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.     

Mesenchymal Stem Cell-Derived Exosomes: A Promising Therapeutic Agent for the Treatment of Liver Diseases

Liver disease has become a major global health and economic burden due to its broad spectrum of diseases, multiple causes and difficult treatment. Most liver diseases progress to end-stage liver disease, which has a large amount of matrix deposition that makes it difficult for the liver and hepatocytes to regenerate. Liver transplantation is the only treatment for end-stage liver disease, but the shortage of suitable organs, expensive treatment costs and surgical complications greatly reduce patient survival rates. Therefore, there is an urgent need for an effective treatment modality. Cell-free therapy has become a research hotspot in the field of regenerative medicine. Mesenchymal stem cell (MSC)-derived exosomes have regulatory properties and transport functional “cargo” through physiological barriers to target cells to exert communication and regulatory activities. These exosomes also have little tumorigenic risk. MSC-derived exosomes promote hepatocyte proliferation and repair damaged liver tissue by participating in intercellular communication and regulating signal transduction, which supports their promise as a new strategy for the treatment of liver diseases. This paper reviews the physiological functions of exosomes and highlights the physiological changes and alterations in signaling pathways related to MSC-derived exosomes for the treatment of liver diseases in some relevant clinical studies. We also summarize the advantages of exosomes as drug delivery vehicles and discuss the challenges of exosome treatment of liver diseases in the future.     

Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Ocular Graft-Versus-Host Disease

Ocular GVHD (oGVHD), manifested by severe injury of corneal epithelial cells, meibomian and lacrimal glands’ dysfunction, is a serious complication of systemic GVHD which develops as a consequence of donor T and natural killer cell-driven inflammation in the eyes of patients who received allogeneic hematopoietic stem cell transplantation. Mesenchymal stem cells (MSC) are, due to their enormous differentiation potential and immunosuppressive characteristics, considered as a potentially new remedy in ophthalmology. MSC differentiate in corneal epithelial cells, suppress eye inflammation, and restore meibomian and lacrimal glands’ function in oGVHD patients. MSC-sourced exosomes (MSC-Exos) are extracellular vesicles that contain MSC-derived growth factors and immunoregulatory proteins. Due to the lipid membrane and nano-sized dimension, MSC-Exos easily by-pass all biological barriers in the eyes and deliver their cargo directly in injured corneal epithelial cells and eye-infiltrated leukocytes, modulating their viability and function. As cell-free agents, MSC-Exos address all safety issues related to the transplantation of their parental cells, including the risk of unwanted differentiation and aggravation of intraocular inflammation. In this review article, we summarized current knowledge about molecular mechanisms which are responsible for beneficial effects of MSC and MSC-Exos in the therapy of inflammatory eye diseases, emphasizing their therapeutic potential in the treatment of oGVHD.     

Mesenchymal Stem Cells Based Treatment in Dental Medicine: A Narrative Review

Application of mesenchymal stem cells (MSC) in regenerative therapeutic procedures is becoming an increasingly important topic in medicine. Since the first isolation of dental tissue-derived MSC, there has been an intense investigation on the characteristics and potentials of these cells in regenerative dentistry. Their multidifferentiation potential, self-renewal capacity, and easy accessibility give them a key role in stem cell-based therapy. So far, several different dental stem cell types have been discovered and their potential usage is found in most of the major dental medicine branches. These cells are also researched in multiple fields of medicine for the treatment of degenerative and inflammatory diseases. In this review, we summarized dental MSC sources and analyzed their treatment modalities with particular emphasis on temporomandibular joint osteoarthritis (TMJ OA).     

The Cross-Talk between Mesenchymal Stem Cells and Immune Cells in Tissue Repair and Regeneration

Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.     

Non-Coding RNAs in Stem Cell Regulation and Cardiac Regeneration: Current Problems and Future Perspectives

Although advances in rapid revascularization strategies following acute myocardial infarction (AMI) have led to improved short and long-term outcomes, the associated loss of cardiomyocytes and the subsequent remodeling result in an impaired ventricular function that can lead to heart failure or death. The poor regenerative capacity of the myocardium and the current lack of effective regenerative therapies have driven stem cell research in search of a possible solution. One approach involves the delivery of stem cells to the site of injury in order to stimulate repair response. Although animal studies initially delivered promising results, the application of similar techniques in humans has been hampered by poor target site retention and oncogenic considerations. In response, several alternative strategies, including the use of non-coding RNAs (ncRNAs), have been introduced with the aim of activating and regulating stem cells or inducing stem cell status in resident cells. Circular RNAs (circRNAs) and microRNAs (miRNAs) are ncRNAs with pivotal functions in cell proliferation and differentiation, whose role in stem cell regulation and potential significance for the field of cardiac regeneration is the primary focus of this review. We also address the general advantages of ncRNAs as promising drivers of cardiac regeneration and potent stem cell regulators.     

Exosomes Derived from Human Amniotic Fluid Mesenchymal Stem Cells Preserve Microglia and Neuron Cells from Aβ

Background: Neuroinflammation is involved in neuronal cell death that occurs in neurodegenerative diseases such as Alzheimer’s disease (AD). Microglia play important roles in regulating the brain amyloid beta (Aβ) levels, so immunomodulatory properties exerted by mesenchymal stem cells may be exploited to treat this pathology. The evidence suggests that the mechanism of action of human amniotic fluid stem cells (hAFSCs) is through their secretome, which includes exosomes (exo). Methods: We examined the effect of exosomes derived from human amniotic fluid stem cells (hAFSCs-exo) on activated BV-2 microglia cells by lipopolysaccharide (LPS) as a neuroinflammation model. To investigate the exo effect on the interplay between AD neurons and microglia, SH-SY5Y neuroblastoma cells treated with Aβ were exposed to a conditioned medium (CM) obtained from activated BV-2 or co-culture systems. Results: We found that the upregulation of the markers of pro-inflammatory microglia was prevented when exposed to hAFSC-exo whereas the markers of the anti-inflammatory macrophage phenotype were not affected. Interestingly, the hAFSC-exo pretreatment significantly inhibited the oxidative stress rise and apoptosis occurring in the neurons in presence of both microglia and Aβ. Conclusion: We demonstrated that hAFSC-exo mitigated an inflammatory injury caused by microglia and significantly recovered the neurotoxicity, suggesting that hAFSC-exo may be a potential therapeutic agent for inflammation-related neurological conditions, including AD.     

Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration

Mesenchymal stem/stromal cells (MSCs) are widely described in the context of their regenerative and immunomodulatory activity. MSCs are isolated from various tissues and organs. The most frequently described sources are bone marrow and adipose tissue. As stem cells, MSCs are able to differentiate into other cell lineages, but they are usually reported with respect to their paracrine potential. In this review, we focus on MSCs derived from adipose tissue (AT-MSCs) and their secretome in regeneration processes. Special attention is given to the contribution of AT-MSCs and their derivatives to angiogenic processes described mainly in the context of angiogenic dysfunction. Finally, we present clinical trials registered to date that concern the application of AT-MSCs and their secretome in various medical conditions.     

MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells

Mesenchymal stem cells (MSCs) have been identified in many adult tissues and they have been closely studied in recent years, especially in view of their potential use for treating diseases and damaged tissues and organs. MSCs are capable of self-replication and differentiation into osteoblasts and are considered an important source of cells in tissue engineering for bone regeneration. Several epigenetic factors are believed to play a role in the osteogenic differentiation of MSCs, including microRNAs (miRNAs). MiRNAs are small, single-stranded, non-coding RNAs of approximately 22 nucleotides that are able to regulate cell proliferation, differentiation and apoptosis by binding the 3′ untranslated region (3′-UTR) of target mRNAs, which can be subsequently degraded or translationally silenced. MiRNAs control gene expression in osteogenic differentiation by regulating two crucial signaling cascades in osteogenesis: the transforming growth factor-beta (TGF-β)/bone morphogenic protein (BMP) and the Wingless/Int-1(Wnt)/β-catenin signaling pathways. This review provides an overview of the miRNAs involved in osteogenic differentiation and how these miRNAs could regulate the expression of target genes.     

Therapeutic Potential of Exosomes Derived from Adipose Tissue-Sourced Mesenchymal Stem Cells in the Treatment of Neural and Retinal Diseases

Therapeutic agents that are able to prevent or attenuate inflammation and ischemia-induced injury of neural and retinal cells could be used for the treatment of neural and retinal diseases. Exosomes derived from adipose tissue-sourced mesenchymal stem cells (AT-MSC-Exos) are extracellular vesicles that contain neurotrophins, immunoregulatory and angio-modulatory factors secreted by their parental cells. AT-MSC-Exos are enriched with bioactive molecules (microRNAs (miRNAs), enzymes, cytokines, chemokines, immunoregulatory, trophic, and growth factors), that alleviate inflammation and promote the survival of injured cells in neural and retinal tissues. Due to the nano-sized dimension and bilayer lipid envelope, AT-MSC-Exos easily bypass blood–brain and blood–retinal barriers and deliver their cargo directly into the target cells. Accordingly, a large number of experimental studies demonstrated the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases. By delivering neurotrophins, AT-MSC-Exos prevent apoptosis of injured neurons and retinal cells and promote neuritogenesis. AT-MSC-Exos alleviate inflammation in the injured brain, spinal cord, and retinas by delivering immunoregulatory factors in immune cells, suppressing their inflammatory properties. AT-MSC-Exos may act as biological mediators that deliver pro-angiogenic miRNAs in endothelial cells, enabling re-vascularization of ischemic neural and retinal tissues. Herewith, we summarized current knowledge about molecular mechanisms which were responsible for the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases, emphasizing their therapeutic potential in neurology and ophthalmology.     

Inflammation Regulates Haematopoietic Stem Cells and Their Niche

Haematopoietic stem cells (HSCs) reside in the bone marrow and are supported by the specialised microenvironment, a niche to maintain HSC quiescence. To deal with haematopoietic equilibrium disrupted during inflammation, HSCs are activated from quiescence directly and indirectly to generate more mature immune cells, especially the myeloid lineage cells. In the process of proliferation and differentiation, HSCs gradually lose their self-renewal potential. The extensive inflammation might cause HSC exhaustion/senescence and malignant transformation. Here, we summarise the current understanding of how HSC functions are maintained, damaged, or exhausted during acute, prolonged, and pathological inflammatory conditions. We also highlight the inflammation-altered HSC niche and its impact on escalating the insults on HSCs.     

Cancer Stem Cells and Their Vesicles,Together with Other Stem and Non-Stem Cells,Govern Critical Cancer Processes: Perspectives for Medical Development

Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases.     

A Cell-Based Approach to Dental Pulp Regeneration Using Mesenchymal Stem Cells: A Scoping Review

Despite the recent explosion of investigations on dental pulp regeneration using various tissue engineering strategies, the translation of the findings from such studies into therapeutic applications has not been properly achieved. The purpose of this scoping review was to systematically review the efficacy of mesenchymal stem cell transplantation for dental pulp regeneration. A literature search was conducted using five electronic databases from their inception to January 2021 and supplemented by hand searches. A total of 17 studies, including two clinical trials and 15 animal studies using orthotopic pulp regeneration models, were included for the review. The risk of bias for the individual studies was assessed. This scoping review demonstrated that the regeneration of vascularized pulp-like tissue was achieved using the stem cell transplantation strategy in animal models. Autologous cell transplantation in two clinical studies also successfully regenerated vascularized vital tissue. Dental pulp stem cell subpopulations, such as mobilized dental pulp stem cells, injectable scaffolds such as atelocollagen, and a granulocyte-colony forming factor, were the most commonly used for pulp regeneration. The overall risk of bias was unclear for animal studies and was moderate or judged to raise some concerns for clinical studies. More high-quality clinical studies are needed to further determine the safety and efficacy of the stem cell transplantation strategy for dental pulp regeneration.     

Addition of Adipose-Derived Stem Cells to Mesenchymal Stem Cell Sheets Improves Bone Formation at an Ectopic Site

To determine the effect of adipose-derived stem cells (ADSCs) added to bone marrow-derived mesenchymal stem cell (MSC) sheets on bone formation at an ectopic site. We isolated MSCs and ADSCs from the same rabbits. We then prepared MSC sheets for implantation with or without ADSCs subcutaneously in the backs of severe combined immunodeficiency (SCID) mice. We assessed bone formation at eight weeks after implantation by micro-computed tomography and histological analysis. In osteogenic medium, MSCs grew to form multilayer sheets containing many calcium nodules. MSC sheets without ADSCs formed bone-like tissue; although neo-bone and cartilage-like tissues were sparse and unevenly distributed by eight weeks after implantation. In comparison, MSC sheets with ADSCs promoted better bone regeneration as evidenced by the greater density of bone, increased mineral deposition, obvious formation of blood vessels, large number of interconnected ossified trabeculae and woven bone structures, and greater bone volume/total volume within the composite constructs. Our results indicate that although sheets of only MSCs have the potential to form tissue engineered bone at an ectopic site, the addition of ADSCs can significantly increase the osteogenic potential of MSC sheets. Thus, the combination of MSC sheets with ADSCs may be regarded as a promising therapeutic strategy to stimulate bone regeneration.     

Extracellular Vesicles Secreted by Glioma Stem Cells Are Involved in Radiation Resistance and Glioma Progression

Glioblastoma is the most aggressive brain tumour with short survival, partly due to resistance to conventional therapy. Glioma stem cells (GSC) are likely to be involved in treatment resistance, by releasing extracellular vesicles (EVs) containing specific molecular cargoes. Here, we studied the EVs secreted by glioma stem cells (GSC-EVs) and their effects on radiation resistance and glioma progression. EVs were isolated from 3 GSCs by serial centrifugation. NanoSight measurement, cryo-electron microscopy and live imaging were used to study the EVs size, morphology and uptake, respectively. The non-GSC glioma cell lines LN229 and U118 were utilised as a recipient cell model. Wound healing assays were performed to detect cell migration. Colony formation, cell viability and invadopodium assays were conducted to detect cell survival of irradiated recipient cells and cell invasion post GSC-EV treatment. NanoString miRNA global profiling was used to select for the GSC-EVs’ specific miRNAs. All three GSC cell lines secreted different amounts of EVs, and all expressed consistent levels of CD9 but different level of Alix, TSG101 and CD81. EVs were taken up by both LN229 and U118 recipient cells. In the presence of GSC-EVs, these recipient cells survived radiation exposure and initiated colony formation. After GSC-EVs exposure, LN229 and U118 cells exhibited an invasive phenotype, as indicated by an increase in cell migration. We also identified 25 highly expressed miRNAs in the GSC-EVs examined, and 8 of these miRNAs can target PTEN. It is likely that GSC-EVs and their specific miRNAs induced the phenotypic changes in the recipient cells due to the activation of the PTEN/Akt pathway. This study demonstrated that GSC-EVs have the potential to induce radiation resistance and modulate the tumour microenvironment to promote glioma progression. Future therapeutic studies should be designed to interfere with these GSC-EVs and their specific miRNAs.     

Treatment of Stress Urinary Incontinence with Muscle Stem Cells and Stem Cell Components: Chances,Challenges and Future Prospects

Urinary incontinence (UI) is a major problem in health care and more than 400 million people worldwide suffer from involuntary loss of urine. With an increase in the aging population, UI is likely to become even more prominent over the next decades and the economic burden is substantial. Among the different subtypes of UI, stress urinary incontinence (SUI) is the most prevalent and focus of this review. The main underlying causes for SUI are pregnancy and childbirth, accidents with direct trauma to the pelvis or medical treatments that affect the pelvic floor, such as surgery or irradiation. Conservative approaches for the treatment of SUI are pelvic physiotherapy, behavioral and lifestyle changes, and the use of pessaries. Current surgical treatment options include slings, colposuspensions, bulking agents and artificial urinary sphincters. These treatments have limitations with effectiveness and bear the risk of long-term side effects. Furthermore, surgical options do not treat the underlying pathophysiological causes of SUI. Thus, there is an urgent need for alternative treatments, which are effective, minimally invasive and have only a limited risk for adverse effects. Regenerative medicine is an emerging field, focusing on the repair, replacement or regeneration of human tissues and organs using precursor cells and their components. This article critically reviews recent advances in the therapeutic strategies for the management of SUI and outlines future possibilities and challenges.     

Therapeutic Potential of Human Fetal Mesenchymal Stem Cells in Musculoskeletal Disorders: A Narrative Review

Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for diverse diseases and injuries. The biological and clinical advantages of human fetal MSCs (hfMSCs) have recently been reported. In terms of promising therapeutic approaches for diverse diseases and injuries, hfMSCs have gained prominence as healing tools for clinical therapies. Therefore, this review assesses not the only biological advantages of hfMSCs for healing human diseases and regeneration, but also the research evidence for the engraftment and immunomodulation of hfMSCs based on their sources and biological components. Of particular clinical relevance, the present review also suggests the potential therapeutic feasibilities of hfMSCs for musculoskeletal disorders, including osteoporosis, osteoarthritis, and osteogenesis imperfecta.     

Isolation of Multipotent Nestin-Expressing Stem Cells Derived from the Epidermis of Elderly Humans and TAT-VHL Peptide-Mediated Neuronal Differentiation of These Cells

A specialized population of cells residing in the hair follicle is quiescent but shows pluripotency for differentiating into epithelial-mesenchymal lineage cells. Therefore, such cells are hoped to be useful as implantable donor cells for regenerative therapy. Recently, it was reported that intracellular delivery of TAT-VHL peptide induces neuronal differentiation of skin-derived precursors. In the present study, we successfully isolated multipotent stem cells derived from the epidermis of elderly humans, characterized these cells as being capable of sphere formation and strong expression of nestin, fibronectin, and CD34 but not of keratin 15, and identified the niche of these cells as being the outer root sheath of the hair follicles. In addition, we showed that TAT-VHL peptide induced their neuronal differentiation in vitro, and confirmed by fluorescence immunohistochemistry the neuronal differentiation of such peptide-treated cells implanted into rodent brains. These multipotent nestin-expressing stem cells derived from human epidermis are easily accessible and should be useful as donor cells for neuronal regenerative cell therapy.