Therapeutic applications of mesenchymal/medicinal stem/signaling cells preconditioned with external factors: Are there more efficient approaches to utilize their regenerative potential?

Mesenchymal/medicinal stem/signaling cells (MSCs) have emerged as a promising treatment option for various disorders. However, the donor's age, advanced stage of disease, and prolonged in vitro expansion often diminish the innate regenerative potential of MSCs. Besides that, the absence of MSCs' comprehensive "pre-admission testing" can result in the injection of cells with reduced viability and function, which may negatively affect the overall outcome of MSC-based therapies. It is, therefore, essential to develop effective strategies to improve the impaired biological performance of MSCs. This review focuses on the comprehensive characterization of various methods of external MSCs stimulation (hypoxia, heat shock, caloric restriction, acidosis, 3D culture, and application of extracellular matrix) that augment their medicinal potential. To emphasize the significance of MSCs priming, we summarize the effects of individual and combined preconditioning approaches, highlighting their impact on MSCs' response to either physiological or pathological conditions. We further investigate the synergic action of exogenous factors to maximize MSCs' therapeutic potential. Not to omit the field of tissue engineering, the application of pretreated MSCs seeded on scaffolds is discussed as well.

The Neglected Uterine NK Cells/Hamperl Cells/Endometrial Stromal Granular Cell, or K Cells: A Narrative Review from History through Histology and to Medical Education.

Reproductive immunology is at the forefront of research interests, aiming to better understand the mechanisms of immune regulation during gestation. The relationship between the immune system and the implanting embryo is profound because the embryo is semi-allogenic but not targeted by the maternal immune system, as expected in graft-versus-host reactions. The most prominent cell population at the maternal-fetal interface is the population of uterine natural killer (uNK) cells. Uterine NK cells are two-faced immunologically active cells, bearing comparison with Janus, the ancient Roman god of beginnings and endings. Their first face can be seen as natural killer cells, namely lymphocytes, which are critical for host defense against viruses and tumors. Even though uNK cells contain cytolytic molecules, their cytotoxic effect is not applied to classical target cells in vivo, playing a permissive rather than a defensive role. Their second face is crucial in maintaining physiological gestation-uNK cells show critical immunomodulatory functions with the potential to control embryo implantation and trophoblast invasion, regulate placental vascular remodeling, and promote embryonic/fetal growth. Therefore, we believe that their current designation "natural killer cells" (the first "cytotoxic" Janus's face) is misleading and inappropriate, considering their principal function is supporting and maintaining pregnancy. In this narrative review, we will focus on three lesser-known areas of knowledge about uNK cells. First, from the point of view of histology, we will comprehensively map the history of the discovery of these cells, as well as the current histological possibilities of their identification within the endometrium. To be brief, the discovery of uNK cells is generally attributed to Herwig Hamperl, one of the most influential and prominent representatives of German pathology in the 20th century, and his co-worker, Gisela Hellweg. Secondly, we will discuss the interesting aspect of terminology, since uNK cells are probably one of the human cells with the highest number of synonymous names, leading to significant discrepancies in their descriptions in scientific literature. From the first description of this cell type, they were referred to as endometrial granulocytes, granular endometrial stromal cells, or large granular lymphocytes until the end of the 1980s and the beginning of the 1990s of the last century, when the first publications appeared where the name "uterine NK cells" was used. The third area of present review is medical teaching of histology and clinical embryology. We can confirm that uNK cells are, in most textbooks, overlooked and almost forgotten cells despite their enormous importance. In the present narrative review, we summarize the lesser-known historical and terminological facts about uNK cells. We can state that within the textbooks of histology and embryology, this important cell population is still "overlooked and neglected" and is not given the same importance as in fields of clinical research and clinical practice.

Stem Cells and Their Derivatives: An Implication for the Regeneration of Nonunion Fractures.

Despite advances in biomedical research, fracture nonunion rates have remained stable throughout the years. Long-bone fractures have a high likelihood of nonunion, but the specific biological pathways involved in this severe consequence are unknown. Fractures often heal in an organized sequence, including the production of a hematoma and an early stage of inflammation, the development of a soft callus and hard callus, and eventually the stage of bone remodeling. Deficient healing can result in a persistent bone defect with instability, discomfort, and loss of function. In the treatment of nonunions, mesenchymal stem cells (MSCs) prove to be a promising and safe alternative to the standard therapeutic strategies. Moreover, novel scaffolds are being created in order to use a synergistic biomimetic technique to rapidly generate bone tissue. MSCs respond to acellular biomimetic matrices by regenerating bone. Extracellular vesicles (EVs) derived from MSCs have recently gained interest in the field of musculoskeletal regeneration. Although many of these techniques and technologies are still in the preclinical stage and have not yet been approved for use in humans, novel approaches to accelerate bone healing via MSCs and/or MSC derivatives have the potential to reduce the physical, economic, and social burdens associated with nonhealing fractures and bone defects. In this review, we focus on providing an up-to-date summary of recent scientific studies dealing with the treatment of nonunion fractures in clinical and preclinical settings employing MSC-based therapeutic techniques.

The Immunomodulatory Role of Cell-Free Approaches in SARS-CoV-2-Induced Cytokine Storm-A Powerful Therapeutic Tool for COVID-19 Patients.

Currently, there is still no effective and definitive cure for the coronavirus disease 2019 (COVID-19) caused by the infection of the novel highly contagious severe acute respiratory syndrome virus (SARS-CoV-2), whose sudden outbreak was recorded for the first time in China in late December 2019. Soon after, COVID-19 affected not only the vast majority of China's population but the whole world and caused a global health public crisis as a new pandemic. It is well known that viral infection can cause acute respiratory distress syndrome (ARDS) and, in severe cases, can even be lethal. Behind the inflammatory process lies the so-called cytokine storm (CS), which activates various inflammatory cytokines that damage numerous organ tissues. Since the first outbreak of SARS-CoV-2, various research groups have been intensively trying to investigate the best treatment options; however, only limited outcomes have been achieved. One of the most promising strategies represents using either stem cells, such as mesenchymal stem cells (MSCs)/induced pluripotent stem cells (iPSCs), or, more recently, using cell-free approaches involving conditioned media (CMs) and their content, such as extracellular vesicles (EVs) (e.g., exosomes or miRNAs) derived from stem cells. As key mediators of intracellular communication, exosomes carry a cocktail of different molecules with anti-inflammatory effects and immunomodulatory capacity. Our comprehensive review outlines the complex inflammatory process responsible for the CS, summarizes the present results of cell-free-based pre-clinical and clinical studies for COVID-19 treatment, and discusses their future perspectives for therapeutic applications.

Decellularization of the human urethra for tissue engineering applications.

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 < 0.001), and so the criteria for decellularized tissue were met. Cytotoxicity analysis data showed that the matrix-conditioned medium did not contain soluble toxins and had no significant inhibitory effect on cell proliferation, providing evidence that the decellularized samples are not toxic. This study demonstrates the feasibility of the enzyme-detergent-enzyme-based decellularization protocol for removing cellular components and maintaining urethral ECM and its ultrastructure. Moreover, obtained results provide solid ground for recellularization and urethral tissue engineering, which will follow.

Traditional and contemporary views on the functional morphology of the fallopian tubes and their importance for gynecological practice.

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.

Induced Pluripotent Stem Cell-Derived Organoids: Their Implication in COVID-19 Modeling.

The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a significant global health issue. This novel virus's high morbidity and mortality rates have prompted the scientific community to quickly find the best COVID-19 model to investigate all pathological processes underlining its activity and, more importantly, search for optimal drug therapy with minimal toxicity risk. The gold standard in disease modeling involves animal and monolayer culture models; however, these models do not fully reflect the response to human tissues affected by the virus. However, more physiological 3D in vitro culture models, such as spheroids and organoids derived from induced pluripotent stem cells (iPSCs), could serve as promising alternatives. Different iPSC-derived organoids, such as lung, cardiac, brain, intestinal, kidney, liver, nasal, retinal, skin, and pancreatic organoids, have already shown immense potential in COVID-19 modeling. In the present comprehensive review article, we summarize the current knowledge on COVID-19 modeling and drug screening using selected iPSC-derived 3D culture models, including lung, brain, intestinal, cardiac, blood vessels, liver, kidney, and inner ear organoids. Undoubtedly, according to reviewed studies, organoids are the state-of-the-art approach to COVID-19 modeling.

Cell-Based and Selected Cell-Free Therapies for Myocardial Infarction: How Do They Compare to the Current Treatment Options?

Because of cardiomyocyte death or dysfunction frequently caused by myocardial infarction (MI), heart failure is a leading cause of morbidity and mortality in modern society. Paradoxically, only limited and non-curative therapies for heart failure or MI are currently available. As a result, over the past two decades research has focused on developing cell-based approaches promoting the regeneration of infarcted tissue. Cell-based therapies for myocardial regeneration include powerful candidates, such as multipotent stem cells (mesenchymal stem cells (MSCs), bone-marrow-derived stem cells, endothelial progenitor cells, and hematopoietic stem cells) and induced pluripotent stem cells (iPSCs). These possess unique properties, such as potency to differentiate into desired cell types, proliferation capacity, and patient specificity. Preclinical and clinical studies have demonstrated modest improvement in the myocardial regeneration and reduced infarcted areas upon transplantation of pluripotent or multipotent stem cells. Another cell population that need to be considered as a potential source for cardiac regeneration are telocytes found in different organs, including the heart. Their therapeutic effect has been studied in various heart pathologies, such as MI, arrhythmias, or atrial amyloidosis. The most recent cell-free therapeutic tool relies on the cardioprotective effect of complex cargo carried by small membrane-bound vesicles-exosomes-released from stem cells via exocytosis. The MSC/iPSC-derived exosomes could be considered a novel exosome-based therapy for cardiovascular diseases thanks to their unique content. There are also other cell-free approaches, e.g., gene therapy, or acellular cardiac patches. Therefore, our review provides the most recent insights into the novel strategies for myocardial repair based on the regenerative potential of different cell types and cell-free approaches.

Implication of Mesenchymal Stem Cells and Their Derivates for Osteochondral Regeneration.

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.

Telocytes in the Female Reproductive System: Up-to-Date Knowledge, Challenges and Possible Clinical Applications.

From their initial description in 2005 to this day, telocytes (TCs) have been described in the ovary, uterine tubes, uterus, vagina, mammary gland, and placenta. Their morphological features, immunophenotype, physiological functions, and roles in disease have been thoroughly documented in both animal models and human subjects. TCs, with their extremely long cytoplasmic processes called telopodes, play a pivotal role in the morphological and functional interconnection of all the components of the interstitial compartment, but also with constituents of the parenchyma. Although there is no specific immunohistochemical marker for their identification, the most cited are CD 117, CD 34, platelet-derived growth factor receptor (PDGFR), vimentin, and specific markers typical for the female reproductive system (FRS)-estrogen and progesterone receptors (ER and PR). This immunophenotype provides important clues to their physiological roles. Their main functions include the regulation of hormone-dependent processes, intercellular signaling, immune surveillance, microenvironmental maintenance, and the nursing of stem cells. In a situation where TCs are functionally or morphologically decimated, many disease entities may develop, including premature ovarian failure, endometriosis, ectopic pregnancy, infertility, preeclampsia, or even breast cancer. The common denominator of many of these conditions is that their etiopathogenesis is either partially known or completely obscure. Even though the exact role of TCs in these conditions is yet to be revealed, multiple lines of research indicate that their future clinical application may enrich diagnostic-therapeutic strategies of countless conditions. TCs are also heavily debated in terms of their possible use in regenerative medicine and tissue engineering. Some of the concepts related to TC research are strongly substantiated by experimental data, while others are highly speculative. Only future research endeavors will clearly distinguish dead-end lines of research from genuine contributions to the field.

Rheumatoid arthritis: From synovium biology to cell-based therapy.

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.

Tissue Engineering of the Urethra: From Bench to Bedside.

Tissue engineering (TE) is a promising approach for repair/substitution of damaged tissues and organs. Urethral strictures are common and serious health conditions that impair quality of life and may lead to serious organ damage. The search for ideal materials for urethral repair has led to interest of scientists and surgeons in urethral TE. Over the last decades, a significant amount of preclinical studies and considerable progress have been observed. In contrast, urethral TE has made slow progress in clinical practice so far. To address this, we conducted a systematic review of the literature on clinical applications of TE constructs for urethral repair in the last three decades. In summary, the TE approach is promising and effective, but many issues remain that need to be addressed for broader adoption of TE in urethral repair. Better design of trials, better cooperation of research groups and centralization could lead to reduction of costs and slowly proceed to commercialization and routine use of TE products for urethral reconstruction.

Stem Cells and Their Derivatives-Implications for Alveolar Bone Regeneration: A Comprehensive Review.

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.

Cardiac Telocytes 16 Years on-What Have We Learned So Far, and How Close Are We to Routine Application of the Knowledge in Cardiovascular Regenerative Medicine?

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.

iPSCs in Modeling and Therapy of Osteoarthritis.

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.

Recent Overview of the Use of iPSCs Huntington's Disease Modeling and Therapy.

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.

Generation of Pancreatic ß-cells From iPSCs and their Potential for Type 1 Diabetes Mellitus Replacement Therapy and Modelling.

Diabetes type 1 (T1D) is a common autoimmune disease characterized by permanent destruction of the insulin-secreting ß-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 ß-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 ß-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 ß-cells derived from iPSCs. Although animal and human pancreatic development and ß-cell physiology have significant differences, animal models represent an important tool in evaluating the therapeutic potential of iPSC-derived ß-cells on type 1 diabetes treatment. This review outlines the recent progress in iPSC-derived ß-cell differentiation methods, disease modelling, and future perspectives.

Recent Progress in the Regeneration of Spinal Cord Injuries by Induced Pluripotent Stem Cells.

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.

Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy.

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.

Regenerative Medicine in Orthopaedics and Trauma: Challenges, Regulation and Ethical Issues.

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.