Mesenchymal stem/stromal cells (MSCs) are non-hematopoietic, plastic-adherent, and self-renewing cells capable of in vitro trilineage differentiation into fat, bone, and cartilage tissue. Suggestively, MSCs have additional plasticity, as demonstrated by their ability to differentiate in vitro into myocytes, neuron-like cells, and hepatocytes. MSCs are ideal for therapeutic application owing to their numerous advantages; they exhibit limited growth and differentiation abilities, leading to heterogeneous cell populations with inconsistent functions. However, highly purified MSCs, namely, rapidly expanding clones (RECs) that are isolated by single-cell sorting, display uniform functionality. RECs have the potential to offer many benefits, such as transplantable cells for treating several disorders of bone, heart, peripheral nerves, brain, and other organs. This study aimed to assess the effects of RECs on the pheochromocytoma (PC12) cell line, a well-known neuronal cell model.

PC12 cells were cultured under the following conditions: co-culture with RECs, treatment with REC-derived conditioned medium (CM), or co-culture with RECs using Transwell inserts for 7 days. The cells were stained with anti-βIII-tubulin antibody; the lengths of neurites were measured by image analysis.

Regarding the co-culture with RECs, PC12's outgrowth was significantly increased. The RECs expressed nerve growth factor (NGF), a neurotrophic factor that could act on PC12 cells to trigger cellular differentiation.

Our findings suggest that RECs via direct culture, intercellular communication in Transwell culture, and RECs CM promoted PC12 cell survival and outgrowth via NGF signaling.

The mechanism behind Parkinson's disease (PD) is still unclear, and a cure to stop its progression is yet to be found. This is mainly due to the lack of effective human PD models. To address this, we generated an in vitro PD model using Wharton's jelly-derived mesenchymal stem cells (WJMSCs).

WJMSCs were isolated from the umbilical cord using an enzymatic method. MSCs were characterized by RT-PCR, immunofluorescence, and trilineage differentiation. MSCs were differentiated into dopaminergic neuron-like cells (DAN) and further degenerated by treating them with either MPP+ iodide or the A53T mutated α-synuclein variant. Gene expression analysis by qRT-PCR and protein analysis by immunofluorescence, flow cytometry, and ELISA were performed. Assays to measure LDH, ROS, NO, GSH, and mitochondrial membrane potential were also performed after degeneration.

WJMSCs were positive for MSC markers and were able to differentiate into adipocytes, chondrocytes, and osteocytes. DAN obtained after the differentiation of WJMSCs for 48 h expressed neuronal markers such as synapsin 1, neuropilin, neurofilament, and MAPT along with dopaminergic markers such as Nurr1, DAT, TH, DDC, and KCNJ6 and were functionally active. Upon degeneration of DAN by MPP+ or A53T, elevated levels of SNCA and downregulation of TH, Nurr1, DAT, and KCNJ6 were observed. Furthermore, increased expression of α-SYN was detected at the protein level as well. Finally, reduction in mitochondrial membrane potential and GSH levels along with an increase in intracellular ROS, nitrite production, and LDH levels confirmed that the in vitro PD-like model exhibited the molecular characteristics of PD.

This model is rapid, cost-efficient, and effective for understanding the molecular mechanisms of the disease and can also be used for screening of emerging therapeutics for PD.

Recent experimental findings indicate that cancer stem cells originate from transformed very small embryonic-like stem cells. This finding represents an essential advancement in uncovering the processes that drive the onset and progression of cancer. In continuously growing cell lines, for the first time, our team's follow-up research on leukemia, lung cancer, and healthy embryonic kidney cells revealed stages that resembles very small precursor stem cells. This review explores the origin of leukemic stem-like cells from very small leukemic stem-like cells establish from transformed very small embryonic-like stem cells. We explore theoretical model of acute myeloid leukemia initiation and progresses through various stages, as well basing the HL60 cell line, present its hierarchical stage development in vitro, highlighting the role of these very small precursor primitive stages. We also discuss the potential implications of further research into these unique cellular stages for advancing leukemia and cancer treatment and prevention.

The present study investigates the influence of nitrosamines and etoposide on mesenchymal stromal cells (MSCs) in a differentiation state- and biological age-dependent manner. The genotoxic effects of the agents on both neonatal and adult stem cell populations after treatment, before, or during the course of differentiation, and the sensitivity of the different MSC types to different concentrations of MNU or etoposide were assessed. Hereby, the multipotent differentiation capacity of MSCs into osteoblasts, adipocytes, and chondrocytes was analyzed. Our findings reveal that while all cell types exhibit DNA damage upon exposure, neonatal CB-USSCs demonstrate enhanced resistance to genotoxic damage compared with their adult counterparts. Moreover, the osteogenic differentiation of MSCs was more susceptible to genotoxic damage, whereas the adipogenic and chondrogenic differentiation potentials did not show any significant changes upon treatment with genotoxin. Furthermore, we emphasize the cell-specific variability in responses to genotoxic damage and the differences in sensitivity and reaction across different cell types, thus advocating the consideration of these variabilities during drug testing and developmental biological research.

Improved treatment options are urgently needed for neurological injuries resulting from trauma or iatrogenic events causing long-term disabilities that severely impact patients' quality of life. In vitro and animal studies have provided promising proof-of-concept examples of regenerative therapies using mesenchymal stromal cells (MSC) for a wide range of pathological conditions. Over the previous decade, various MSC-based therapies have been investigated in clinical trials to treat traumatic neurological injuries. However, while the safety and feasibility of MSC treatments has been established, the patient outcomes in these studies have not demonstrated significant success in the translation of MSC regenerative therapy for the treatment of human brain and spinal cord injuries. Herein, we have reviewed the literature and ongoing registered trials on the application of MSC for the treatment of traumatic brain injury, traumatic spinal cord injury, and peripheral nerve injury. We have focused on the shortcomings and technological hurdles that must be overcome to further advance clinical research to phase 3 trials, and we discuss recent advancements that represent potential solutions to these obstacles to progress.

Sepsis is a systemic inflammatory response syndrome in which the host response to infection is dysregulated, leading to circulatory dysfunction and multi-organ damage. It has a high mortality rate and its incidence is increasing year by year, posing a serious threat to human life and health. Mesenchymal stem cells (MSC) have the following properties: hematopoietic support, provision of nutrients, activation of endogenous stem/progenitor cells, repair of tissue damage, elimination of inflammation, immunomodulation, promotion of neovascularization, chemotaxis and migration, anti-apoptosis, anti-oxidation, anti-fibrosis, homing, and many other effects. A large number of studies have confirmed that MSC from different sources have their own characteristics. This article reviews the pathogenesis of sepsis, the biological properties of MSC, and the advantages and disadvantages of different sources of MSC for the treatment of sepsis and their characteristics.

Chronic obstructive pulmonary disease(COPD) is an inflammatory disease characterized by the progressive and irreversible structural and functional damage of lung tissue. Although COPD is a significant global disease burden, the available treatments only ameliorate the symptoms, but cannot reverse lung damage. Researchers in regenerative medicine have examined the use of stem cell transplantation for treatment of COPD and other diseases because these cells have the potential for unlimited self-renewal and the ability to undergo directed differentiation. Stem cells are typically classified as embryonic stem cells, induced pluripotent stem cells, and adult stem cells (which includes mesenchymal stem cells [MSCs]), each with its own advantages and disadvantages regarding applications in regenerative medicine. Although the heterogeneity and susceptibility to senescence of MSCs make them require careful consideration for clinical applications. However, the low tumourigenicity and minimal ethical concerns of MSCs make them appear to be excellent candidates. This review summarizes the characteristics of various stem cell types and describes their therapeutic potential in the treatment of COPD, with a particular emphasis on MSCs. We aim to facilitate subsequent in-depth research and preclinical applications of MSCs by providing a comprehensive overview.

Umbilical cord blood (UCB) is a rich source of hematopoietic stem and progenitor cells that are biologically superior to their adult counterparts. UCB cells can be stored for several years without compromising their numbers or function. Today, public and private UCB banks have been established in several countries around the world. After 35 years since the first UCB transplant (UCBT), more than 50,000 UCBTs have been performed worldwide. In pediatric patients, UCBT is comparable to or superior to bone marrow transplantation. In adult patients, UCB can be an alternative source of hematopoietic cells when an HLA-matched unrelated adult donor is not available and when a transplant is urgently needed. Delayed engraftment (due to reduced absolute numbers of hematopoietic cells) and higher costs have led many medical institutions not to consider UCB as a first-line cell source for hematopoietic transplants. As a result, the use of UCB as a source of hematopoietic stem and progenitor cells for transplantation has declined over the past decade. Several approaches are being investigated to make UCBTs more efficient, including improving the homing capabilities of primitive UCB cells and increasing the number of hematopoietic cells to be infused. Several of these approaches have already been applied in the clinic with promising results. UCB also contains immune effector cells, including monocytes and various lymphocyte subsets, which, together with stem and progenitor cells, are excellent candidates for the development of cellular therapies for hematological and non-hematological diseases.

Extracellular vesicles (EVs) are nanoscale lipid bilayer vesicles released during cell activation, cellular damage, or apoptosis. They carry nucleic acids, proteins, and lipids facilitating intercellular communication and activate signaling pathways in target cells. In non-small cell lung cancer (NSCLC), EVs may contribute to tumor growth and metastasis by modulating immune responses, facilitating epithelial-mesenchymal transition, and promoting angiogenesis, while potentially contributing to resistance to chemotherapy drugs. EVs in liquid biopsies serve as non-invasive biomarkers for early cancer detection and diagnosis. Due to their small size, inherent molecular transport properties, and excellent biocompatibility, EVs also act as natural drug delivery vehicles in NSCLC therapy.

Human mesenchymal stem cells (hMSCs) are mesoderm-derived adult stem cells with self-proliferation capacity, pluripotent differentiation potency, and excellent histocompatibility. These advantages make hMSCs a promising tool in clinical application. However, the majority of clinical trials using hMSC therapy for diverse human diseases do not achieve expectations, despite the prospective pre-clinical outcomes in animal models. This is partly attributable to the intrinsic heterogeneity of hMSCs. In this review, the cause of heterogeneity in hMSCs is systematically discussed at multiple levels, including isolation methods, cultural conditions, donor-to-donor variation, tissue sources, intra-tissue subpopulations, etc. Additionally, the effect of hMSCs heterogeneity on the contrary role in tumor progression and immunomodulation is also discussed. The attempts to understand the cellular heterogeneity of hMSCs and its consequences are important in supporting and improving therapeutic strategies for hMSCs.

Spinal cord injury (SCI) is a severe condition that often leads to persistent damage of nerve cells and motor dysfunction. Autophagy is an intracellular system that regulates the recycling and degradation of proteins and lipids, primarily through lysosomal-dependent organelle degradation. Numerous publications have highlighted the involvement of autophagy in the secondary injury of SCI. Therefore, gaining a comprehensive understanding of autophagy research is crucial for designing effective therapies for SCI.

Dates were obtained from Web of Science, including articles and article reviews published from its inception to October 2023. VOSviewer, Citespace, and SCImago were used to visualized analysis. Bibliometric analysis was conducted using the Web of Science data, focusing on various categories such as publications, authors, journals, countries, organizations, and keywords. This analysis was aimed to summarize the knowledge map of autophagy and SCI.

From 2009 to 2023, the number of annual publications in this field exhibited wave-like growth, with the highest number of publications recorded in 2020 (44 publications). Our analysis identified Mei Xifan as the most prolific author, while Kanno H emerged as the most influential author based on co-citations. Neuroscience Letters was found to have published the largest number of papers in this field. China was the most productive country, contributing 232 publications, and Wenzhou Medical University was the most active organization, publishing 39 papers.

We demonstrated a comprehensive overview of the relationship between autophagy and SCI utilizing bibliometric tools. This article could help to enhance the understanding of the field about autophagy and SCI, foster collaboration among researchers and organizations, and identify potential therapeutic targets for treatment.

Background Recently, mesenchymal stromal cells (MSCs) have gained recognition for their clinical utility in transplantation to induce tolerance and to improve/replace pharmacological immunosuppression. Cord blood (CB)-derived MSCs are particularly attractive for their immunological naivety and peculiar anti-inflammatory and anti-apoptotic properties.

The objective of this study was to obtain an inventory of CB MSCs able to support large-scale advanced therapy medicinal product (ATMP)-based clinical trials.

We isolated MSCs by plastic adherence in a GMP-compliant culture system. We established a well-characterized master cell bank and expanded a working cell bank to generate batches of finished MSC(CB) products certified for clinical use. The MSC(CB) produced by our facility was used in approved clinical trials or for therapeutic use, following single-patient authorization as an immune-suppressant agent.

We show the feasibility of a well-defined MSC manufacturing process and describe the main indications for which the MSCs were employed. We delve into a regulatory framework governing advanced therapy medicinal products (ATMPs), emphasizing the need of stringent quality control and safety assessments. From March 2012 to June 2023, 263 of our Good Manufacturing Practice (GMP)-certified MSC(CB) preparations were administered as ATMPs in 40 subjects affected by Graft-vs.-Host Disease, nephrotic syndrome, or bronco-pulmonary dysplasia of the newborn. There was no infusion-related adverse event. No patient experienced any grade toxicity. Encouraging preliminary outcome results were reported. Clinical response was registered in the majority of patients treated under therapeutic use authorization.

Our 10 years of experience with MSC(CB) described here provides valuable insights into the use of this innovative cell product in immune-mediated diseases.

Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has been identified to contribute significantly to regenerative and reparative functions. Emerging evidence has suggested that MSC-EVs alone, could be used as therapeutics that emulate the biological function of MSCs. However, just as with MSCs, MSC-EVs have been shown to vary in composition, depending on the tissue source of the MSCs as well as the protocols employed in culturing the MSCs and obtaining the EVs. Therefore, the importance of careful choice of cell sources and culture environments is receiving increasing attention. Many factors contribute to the therapeutic potential of MSC-EVs, including the source tissue, isolation technique, and culturing conditions. This review illustrates the molecular landscape of EVs derived from different types of MSC cells along with culture strategies. A thorough analysis of publicly available omic datasets was performed to advance the precision understanding of MSC-EVs with unique tissue source-dependent molecular characteristics. The tissue-specific protein and miRNA-driven Reactome ontology analysis was used to reveal distinct patterns of top Reactome ontology pathways across adipose, bone marrow, and umbilical MSC-EVs. Moreover, a meta-analysis assisted by an AI technique was used to analyze the published literature, providing insights into the therapeutic translation of MSC-EVs based on their source tissues.

Cerebrovascular diseases are the second leading cause of death worldwide. Despite significant research investment, the only available therapeutic options are mechanical thrombectomy and tissue plasminogen activator thrombolysis. None of the more than a thousand drugs tested on animal models have proven successful in human clinical trials. Several factors contribute to this poor translation of data from stroke-related animal models to human stroke patients. Firstly, our understanding of the molecular and cellular processes involved in recovering from an ischemic stroke is severely limited. Secondly, although the risk of stroke is particularly high among older patients with comorbidities, most drugs are tested on young, healthy animals in controlled laboratory conditions. Furthermore, in animal models, the tracking of post-stroke recovery typically spans only 3 to 28 days, with occasional extensions to 60 days, whereas human stroke recovery is a more extended and complex process. Thirdly, young animal models often exhibit a considerably higher rate of spontaneous recovery compared to humans following a stroke. Fourth, only a very limited number of animals are utilized for each condition, including control groups. Another contributing factor to the much smaller beneficial effects in humans is that positive outcomes from numerous animal studies are more readily accepted than results reported in human trials that do not show a clear benefit to the patient. Useful recommendations for conducting experiments in animal models, with increased chances of translatability to humans, have been issued by both the STEPS investigative team and the STAIR committee. However, largely, due to economic factors, these recommendations are largely ignored. Furthermore, one might attribute the overall failures in predicting and subsequently developing effective acute stroke therapies beyond thrombolysis to potential design deficiencies in clinical trials.

Mesenchymal stromal cells (MSCs) have displayed potential in regenerating organ function due to their anti-fibrotic, anti-inflammatory, and regenerative properties. However, there is a need for delivery systems to enhance MSC retention while maintaining their anti-fibrotic characteristics. This study investigates the feasibility of using alginate hydrogel microstrands as a cell delivery vehicle to maintain MSC viability and phenotype. To accommodate cell implantation needs, we invented a Syringe-in-Syringe approach to reproducibly fabricate microstrands in small numbers with a diameter of around 200 µm and a porous structure, which would allow for transporting nutrients to cells by diffusion. Using murine NIH 3T3 fibroblasts and primary embryonic 16 (E16) salivary mesenchyme cells as primary stromal cell models, we assessed cell viability, growth, and expression of mesenchymal and fibrotic markers in microstrands. Cell viability remained higher than 90% for both cell types. To determine cell number within the microstrands prior to in vivo implantation, we have further optimized the alamarBlue assay to measure viable cell growth in microstrands. We have shown the effect of initial cell seeding density and culture period on cell viability and growth to accommodate future stromal cell delivery and implantation. Additionally, we confirmed homeostatic phenotype maintenance for E16 mesenchyme cells in microstrands.

Glioblastoma is the most aggressive, malignant, and lethal brain tumor of the central nervous system. Its poor prognosis lies in its inefficient response to currently available treatments that consist of surgical resection, radiotherapy, and chemotherapy. Recently, the use of mesenchymal stem cells (MSCs) as a possible kind of cell therapy against glioblastoma is gaining great interest due to their immunomodulatory properties, tumor tropism, and differentiation into other cell types. However, MSCs seem to present both antitumor and pro-tumor properties depending on the tissue from which they come. In this work, the possibility of using MSCs to deliver therapeutic genes, oncolytic viruses, and miRNA is presented, as well as strategies that can improve their therapeutic efficacy against glioblastoma, such as CAR-T cells, nanoparticles, and exosomes.

Previously, we achieved large-scale expansion of bone marrow-derived suppressor cells (MDSCs) derived from cluster of differentiation (CD)34+ cells cultured in human umbilical cord blood (hUCB) and demonstrated their immunomodulatory properties. In the present study, we assessed the therapeutic efficacy of hUCB-MDSCs in atopic dermatitis (AD).

Dermatophagoides farinae (Df)-induced NC/Nga mice (clinical score of 7) were treated with hUCB-MDSCs or a control drug. The mechanisms underlying the therapeutic effects of hUCB-MDSCs were evaluated.

hUCB-MDSCs demonstrated immunosuppressive effects in both human and mouse CD4+ T cells. hUCB-MDSCs significantly reduced the clinical severity scores, which were associated with histopathological changes, and reduced inflammatory cell infiltration, epidermal hyperplasia, and fibrosis. Furthermore, hUCB-MDSCs decreased the serum levels of immunoglobulin E, interleukin (IL)-4, IL-5, IL-13, IL-17, thymus- and activation-regulated chemokines, and thymic stromal lymphopoietin. Additionally, they altered the expression of the skin barrier function-related proteins filaggrin, involucrin, loricrin, cytokeratin 10, and cytokeratin 14 and suppressed the activation of Df-restimulated T-cells via cell-cell interactions. hUCB-MDSCs promoted skin recovery and maintained their therapeutic effect even after recurrence. Consequently, hUCB-MDSC administration improved Df-induced AD-like skin lesions and restored skin barrier function. Our findings support the potential of hUCB-MDSCs as a novel treatment strategy for AD.

In recent years, there has been a significant increase in the practice of regenerative medicine by health practitioners and direct-to-consumer businesses globally. Among different tools of regenerative medicine, platelet-rich plasma (PRP) and stem cell-based therapies have received considerable attention. The use of PRP, in particular, has gained popularity due to its easy access, simple processing techniques, and regenerative potential. However, it is important to address a common misconception amongst the general public equating to PRP and stem cells due to the demonstrated efficacy of PRP in treating musculoskeletal and dermatological disorders. Notably, PRP promotes regeneration by providing growth factors or other paracrine factors only. Therefore, it cannot replenish or replace the lost cells in conditions where a large number of cells are required to regenerate tissues and/or organs. In such cases, cellbased therapies are the preferred option. Additionally, other tools of regenerative medicine, such as bioprinting, organoids, and mechanobiology also rely on stem cells for their success. Hence, healthcare and commercial entities offering direct-to-customer regenerative therapies should not mislead the public by claiming that the application of PRP is a stem cell-based therapy. Furthermore, it is important for regulatory bodies to strictly monitor these profit-driven entities to prevent them from providing unregulated regenerative treatments and services that claim a broad variety of benefits with little proof of efficacy, safety concerns, and obscure scientific justification.

Osteoarthritis (OA) is a chronic, degenerative joint disease presenting a significant global health threat. While current therapeutic approaches primarily target symptom relief, their efficacy in repairing joint damage remains limited. Recent research has highlighted mesenchymal stem cells (MSCs) as potential contributors to cartilage repair, anti-inflammatory modulation, and immune regulation in OA patients. Notably, MSCs from different sources and their derivatives exhibit variations in their effectiveness in treating OA. Moreover, pretreatment and gene editing techniques of MSCs can enhance their therapeutic outcomes in OA. Additionally, the combination of novel biomaterials with MSCs has shown promise in facilitating the repair of damaged cartilage. This review summarizes recent studies on the role of MSCs in the treatment of OA, delving into their advantages and exploring potential directions for development, with the aim of providing fresh insights for future research in this critical field.

Human cartilage tissue can be categorized into three types: hyaline cartilage, elastic cartilage and fibrocartilage. Each type of cartilage tissue possesses unique properties and functions, which presents a significant challenge for the regeneration and repair of damaged tissue. Bionics is a discipline in which humans study and imitate nature. A bionic strategy based on comprehensive knowledge of the anatomy and histology of human cartilage is expected to contribute to fundamental study of core elements of tissue repair. Moreover, as a novel tissue-engineered technology, 3D bioprinting has the distinctive advantage of the rapid and precise construction of targeted models. Thus, by selecting suitable materials, cells and cytokines, and by leveraging advanced printing technology and bionic concepts, it becomes possible to simultaneously realize multiple beneficial properties and achieve improved tissue repair. This article provides an overview of key elements involved in the combination of 3D bioprinting and bionic strategies, with a particular focus on recent advances in mimicking different types of cartilage tissue.

Microcarriers provide a high surface-area-to-volume ratio that can realize high yields of cell products, including human mesenchymal stem cells (hMSCs). Here, we report a novel poly(vinyl alcohol) (PVA)-based microcarrier for hMSC expansion in suspension culture. PVA microcarriers were prepared as collagen-coated PVA hydrogels 181 μm in size and a high surface-area-to-weight ratio of 2945 cm2/g. The PVA microcarriers supported a 2.6-fold expansion of hMSCs in a 30-mL single-use stirred bioreactor after a 7 d culture period, comparable to that of commercially available microcarriers. Interestingly, we observed that hMSCs on PVA microcarriers adhered to adjacent microcarriers, resulting in the aggregation of hMSC-PVA microcarriers. Therefore, we conducted a long-term expansion culture using a bead-to-bead cell transfer method with PVA microcarriers. Fresh microcarriers were added to the cell-populated microcarriers in the bioreactor on days 7 and 14. hMSCs on PVA microcarriers continued to grow for 21 d using the bead-to-bead cell transfer method. Furthermore, magnetic PVA (PVA-mag) microcarriers were developed by loading magnetic nanoparticles into PVA microcarriers, and we demonstrated that these PVA-mag microcarriers enabled cell recovery by magnetic separation. These results suggest that these PVA microcarriers can contribute to the large-scale culture of hMSCs for regenerative medicine and cell therapy.

Skeletal problems are an increasing issue due to the increase in the global aging population. Different statistics reports show that today, the global population is aging that results in skeletal problems, increased health system costs, and even higher mortality associated with skeletal problems. Common treatments such as surgery and bone grafts are not always effective and in some cases, they can even cause secondary problems such as infections or improper repair. Cell therapy is a method that can be utilized along with common treatments independently. Mesenchymal stem cells (MSCs) are a very important and efficient source in terms of different diseases, especially bone problems. These cells are present in different tissues such as bone marrow, adipose tissue, umbilical cord, placenta, dental pulp, peripheral blood, amniotic fluid and others. Among the types of MSCs, bone marrow mesenchymal stem cells (BMMSCs) are the most widely used source of these cells, which have appeared to be very effective and promising in terms of skeletal diseases, especially compared to the other sources of MSCs. This study focuses on the specific potential and content of BMMSCs from which the specific capacity of these cells originates, and compares their osteogenic potential with other types of MSCs, and also the future directions in the application of BMMSCs as a source for cell therapy.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury characterized by diffuse alveolar damage. The period prevalence of ARDS was 10.4% of ICU admissions in 50 countries. Although great progress has been made in supportive care, the hospital mortality rate of severe ARDS is still up to 46.1%. Moreover, up to now, there is no effective pharmacotherapy for ARDS and most clinical trials focusing on consistently effective drugs have met disappointing results. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have spawned intense interest of a wide range of researchers and clinicians due to their robust anti-inflammatory, anti-apoptotic and tissue regeneration properties. A growing body of evidence from preclinical studies confirmed the promising therapeutic potential of MSCs and their EVs in the treatment of ARDS. Based on the inspiring experimental results, clinical trials have been designed to evaluate safety and efficacy of MSCs and their EVs in ARDS patients. Moreover, trials exploring their optimal time window and regimen of drug administration are ongoing. Therefore, this review aims to present an overview of the characteristics of mesenchymal stem cells and their derived EVs, therapeutic mechanisms for ARDS and research progress that has been made over the past 5 years.

The shortage of corneal donors has prompted the development of tissue-engineered corneal grafts as an alternative solution. Currently, amniotic membranes with good biocompatibility are widely used as scaffolds for loading stem cells in the treatment of corneal injury. However, this approach has its limitations. In this study, BMSCs were induced to differentiate into corneal epithelial cells via direct contact co-culture, and platelet-poor plasma was used to prepare fibrin gels, which were compressed to remove excess liquid and then lyophilized to obtain plasma fibrin membranes (PFMs). A tissue-engineered corneal implant with PFMs as a scaffold loaded with BMSCs and corneal epithelial cells was designed and obtained. Scanning electron microscopy showed that PFMs have a uniformly distributed microporous surface that facilitates cell attachment and nutrient transport. The rheological results showed that the freeze-dried and rehydrated PFMs were more rigid than fresh membranes, which makes it easier to use them for transplantation after cell loading. The experimental results of a rat alkali burn cornea injury model showed that PFMs effectively reduced the inflammatory reaction, inhibited fibrosis, and accelerated the healing of corneal wounds. It was also found that some of the BMSCs were successfully implanted into the corneal injury site in rats and differentiated into corneal epithelial cells. These results demonstrate the potential of tissue-engineered corneal implants using BMSCs and corneal epithelial cells and PFMs as scaffolds as a new treatment option for corneal injury.

Mesenchymal stromal cells nowadays emerge as a major player in the field of regenerative medicine and translational research. They constitute, with their derived products, the most frequently used cell type in different therapies. However, their heterogeneity, including different subpopulations, the anatomic source of isolation, and high donor-to-donor variability, constitutes a major controversial issue that affects their use in clinical applications. Furthermore, the intrinsic and extrinsic molecular mechanisms underlying their self-renewal and fate specification are still not completely elucidated. This review dissects the different heterogeneity aspects of the tissue source associated with a distinct developmental origin that need to be considered when generating homogenous products before their usage for clinical applications.

The biosafety of gene therapy remains a crucial issue for both the direct and cell-mediated delivery of recombinant cDNA encoding biologically active molecules for the pathogenetic correction of congenital or acquired disorders. The diversity of vector systems and cell carriers for the delivery of therapeutic genes revealed the difficulty of developing and implementing a safe and effective drug containing artificial genetic material for the treatment of human diseases in practical medicine. Therefore, in this study we assessed changes in the transcriptome and secretome of umbilical cord blood mononuclear cells (UCB-MCs) genetically modified using adenoviral vector (Ad5) carrying cDNA encoding human vascular endothelial growth factor (VEGF165) or reporter green fluorescent protein (GFP). A preliminary analysis of UCB-MCs transduced with Ad5-VEGF165 and Ad5-GFP with MOI of 10 showed efficient transgene expression in gene-modified UCB-MCs at mRNA and protein levels. The whole transcriptome sequencing of native UCB-MCs, UCB-MC+Ad5-VEGF165, and UCB-MC+Ad5-GFP demonstrated individual sample variability rather than the effect of Ad5 or the expression of recombinant vegf165 on UCB-MC transcriptomes. A multiplex secretome analysis indicated that neither the transduction of UCB-MCs with Ad5-GFP nor with Ad5-VEGF165 affects the secretion of the studied cytokines, chemokines, and growth factors by gene-modified cells. Here, we show that UCB-MCs transduced with Ad5 carrying cDNA encoding human VEGF165 efficiently express transgenes and preserve transcriptome and secretome patterns. This data demonstrates the biosafety of using UCB-MCs as cell carriers of therapeutic genes.

Over the last decade, adipose-derived stem cells (ADSCs) have attracted increasing attention in the field of regenerative medicine. ADSCs appear to be the most advantageous cell type for regenerative therapies owing to their easy accessibility, multipotency, and active paracrine activity. This review highlights current challenges in translating ADSC-based therapies into clinical settings and discusses novel strategies to overcome the limitations of ADSCs. To further establish ADSC-based therapies as an emerging platform for regenerative medicine, this review also provides an update on the advancements in this field, including fat grafting, wound healing, bone regeneration, skeletal muscle repair, tendon reconstruction, cartilage regeneration, cardiac repair, and nerve regeneration. ADSC-based therapies are expected to be more tissue-specific and increasingly important in regenerative medicine.

Since the discovery of mesenchymal stem cells (MSCs) in the 1970s, they have been widely used in the treatment of a variety of diseases because of their wide sources, strong differentiation potential, rapid expansion in vitro, low immunogenicity, and so on. At present, most of the related research is on mesoderm-derived MSCs (M-MSCs) such as bone marrow MSCs and adipose-derived MSCs. As a type of MSC, ectoderm-derived MSCs (E-MSCs) have a stronger potential for self-renewal, multidirectional differentiation, and immunomodulation and have more advantages than M-MSCs in some specific conditions. This paper analyzes the relevant research development of E-MSCs compared with that of M-MSCs; summarizes the extraction, discrimination and culture, biological characteristics, and clinical application of E-MSCs; and discusses the application prospects of E-MSCs. This summary provides a theoretical basis for the better application of MSCs from both ectoderm and mesoderm in the future.

Hepatic fibrosis/cirrhosis is a significant health burden worldwide, resulting in liver failure or hepatocellular carcinoma (HCC) and accounting for many deaths each year. The pathogenesis of hepatic fibrosis/cirrhosis is very complex, which makes treatment challenging. Endogenous mesenchymal stromal cells (MSCs) have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis. Paradoxically, exogenous MSCs have also been used in clinical trials for liver cirrhosis, and their effectiveness has been observed in most completed clinical trials. There are still many issues to be resolved to promote the use of MSCs in the clinic in the future. In this review, we will examine the controversial role of MSCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis. We also investigated the clinical trials involving MSCs in liver cirrhosis, summarized the parameters that need to be standardized, and discussed how to promote the use of MSCs from a clinical perspective.

Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients' quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.

While cord blood (CB) is primarily utilized in allogeneic hematopoietic cell transplantation (HCT), the development of novel cell therapy products from CB is a growing and developing field. Compared to adult blood, CB is characterized by a higher percentage of hematopoietic stem cells (HSCs) and progenitor cells, less mature immune cells that retain a high capacity of proliferation, and stronger immune tolerance that requires less stringent HLA-matching when used in the allogenic setting. Given that CB is an FDA regulated product and along with its unique cellular composition, CB lends itself as a readily available and safe starting material for the development of off-the-shelf cell therapies. Moreover, non-hematologic cells such as mesenchymal stem cell (MSCs) residing in CB or CB tissue also have potential in regenerative medicine and inflammatory and autoimmune conditions. In this review, we will focus on recent clinical development on CB-derived cellular therapies in the field of oncology, including T-cell therapies such as chimeric antigen receptor (CAR) T-cells, regulatory T-cells, and virus-specific T-cells; NK-cell therapies, such as NK cell engagers and CAR NK-cells; CB-HCT and various modifications; as well as applications of MSCs in HCT.

Lipoaspirates represent a source of adult stem cells, cytokines, and growth factors of adipocyte origin with immunomodulation and regenerative medicine potential. However, rapid and simple protocols for their purification using self-contained devices that can be deployed at the points of care are lacking. Here, we characterize and benchmark a straightforward mechanical dissociation procedure to collect mesenchymal stem cells (MSCs) and soluble fractions from lipoaspirates. IStemRewind, a benchtop self-contained cell purification device, allowed a one-procedure purification of cells and soluble material from lipoaspirates with minimal manipulation. The recovered cellular fraction contained CD73⁺, CD90⁺, CD105⁺, CD10⁺ and CD13⁺ MSCs. These markers were comparably expressed on MSCs isolated using IstemRewind or classic enzymatic dissociation procedures, apart from CD73⁺ MSCs, which were even more abundant in IStemRewind isolates. IstemRewind-purified MSCs retained viability and differentiation into adipocytes and osteocytes, even after a freezing-thawing cycle. Levels of IL4, IL10, bFGF and VEGF were higher compared to the pro-inflammatory cytokines TNFα, IL1β and IL6 in the IStemRewind-isolated liquid fraction. In sum, IStemRewind can be useful for straightforward, rapid, and efficient isolation of MSCs and immunomodulatory soluble factors from lipoaspirates, opening the possibility to directly isolate and employ them at the point-of-care.

Osteoclasts are multinucleated bone resorbing cells that can be differentiated from human monocytes in vitro. There are few studies comparing osteoclastogenesis of different monocyte sources. We compared monocytes from human bone marrow (BM), peripheral blood (PB), and umbilical cord blood (CB) and their osteoclastogenic potential by culturing them with RANKL (20 and 80 ng/ml) and M-CSF (10 ng/ml) for 14 days. We also cultured cells without growth factors, as umbilical cord blood monocytes have been reported to be able to fuse spontaneously into osteoclasts. The data was analysed on d4, d8, d11, and d14. After culture with RANKL and M-CSF, all types of cell cultures developed TRACP -positive multinuclear cells that were able to form resorption pits on human bone slices. Only occasional multinuclear cells and small infrequent resorbed areas could be found in PB and CB-derived cultures without growth factors. BM-derived cells formed greater resorption areas than PB- and CB-derived monocytes. The greatest monocyte population in BM samples were intermediate (CD14⁺⁺CD16⁺) and in PB and CB classical monocytes (76.3% and 54.4%, respectively). In conclusion, our data demonstrates that bone resorbing osteoclasts can be differentiated from BM, PB and CB. However, the osteoclast precursor origin can affect the osteoclast properties and function.

The recent tendency to delay pregnancy has increased the incidence of age-related infertility, as female reproductive competence decreases with aging. Along with aging, a lowered capacity of antioxidant defense causes a loss of normal function in the ovaries and uterus due to oxidative damage. Therefore, advancements have been made in assisted reproduction to resolve infertility caused by reproductive aging and oxidative stress, following an emphasis on their use. The application of mesenchymal stem cells (MSCs) with intensive antioxidative properties has been extensively validated as a regenerative therapy, and proceeding from original cell therapy, the therapeutic effects of stem cell conditioned medium (CM) containing paracrine factors secreted during cell culture have been reported to be as effective as that of direct treatment of source cells. In this review, we summarized the current understanding of female reproductive aging and oxidative stress and present MSC-CM, which could be developed as a promising antioxidant intervention for assisted reproductive technology.

Perinatal brain injury is a major contributor to long-term adverse neurodevelopment. There is mounting preclinical evidence for use of umbilical cord blood (UCB)-derived cell therapy as potential treatment. To systematically review and analyse effects of UCB-derived cell therapy on brain outcomes in preclinical models of perinatal brain injury. MEDLINE and Embase databases were searched for relevant studies. Brain injury outcomes were extracted for meta-analysis to calculate standard mean difference (SMD) with 95% confidence interval (CI), using an inverse variance, random effects model. Outcomes were separated based on grey matter (GM) and white matter (WM) regions where applicable. Risk of bias was assessed using SYRCLE, and GRADE was used to summarise certainty of evidence. Fifty-five eligible studies were included (7 large, 48 small animal models). UCB-derived cell therapy significantly improved outcomes across multiple domains, including decreased infarct size (SMD 0.53; 95% CI (0.32, 0.74), p < 0.00001), apoptosis (WM, SMD 1.59; 95%CI (0.86, 2.32), p < 0.0001), astrogliosis (GM, SMD 0.56; 95% CI (0.12, 1.01), p = 0.01), microglial activation (WM, SMD 1.03; 95% CI (0.40, 1.66), p = 0.001), neuroinflammation (TNF-α, SMD 0.84; 95%CI (0.44, 1.25), p < 0.0001); as well as improved neuron number (SMD 0.86; 95% CI (0.39, 1.33), p = 0.0003), oligodendrocyte number (GM, SMD 3.35; 95 %CI (1.00, 5.69), p = 0.005) and motor function (cylinder test, SMD 0.49; 95 %CI (0.23, 0.76), p = 0.0003). Risk of bias was determined as serious, and overall certainty of evidence was low. UCB-derived cell therapy is an efficacious treatment in pre-clinical models of perinatal brain injury, however findings are limited by low certainty of evidence.

Ischemic stroke is the main cause of death and the most common cause of acquired physical disability worldwide. Recent demographic changes increase the relevance of stroke and its sequelae. The acute treatment for stroke is restricted to causative recanalization and restoration of cerebral blood flow, including both intravenous thrombolysis and mechanical thrombectomy. Still, only a limited number of patients are eligible for these time-sensitive treatments. Hence, new neuroprotective approaches are urgently needed. Neuroprotection is thus defined as an intervention resulting in the preservation, recovery, and/or regeneration of the nervous system by interfering with the ischemic-triggered stroke cascade. Despite numerous preclinical studies generating promising data for several neuroprotective agents, successful bench-to-bedside translations are still lacking. The present study provides an overview of current approaches in the research field of neuroprotective stroke treatment. Aside from "traditional" neuroprotective drugs focusing on inflammation, cell death, and excitotoxicity, stem-cell-based treatment methods are also considered. Furthermore, an overview of a prospective neuroprotective method using extracellular vesicles that are secreted from various stem cell sources, including neural stem cells and bone marrow stem cells, is also given. The review concludes with a short discussion on the microbiota-gut-brain axis that may serve as a potential target for future neuroprotective therapies.

Cartilage lesions are common conditions, affecting elderly and non-athletic populations. Despite recent advances, cartilage regeneration remains a major challenge today. The absence of an inflammatory response following damage and the inability of stem cells to penetrate into the healing site due to the absence of blood and lymph vessels are assumed to hinder joint repair. Stem cell-based regeneration and tissue engineering have opened new horizons for treatment. With advances in biological sciences, especially stem cell research, the function of various growth factors in the regulation of cell proliferation and differentiation has been established. Mesenchymal stem cells (MSCs) isolated from different tissues have been shown to increase into therapeutically relevant cell numbers and differentiate into mature chondrocytes. As MSCs can differentiate and become engrafted inside the host, they are considered suitable candidates for cartilage regeneration. Stem cells from human exfoliated deciduous teeth (SHED) provide a novel and non-invasive source of MSCs. Due to their simple isolation, chondrogenic differentiation potential, and minimal immunogenicity, they can be an interesting option for cartilage regeneration. Recent studies have reported that SHED-derived secretome contains biomolecules and compounds that efficiently promote regeneration in damaged tissues, including cartilage. Overall, this review highlighted the advances and challenges of cartilage regeneration using stem cell-based therapies by focusing on SHED.

Management of relapses and refractory rheumatoid arthritis (RA) patients is complex and difficult. Even after the administration of new biological disease-modifying anti-rheumatic drugs (DMARDs), only a few patients achieve the complete remission phase. DMARDs help only in modifying the disease activity, which sooner or later fails. They do not manage the disease at the patho-etiological level. There are some serious side effects as well as drug interaction with DMARDs. There are few subsets of RA patients who do not respond to DMARDs, reasons unknown. Mesenchymal stem cells (MSCs) provide a promising alternative, especially in such cases. This review elaborates on the studies pertaining to the application of MSCs in rheumatoid arthritis over the last two decades. A total of 14 studies (one review article) including 447 patients were included in the study. Most of the studies administered MSCs in refractory RA patients through the intravenous route with varied dosages and frequency of administration. MSCs help in RA treatment via various mechanisms including paracrine effects. All the studies depicted a better clinical outcome with minimal adverse events. The functional scores including the VAS scores improved significantly in all studies irrespective of dosage and source of MSCs. The majority of the studies depicted no complications. Although the use of MSCs in RA is still in the early stages requiring further refinement in the source of MSCs, dosage, and frequency. The role of MSCs in the management of RA has a promising prospect. MSCs target the RA at the molecular level and has the potential to manage refractory RA cases not responding to conventional treatment. Multicentric, large sample populations, and long-term studies are required to ascertain efficacy and safety.

Mesenchymal stromal/stem cells (MSCs) are multipotent cells that reside in multiple tissues are capable of self-renewal and differentiation into various cell types. These properties make them promising candidates for regenerative therapies. MSC identification is critical in yielding pure populations for successful therapeutic applications; however, the criteria for MSC identification proposed by the International Society for Cellular Therapy (ISCT) are inconsistent across different tissue sources. This study aimed to identify potential markers to be used together with the ISCT criteria to provide a more accurate means of MSC identification. Thus, we carried out a computational comparative analysis of the gene expression in human and mouse MSCs derived from multiple tissues to identify the differentially expressed genes that are shared between the two species. We show that six members of the proteasome degradation system are similarly expressed across MSCs derived from bone marrow, adipose tissue, amnion, and umbilical cord. Additionally, with the help of predictive models, we found that the expression profile of these genes correctly validated the identity of the MSCs across all the tissue sources tested. Moreover, using genetic interaction networks, we showed a possible link between these genes and antioxidant enzymes in the MSC antioxidant defense system, thereby pointing to their potential role in prolonging the life span of MSCs. According to our findings, members of the proteasome degradation system may serve as stemness-related markers.

Mesenchymal stem cells (MSCs) are multipotent cells that exhibit two main characteristics which define stem cells: self-renewal and differentiation. MSCs can migrate to sites of injury, inflammation, and tumor. Moreover, MSCs undergo myofibroblast-like differentiation, including increased production of α-SMA in response to transforming growth factor-β (TGF-β), a growth factor commonly secreted by tumor cells to evade immune surveillance. Based on our previous findings, hMSCs become activated and resemble carcinoma-associated myofibroblasts upon prolonged exposure to a conditioned medium from MDAMB231 human breast cancer cells. In this section, we show using immunofluorescence that keratinocyte-conditioned medium (KCM) induces differentiation of MSCs to resemble dermal myofibroblast-like cells with punctate vinculin staining and F-actin filaments.

We sought to determine the feasibility of identifying and quantifying mesenchymal stem cells (MSCs) from umbilical cord blood (UCB) after delayed cord clamping in preterm and term births. We obtained 3 mL of UCB at various gestational ages after delayed cord clamping. UCB separated by density gradient centrifugation within 4 h of delivery was passed through magnetic bead micro-columns to exclude the CD34 + cell population. The samples were incubated with fluorescent-tagged mesenchymal cell marker antibodies CD 29, CD44, CD73, CD105, and hematopoietic cell marker CD45. The cell populations were analyzed by flow cytometry. Viable cells were assessed with 7-aminoactinomycin-D. The results were expressed in median (minimum to maximum) MSCs and compared between preterm and term samples. A total of 12 UCB samples (32-40 weeks) were obtained, 10 of which demonstrated MSCs, accounting for 0.0174% (0-14.7%) of the viable UCB mononuclear cells. MSCs comprised 0.148% (0.0006-1.59%) and 0.116% (0-14.7%) of the viable UCB mononuclear cells in the term (n = 5), 38.4 ± 1.3 weeks, and preterm (n = 7) samples, 34.6 ± 1.1, respectively, p = 0.17. There was an overall median of 96 (0-39,574) MSCs. There was no difference in the median numbers of MSCs identified between term and preterm UCB samples, 3384 (23-6042) and 36 (0-39,574), respectively, p = 0.12. Mesenchymal stem cells were identified and quantified in 5 of 7 preterm and all 5 term UCB 3-mL samples obtained after delayed cord clamping.