somatic mammalian cells can be epigenetically reprogrammed to a pluripotent state through the exogenous expression of the transcription factors Oct4, Sox2, Klf4 and c -myc, has yielded a new cell type for potential applicati on in regenerative medicine, the induced Pluripoten t Stem Cells (iPSCs). Since the first demonstration of cre ating iPSCs in 2006 great efforts have been made in to improving iPS cell generation methods and understanding the reprogramming mechanism as well as the nature of iPSCs. The iPSCs technique makes it possi ble to produce patient-specific pluripotent stem ce lls for transplantation therapy without immune rejectio n. However, some restriction still remain, includin g viral vector integration into the genome, the existence o f exogenous oncogenic factors and low induction efficiency. In this review we discuss recent advanc es in methods of generating safer iPSCs lines and t heir possible use for biomedical applications.

Neurodegenerative disorders include a variety of hereditary or sporadic diseases involving the chronic, progressive loss on neural tissue. Parkinson's disease (PD) is the second most common neurodegenerative disease, affecting more than 6 million people worldwide (Wan et al., 2015). Degeneration of nigrostriatal dopamine (DA) neurons is the main pathology in PD, although other dopaminergic and non-dopaminergic systems are also affected. Characteristic symptoms are rigidity, hypokinesia, tremor, and postural instability. The loss of DA neurons is accompanied by lewy bodies and lewy neuritis, which are mainly formed by insoluble aggregates of alpha-synuclein and Tau protein and might restrain the survival and development of newborn neurons. Etiology of PD remains unclear, however interactions between environmental and genetic factors are believed to cause the loss of nigral DA neurons and ensuing locomotor system. Research indicated that increasing level of iron, oxidative stress, mitochondrial and ubiquitin-proteasome system dysfunction, inflammation, and apoptosis may lead to the progression of PD (Pu et al., 2012; Zhu et al., 2016).

Induced pluripotent stem cells (iPSCs) hold great promise for basic research and regenerative medicine. They offer the same advantages as embryonic stem cells (ESCs) and moreover new perspectives for personalized medicine. iPSCs can be generated from adult somatic tissues by over-expression of a few defined transcription factors, including Oct4, Sox2, Klf4, and c-myc. For regenerative medicine in particular, the technology provides great hope for patients with incurable diseases or potentially fatal disorders such as heart failure. The endogenous regenerative potentials of adult hearts are extremely limited and insufficient to compensate for myocardial loss occurring after myocardial infarction. Recent discoveries have demonstrated that iPSCs have the potential to significantly advance future cardiovascular regenerative therapies. Moreover, iPSCs can be generated from somatic cells of patients with genetic basis for their disease. This human iPSC derivates offer tremendous potential for new disease models. This paper reviews current applications of iPSCs in cardiovascular regenerative medicine and discusses progress in modeling cardiovascular diseases using iPSCs-derived cardiac cells.

In 2006 Yamanaka's group showed that stem cells with properties similar to embryonic stem cells could be generated from mouse fibroblasts by introducing four genes. These cells were termed induced pluripotent stem cells (iPSCs). Because iPSCs avoid many of ethical concerns associated with the use of embryonic material, they have great potential in cell-based regenerative medicine. They are suitable also for other various purposes, including disease modelling, personalized cell therapy, drug or toxicity screening and basic research. Moreover, in the future, there might become possible to generate organs for human transplantation. Despite these progresses, several studies have raised the concern for genetic and epigenetic abnormalities of iPSCs that could contribute to immunogenicity of some cells differentiated from iPSCs. Recent methodological improvements are increasing the ease and efficacy of reprogramming, and reducing the genomic modification. However, to minimize or eliminate genetic alternations in the derived iPSC line creation, factor-free human iPSCs are necessary. In this review we discuss recent possibilities of using iPSCs for clinical applications and new advances in field of their reprogramming methods. The main goal of present article was to review the current knowledge about iPSCs and to discuss their potential for regenerative medicine.