Human dental pulp stem cells (hDPSCs) have emerged as a promising resource in regenerative medicine due to their unique ability to secrete exosomes containing a diverse array of bioactive molecules, particularly microRNAs (miRNAs). These exosomes appear to be essential for stimulating regenerative mechanisms, especially those associated with stem cell pluripotency and tissue repair. However, several challenges such as cargo specificity and delivery efficiency need to be addressed to maximise the therapeutic potential of hDPSC-derived exosomes and miRNA-based therapies. This narrative review explores hDPSCs' potential in regenerative medicine by examining their role in tissue engineering, secretome composition, exosome function, exosomal miRNA in diverse models, and miRNA profiling. Therefore, it is imperative to sustain ongoing research on miRNA to advance clinical applications in the field of regenerative medicine and dentistry. A comprehensive understanding of the specific miRNA composition within hDPSC-derived exosomes is essential to elucidate their mechanistic roles in diverse disease states and to inform the development of innovative therapeutic strategies. These findings hold significant potential for the development of innovative regenerative therapies and emphasises the importance of establishing a strong connection between translational research discoveries and clinical applications. hDPSC-derived exosomes and miRNA-based therapies play a crucial role in immune modulation, regenerative dentistry, and tissue repair.

Mesenchymal stem cell (MSC)-based therapies have yielded beneficial effects in a broad range of preclinical models and clinical trials for human diseases. In the context of MSC transplantation, it is widely recognized that the main mechanism for the regenerative potential of MSCs is not their differentiation, with in vivo data revealing transient and low engraftment rates. Instead, MSCs therapeutic effects are mainly attributed to its secretome, i.e., paracrine factors secreted by these cells, further offering a more attractive and innovative approach due to the effectiveness and safety of a cell-free product.

In this review, we will discuss the potential benefits of MSC-derived secretome in regenerative medicine with particular focus on respiratory, hepatic, and neurological diseases. Both free and vesicular factors of MSC secretome will be detailed. We will also address novel potential strategies capable of improving their healing potential, namely by delivering important regenerative molecules according to specific diseases and tissue needs, as well as non-clinical and clinical studies that allow us to dissect their mechanisms of action.

MSC-derived secretome includes both soluble and non-soluble factors, organized in extracellular vesicles (EVs). Importantly, besides depending on the cell origin, the characteristics and therapeutic potential of MSC secretome is deeply influenced by external stimuli, highlighting the possibility of optimizing their characteristics through preconditioning approaches. Nevertheless, the clarity around their mechanisms of action remains ambiguous, whereas the need for standardized procedures for the successful translation of those products to the clinics urges.

Mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) are nanoscale lipid bilayer vesicles secreted by mesenchymal stem cells. They inherit the parent cell's attributes, facilitating tissue repair and regeneration, promoting angiogenesis, and modulating the immune response, while offering advantages like reduced immunogenicity, straightforward administration, and enhanced stability for long-term storage. These characteristics elevate MSC-EVs as highly promising in cell-free therapy with notable clinical potential. It is critical to delve into their pharmacokinetics and thoroughly elucidate their intracellular and in vivo trajectories. A detailed summary and evaluation of existing tracing strategies are needed to establish standardized protocols. Here, we have summarized and anticipated the research progress of MSC-EVs in various biomedical imaging techniques, including fluorescence imaging, bioluminescence imaging, nuclear imaging (PET, SPECT), tomographic imaging (CT, MRI), and photoacoustic imaging. The challenges and prospects of MSC-EV tracing strategies, with particular emphasis on clinical translation, have been analyzed, with promising solutions proposed.

Cardiovascular disease remains one of the leading causes of mortality in the Western world. Congenital heart disease affects nearly 1 % of newborns, with approximately one-fourth requiring reconstructive surgery during their lifetime. Current cardiovascular replacement options have significant limitations. Their inability to grow poses particular challenges for pediatric patients. Tissue Engineered Matrix (TEM)-based in situ constructs, with their self-repair and growth potential, offer a promising solution to overcome the limitations of current clinically used replacement options. Various functionalization strategies, involving the integration of biomechanical or biochemical components to enhance biocompatibility, have been developed for Tissue Engineered Vascular Grafts (TEVG) and Tissue Engineered Heart Valves (TEHV) to foster their capacity for in vivo remodeling. In this review, we present the current state of clinical translation for TEVG and TEHV, and provide a comprehensive overview of biomechanical and biochemical functionalization strategies for TEVG and TEHV. We discuss the rationale for functionalization, the implementation of functionalization cues in TEM-based TEVG and TEHV, and the interrelatedness of biomechanical and biochemical cues in the in vivo response. Finally, we address the challenges associated with functionalization and discuss how interdisciplinary research, especially when combined with in silico models, could enhance the translation of these strategies into clinical applications. STATEMENT OF SIGNIFICANCE: Cardiovascular disease remains one of the leading causes of mortality, with current replacements being unable to grow and regenerate. In this review, we present the current state of clinical translation for tissue engineered vascular grafts (TEVG) and heart valves (TEHV). Particularly, we discuss the rationale and implementation for functionalization cues in tissue engineered matrix-based TEVGs and TEHVs, and for the first time we introduce the interrelatedness of biomechanical and biochemical cues in the in-vivo response. These insights pave the way for next-generation cardiovascular implants that promise better durability, biocompatibility, and growth potential. Finally, we address the challenges associated with functionalization and discuss how interdisciplinary research, especially when combined with in silico models, could enhance the translation of these strategies into clinical applications .

We previously have shown the potential of human endomyocardial biopsy (EMB)-derived cardiac adherent proliferating cells (CardAPs) as a new cell-therapeutic treatment option for virus-induced myocarditis. To overcome the limited cell yield per EMB, CardAPs have been isolated from the human right atrial appendage (RAA) in view of allogeneic application and off-the-shelf use. We aimed to investigate the cardioprotective and immunomodulatory potential of RAA-CardAPs in experimental acute and chronic Coxsackievirus B3 (CVB3)-induced myocarditis upon injection in the viral and inflammatory phase. In the acute model, male C57BL6/J mice were intraperitoneally (i.p.) injected with the CVB3 Nancy strain or phosphate buffered saline (PBS). One day after infection, mice were intravenously (i.v.) injected with RAA-CardAPs, EMB-CardAPs (as reference cells) or PBS. For the chronic model, male Naval Medical Research Institute mice were i.p. injected with the CVB3 31-1-93 strain or PBS. Ten days after infection, mice were i.v. injected with RAA-CardAPs. Cardiac function was characterized, followed by harvest of the left ventricle (LV) and spleen for subsequent analysis, 7 and 28 days after CVB3 infection in the acute and chronic model, respectively. In the acute model, RAA-CardAPs decreased cardiac fibrosis and improved cardiac function in CVB3 mice. RAA-CardAPs mice exerted immunomodulatory effects as evidenced by lower LV chemokines expression (C-C motif ligand [CCL]2 and CCL7), CD68+ cells presence, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α, and IL-6 mRNA expression. In the chronic model, RAA-CardAPs reduced cardiac fibrosis and the severity of myocarditis, associated with an improvement in LV function. We conclude that RAA-CardAPs represent a treatment strategy to reduce the development of acute and chronic CVB3-induced myocarditis.

Myocardial infarction (MI) with resulting congestive heart failure is one of the leading causes of death worldwide. Current therapies for treating MI, such as devices, traditional medicine, and surgeries, come with many limitations as patients in their final stages of heart failure have little chances of experiencing any reversible changes. In recent decades, Mesenchymal stem cell (MSC) based therapy has become one of the most popular and rapidly developing fields in treating MI. Their supremacy for clinical applications is partially due to their unique properties and encouraging pre-clinical outcomes in various animal disease models. However, the majority of clinical trials registered for MSC therapy for diverse human diseases, including MI, have fallen short of expectations. This review intends to discuss the recent advances in the clinical application of using MSCs for cardiac repair and discuss challenges facing the clinical translation of MSCs for cardiac regeneration such as restoration of endothelial-cardiomyocyte crosstalk, immunomodulation and immune rejection, poor homing and migration, as well as low retention and survival. Furthermore, we will discuss recent strategies being investigated to help overcome some of these challenges.

Cardiomyocytes can be implanted to remuscularize the failing heart1-7. Challenges include sufficient cardiomyocyte retention for a sustainable therapeutic impact without intolerable side effects, such as arrhythmia and tumour growth. We investigated the hypothesis that epicardial engineered heart muscle (EHM) allografts from induced pluripotent stem cell-derived cardiomyocytes and stromal cells structurally and functionally remuscularize the chronically failing heart without limiting side effects in rhesus macaques. After confirmation of in vitro and in vivo (nude rat model) equivalence of the newly developed rhesus macaque EHM model with a previously established Good Manufacturing Practice-compatible human EHM formulation8, long-term retention (up to 6 months) and dose-dependent enhancement of the target heart wall by EHM grafts constructed from 40 to 200 million cardiomyocytes/stromal cells were demonstrated in macaques with and without myocardial infarction-induced heart failure. In the heart failure model, evidence for EHM allograft-enhanced target heart wall contractility and ejection fraction, which are measures for local and global heart support, was obtained. Histopathological and gadolinium-based perfusion magnetic resonance imaging analyses confirmed cell retention and functional vascularization. Arrhythmia and tumour growth were not observed. The obtained feasibility, safety and efficacy data provided the pivotal underpinnings for the approval of a first-in-human clinical trial on tissue-engineered heart repair. Our clinical data confirmed remuscularization by EHM implantation in a patient with advanced heart failure.

The prevalence of acute myocardial infarction, a severe ischemic cardiac disease, is on the rise annually. The establishment of coronary collateral circulation in the border zone of the infarct can effectively relieve myocardial ischemia and impede cell death, while angiogenesis can promote the formation of collateral circulation in the ischemic tissues. Over the past two decades, studies related to angiogenesis in acute myocardial infarction have increased rapidly. However, there is a lack of bibliometric studies in this particular field.

For this study, we employed bibliometric analysis to outline focal points and patterns in scientific and clinical research. The collection of literature was gathered using the Web of Science Core Collection database. Bibliometric and visual analysis were conducted. Knowledge maps were generated using CiteSpace and VOSviewer software.

With the deepening of the research, therapeutic angiogenesis will become a treatment direction for acute myocardial infarction in the future.

Healthy aging is a common goal for humanity and society, and one key to achieving it is the rejuvenation of senescent resident stem cells and empowerment of aging organ regeneration. However, the mechanistic understandings of stem cell senescence and the potential strategies to counteract it remain elusive. Here, we reveal that the aging bone microenvironment impairs the Golgi apparatus thus diminishing mesenchymal stem cell (MSC) function and regeneration. Interestingly, replenishment of cell aggregates-derived extracellular vesicles (CA-EVs) rescues Golgi dysfunction and empowers senescent MSCs through the Golgi regulatory protein Syntaxin 5. Importantly, in vivo administration of CA-EVs significantly enhanced the bone defect repair rate and improved bone mass in aging mice, suggesting their therapeutic value for treating age-related osteoporosis and promoting bone regeneration. Collectively, our findings provide insights into Golgi regulation in stem cell senescence and bone aging, which further highlight CA-EVs as a potential rejuvenative approach for aging bone regeneration.

The skeleton is highly innervated by numerous nerve fibers. These nerve fibers, in addition to transmitting information within the bone and mediating bone sensations, play a crucial role in regulating bone tissue formation and regeneration. Traditional bone tissue engineering (BTE) often fails to achieve satisfactory outcomes when dealing with large-scale bone defects, which is frequently related to the lack of effective reconstruction of the neurovascular network. In recent years, increasing research has revealed the critical role of nerves in bone metabolism. Nerve fibers regulate bone cells through neurotransmitters, neuropeptides, and peripheral glial cells. Furthermore, nerves also coordinate with the vascular and immune systems to jointly construct a microenvironment favorable for bone regeneration. As a signaling driver of bone formation, neuroregulation spans the entire process of bone physiological activities from the embryonic formation to postmaturity remodeling and repair. However, there is currently a lack of comprehensive summaries of these regulatory mechanisms. Therefore, this review sketches out the function of nerves during bone formation and regeneration. Then, we elaborate on the mechanisms of neurovascular coupling and neuromodulation of bone immunity. Finally, we discuss several novel strategies for neuro-bone tissue engineering (NBTE) based on neuroregulation of bone, focusing on the coordinated regeneration of nerve and bone tissue.

Despite significant progress in tissue engineering, the full regeneration of chronic wounds persists as a major challenge, with the immune response to tissue damage being a key determinant of the healing process's quality and duration. Post-injury, a crucial aspect is the transition of macrophages from a pro-inflammatory state to an anti-inflammatory. Thus, this alteration in macrophage polarization presents an enticing avenue within the realm of regenerative medicine. Recent advancements have entailed the integration of a myriad of cellular and molecular signals into hydrogel-based constructs, enabling the fine-tuning of immune cell activities during different phases. This discussion explores modern insights into immune cell roles in skin regeneration, underscoring the key role of immune modulation in amplifying the overall efficacy of wounds. Moreover, a comprehensive review is presented on the latest sophisticated technologies employed in the design of immunomodulatory hydrogels to regulate macrophage polarization. Furthermore, the deliberate design of hydrogels to deliver targeted immune stimulation through manipulation of chemistry and cell integration is also emphasized. Moreover, an overview is provided regarding the influence of hydrogel properties on immune traits and tissue regeneration process. Conclusively, the accent is on forthcoming pathways directed toward modulating immune responses in the milieu of chronic healing.

As the number of patients requiring organ transplants continues to rise exponentially, there is a dire need for therapeutics, with repair and regenerative properties, to assist in alleviating this medical crisis. Over the past decade, there has been a shift from conventional stem cell treatments towards the use of the secretome, the protein and factor secretions from cells. These components may possess novel druggable targets and hold the key to profoundly altering the field of regenerative medicine. Despite the progress in this field, clinical translation of secretome-containing products is limited by several challenges including but not limited to ensuring batch-to-batch consistency, the prevention of further heterogeneity, production of sufficient secretome quantities, product registration, good manufacturing practice protocols and the pharmacokinetic/pharmacodynamic profiles of all the components. Despite this, the secretome may hold the key to unlocking the regenerative blockage scientists have encountered for years. This review critically analyses the secretome derived from different cell sources and used in several tissues for tissue regeneration. Furthermore, it provides an overview of the current delivery strategies and the future perspectives for the secretome as a potential therapeutic. The success and possible shortcomings of the secretome are evaluated.

Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted.

To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy.

We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends.

Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress.

This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.

Achieving precise delivery of extracellular vesicles (EVs) to treat pulmonary arterial hypertension (PAH) remains challenging. Here, we propose a strategy using hypoxia-induced and glucuronic acid (GA)-modified mesenchymal stromal-cell-derived EVs (MSC-EVs) to enhance their functionalities and therapeutic targeting. The hypoxia-induced EVs (Hypo-EVs) exhibit enriched exosomal signatures and display heightened inhibition of the proliferation of pulmonary arterial smooth muscle cells (PASMCs) compared to normoxic EVs (Norm-EV). We then modify Hypo-EVs by incorporating GA into their outer membrane, targeting glucose transporter-1 overexpressed on PASMCs. Our studies show that GA-EVs significantly enhance the therapeutic efficacy, both in vitro and in vivo, through improved targeted delivery to diseased PASMCs for improving vascular remodeling. Additionally, we identify miR-5119 involved in the PAH-associated calcium signaling pathway as a key contributor to GA-EVs' superior effects. This work provides a promising strategy for PAH treatment and advances the clinical potential of MSC-EV-based therapies.

Effectively promoting skin wound healing remains a significant challenge in the medical field. Although stem cell-derived exosomes show potential in tissue regeneration, their local delivery and sustained release face challenges. To address these issues, we developed a collagen sponge based on type I and recombinant humanized type III collagen. Our study confirmed that exosomes were successfully loaded onto the sponge (sponge-Exo) and the sponge-Exo gradually released exosomes into the local milieu. The sponge-Exo played a crucial role in promoting the transition of macrophages from an inflammatory M1 phenotype to a regenerative M2 phenotype. Moreover, it enhanced the migration and proliferation of HDFs and promoted angiogenesis in HUVECs. Additionally, our findings revealed that the sponge-Exo accelerated wound healing by suppressing inflammatory response and stimulating angiogenesis in a rat full-thickness skin wounds model. Next generation sequencing (NGS) was used to explore the underlying mechanism of wound healing, and the results showed that the miRNAs (hsa-miR-21-5p and hsa-miR-29a-5p) associated with wound healing in exosomes were significantly up-regulated. These results highlight the remarkable effects of sponge-Exo on macrophage transformation, cell migration, proliferation and angiogenesis, which provide a potential prospect for the application in the field of skin wound healing.

Lung diseases are associated with high morbidity and mortality rates, thereby jeopardizing human health and imposing a great burden on society. Currently, lung diseases are mainly treated with medications, oxygen therapy and mechanical ventilation, but these approaches are unable to effectively reduce the mortality rate. Therefore, lung transplantation remains the ultimate treatment for various chronic lung diseases, but this treatment is also hindered by the limited availability of lung sources, immature technology and a low survival rate after transplantation. With constant changes in the environment, pathogens, type and amount of harmful substances and the prevalence of respiratory diseases, there is an urgent need to identify alternative treatment methods. Research on stem cell therapy has been very successful in recent years, and mesenchymal stem cells (MSCs), together with their secretory bodies, play a significant therapeutic role. Extracellular vesicles of MSCs (MSC-EVs) are also major components of the paracrine secretion of MSCs, including exosomes, microvesicles, and apoptotic bodies, among which exosomes are the most typical. MSC-EVs are believed to be present in various tissues of the human body where they can carry proteins, DNA, RNA and biologically active factors, just to name a few. They can also transmit various biological signals to participate in different biological activities, including the maintenance of homeostasis within the tissue. Several studies have further demonstrated that MSCs and their generated extracellular vesicles play an important role in the treatment of diseases. In this paper, the origin, properties and roles of MSCs and MSC-EVs are reviewed, the mechanisms of different lung diseases, the limitations of current therapeutic options and the roles of MSC-EVs in Chronic Obstructive Pulmonary Disease, asthma, infectious lung disease, lung cancer, pulmonary fibrosis, pulmonary arterial hypertension, and acute lung injury/ acute respiratory distress syndrome are also discussed (Figure 1). In addition, the current limitations and possible future research directions are also discussed in view of providing new ideas for the role of MSC-EVs in the treatment of lung diseases.

Mesenchymal stromal cells (MSCs) have broad immunomodulatory properties that range from regulation, proliferation, differentiation, and immune cell activation to secreting bioactive molecules that inhibit inflammation and regulate immune response. These properties provide MSCs with high therapeutic potency that has been shown to be relevant to tissue engineering and regenerative medicine. Hence, researchers have explored diverse strategies to control the immunomodulatory potential of stromal cells using polymeric substrates or scaffolds. These substrates alter the immunomodulatory response of MSCs, especially through biophysical cues such as matrix mechanical properties. To leverage these cell-matrix interactions as a strategy for priming MSCs, emerging studies have explored the use of stimuli-responsive substrates to enhance the therapeutic value of stromal cells. This review highlights how stimuli-responsive materials, including chemo-responsive, microenvironment-responsive, magneto-responsive, mechano-responsive, and photo-responsive substrates, have specifically been used to promote the immunomodulatory potential of stromal cells by controlling their secretory activity.

Extracellular vesicles (EVs) are vital for cell-to-cell communication, transferring proteins, lipids, and nucleic acids in various physiological and pathological processes. They play crucial roles in immune modulation and tissue regeneration but are also involved in pathogenic conditions like inflammation and degenerative disorders. EVs have heterogeneous populations and cargo, with numerous subpopulations currently under investigations. EV therapy shows promise in stimulating tissue repair and serving as a drug delivery vehicle, offering advantages over cell therapy, such as ease of engineering and minimal risk of tumorigenesis. However, challenges remain, including inconsistent nomenclature, complex characterization, and underdeveloped large-scale production protocols. This review highlights the recent advances and significance of EVs heterogeneity, emphasizing the need for a better understanding of their roles in disease pathologies to develop tailored EV therapies for clinical applications in neurological disorders.

Human CD16+ monocytes (hCD16+ Ms) have proangiogenic properties. We assessed the feasibility, safety and efficacy of hCD16+ Ms in a porcine model of myocardial infarction (MI).

A total of 27 female Large White pigs underwent MI with reperfusion and cardiac magnetic resonance (CMR). Five days later, animals received intramyocardial injections of hCD16+ Ms in saline (n = 13) or saline only (n = 14). hCD16+ Ms were selected from leucocyte cones. Feasibility/safety endpoints included injury at injected sites, malignant arrhythmias, cancer, haematoma, left ventricular (LV) dilatation, troponin release and downstream organ injury. Co-primary efficacy outcome included LV scar and ejection fraction (LVEF) at 30-day post-injections by CMR. Immunohistochemistry included neo-angiogenesis, fibrosis, markers of myofibroblast and inflammation. Four animals were excluded before injections due to untreatable malignant arrhythmias or lung injury. Median cell number and viability were 48.75 million and 87%, respectively. No feasibility/safety concerns were associated with the use of hCD16+ Ms. The LV scar dropped by 14.5gr (from 25.45 ± 8.24 to 10.8 ± 3.4 gr; -55%) and 6.4gr (from 18.83 ± 5.06 to 12.4 ± 3.9gr; -30%) in the hCD16+ Ms and control groups, respectively (p = 0.015). The 30-day LVEF did not differ between groups, but a prespecified sub-analysis within the hCD16+ Ms group showed that LVEF was 2.8% higher and LV scar 1.9gr lower in the subgroup receiving a higher cell dose. Higher tissue levels of neo-angiogenesis, myofibroblast and IL-6 and lower levels of TGF-β were observed in the hCD16+ Ms group.

The use of hCD16+ Ms in acute MI is feasible, safe and associated with reduced LV scar size, increased tissue levels of neo-angiogenesis, myofibroblasts and IL-6 and reduced pro-fibrotic TGF-β at 30-day post-injections. A higher cell dose might increase the LVEF effect while reducing scar size, but this warrants validation in future studies.

Introduction: rhabdomyolysis (RM) is a serious syndrome. A large area of muscle injury and dissolution induces acute kidney injury (AKI), which results in a high incidence and mortality rate. Exosomes released by mesenchymal stem cells (MSCs) have been used to treat AKI induced by rhabdomyolysis and have shown regenerative effects. However, the most serious drawbacks of these methods are poor targeting and a low enrichment rate after systemic administration. Methods: in this study, we demonstrated that magnetic exosomes derived from bone marrow mesenchymal stem cells (BMSCs) can directly target damaged muscles rather than kidneys using an external magnetic field. Results: magnetic navigation exosomes reduced the dissolution of damaged muscles, greatly reduced the release of cellular contents, slowed the development of AKI. Discussion: in summary, our proposed method can overcome the shortcomings of poor targeting in traditional exosome therapy. Moreover, in the rhabdomyolysis-induced AKI model, we propose for the first time an exosome therapy mode that directly targets damaged muscles through magnetic navigation.

Vitiligo is an autoimmune disease characterized by epidermal melanocyte destruction, with abnormal autoimmune responses and excessive oxidative stress as two cardinal mechanisms. Human umbilical mesenchymal stem cells-derived exosomes (hUMSCs-Exos) are regarded as promising therapeutic choice for autoimmune diseases due to potent immunosuppressive and anti-oxidative properties, which can be potentiated under 3D cell culture condition. Nevertheless, whether exosomes derived from 3D spheroids of hUMSCs (3D-Exos) exhibit considerable therapeutic effect on vitiligo and the underlying mechanism remain elusive. In this study, systemic administration of 3D-Exos showed a remarkable effect in treating mice with vitiligo, as revealed by ameliorated skin depigmentation, less CD8+T cells infiltration, and expanded Treg cells in skin, and 3D-Exos exerted a better effect than 2D-Exos. Mechanistically, 3D-Exos can prominently facilitate the expansion of Treg cells in vitiligo lesion and suppress H2O2-induced melanocytes apoptosis. Forward miRNA profile analysis and molecular experiments have demonstrated that miR-132-3p and miR-125b-5p enriched in 3D-Exos greatly contributed to these biological effects by targeting Sirt1 and Bak1 respectively. In aggregate, 3D-Exos can efficiently ameliorate vitiligo by simultaneously potentiating Treg cells-mediated immunosuppression and suppressing oxidative stress-induced melanocyte damage via the delivery of miR-132-3p and miR-125b-5p. The employment of 3D-Exos will be a promising treament for vitiligo.

This study was to determine whether extracellular vesicles (EVs) derived from insulin-producing cells (IPCs) can modulate naïve mesenchymal stromal cells (MSCs) to become insulin-secreting. MSCs were isolated from human adipose tissue. The cells were then differentiated to generate IPCs by achemical-based induction protocol. EVs were retrieved from the conditioned media of undifferentiated (naïve) MSCs (uneducated EVs) and from that of MSC-derived IPCs (educated EVs) by sequential ultracentrifugation. The obtained EVs were co-cultured with naïve MSCs.The cocultured cells were evaluated by immunofluorescence, flow cytometry, C-peptide nanogold silver-enhanced immunostaining, relative gene expression and their response to a glucose challenge.Immunostaining for naïve MSCs cocultured with educated EVs was positive for insulin, C-peptide, and GAD65. By flow cytometry, the median percentages of insulin-andC-peptide-positive cells were 16.1% and 14.2% respectively. C-peptide nanogoldimmunostaining providedevidence for the intrinsic synthesis of C-peptide. These cells released increasing amounts of insulin and C-peptide in response to increasing glucose concentrations. Gene expression of relevant pancreatic endocrine genes, except for insulin, was modest. In contrast, the results of naïve MSCs co-cultured with uneducated exosomes were negative for insulin, C-peptide, and GAD65. These findings suggest that this approach may overcome the limitations of cell therapy.

Loxoscelism refers to a set of clinical manifestations caused by the bite of spiders from the Loxosceles genus. The classic clinical symptoms are characterized by an intense inflammatory reaction at the bite site followed by local necrosis and can be classified as cutaneous loxoscelism. This cutaneous form presents difficult healing, and the proposed treatments are not specific or effective. This study aimed to evaluate the protective effect of mesenchymal stromal cells-derived secretome on dermonecrosis induced by Loxosceles intermedia spider venom in rabbits.

Sixteen rabbits were distributed into four groups (n = 4). Except for group 1 (G1), which received only PBS, the other three groups (G2, G3, and G4) were initially challenged with 10 μg of L. intermedia venom, diluted in 100 μL of NaCl 0.9%, by intradermic injection in the interscapular region. Thirty minutes after the challenge all groups were treated with secretome, except for group 2. Group 1 (G1-control group) received intradermal injection (ID) of 60 μg of secretome in 0.15 M PBS; Group 2 (G2) received 0.9% NaCl via ID; Group 3 (G3) received 60 μg of secretome, via ID and Group 4 (G4), received 60 μg of secretome by intravenous route. Rabbits were evaluated daily and after 15 days were euthanized, necropsied and skin samples around the necrotic lesions were collected for histological analysis.

Rabbits of G1 did not present edema, erythema, hemorrhagic halo, or necrosis. In animals from G2, G3, and G4, edema appeared after 6h. However, minor edema was observed in the animals of G2 and G3. Hemorrhagic halo was observed in animals, six hours and three days after, on G2, G3, and G4. Macroscopically, in G4, only one animal out of four had a lesion that evolved into a dermonecrotic wound. No changes were observed in the skin of the animals of G1, by microscopic evaluation. All animals challenged with L. intermedia venom showed similar alterations, such as necrosis and heterophilic infiltration. However, animals from G4 showed fibroblast activation, early development of connective tissue, neovascularization, and tissue re-epithelialization, indicating a more prominent healing process.

These results suggest that secretome from mesenchymal stromal cells cultured in a xeno-free and human component-free culture media can be promising to treat dermonecrosis caused after Loxosceles spiders bite envenoming.

Pain is a very common and complex medical problem that has a serious impact on individuals' physical and mental health as well as society. Non-steroidal anti-inflammatory drugs and opioids are currently the main drugs used for pain management, but they are not effective in controlling all types of pain, and their long-term use can cause adverse effects that significantly impair patients' quality of life. Mesenchymal stem cells (MSCs) have shown great potential in pain treatment. However, limitations such as the low proliferation rate of MSCs in vitro and low survival rate in vivo restrict their analgesic efficacy and clinical translation. In recent years, researchers have explored various innovative approaches to improve the therapeutic effectiveness of MSCs in pain treatment. This article reviews the latest research progress of MSCs in pain treatment, with a focus on methods to enhance the analgesic efficacy of MSCs, including engineering strategies to optimize the in vitro culture environment of MSCs and to improve the in vivo delivery efficiency of MSCs. We also discuss the unresolved issues to be explored in future MSCs and pain research and the challenges faced by the clinical translation of MSC therapy, aiming to promote the optimization and clinical translation of MSC-based analgesia therapy.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been widely used in therapy of ischemic heart disease. However, there are still remaining issues that limit the therapeutic efficacy, such as immune rejection and low retention of hiPSC-CMs. Human adipose mesenchymal stromal cells (hADSCs) have been reported to be able to regulate the immune response, promote angiogenesis and promote the maturation of hiPSC-CMs. In this study, we co-cultured these two types of cells on fiber scaffold made of biodegradable poly (D,L-lactic-co-glycolic acid) (PLGA) polymer for several days to develop a composited 3D cardiac tissue sheet. As expected, the cells formed 231.00 ± 15.14 μm thickness tissue, with improved organization, alignment, ECM condition, contractile ability, and paracrine function compared to culture hiPSC-CMs only on PLGA fiber. Furthermore, the composited 3D cardiac tissue sheet significantly promoted the engraftment and survival after transplantation. The composited 3D cardiac tissue sheet also increased cardiac function, attenuated ventricular remodeling, decreased fibrosis, and enhanced angiogenesis in rat myocardial infarction model, indicating that this strategy wound be a promising therapeutic option in the clinical scenario.

Multilineage differentiating stress-enduring (Muse) cells, a pluripotent stem cell subset of mesenchymal stem cells (MSCs), have shown promise for various tissue repairs due to their stress tolerance and multipotent capabilities. We aimed to investigate the differentiation potential in vitro, the dynamics in vivo, and the reparative contribution of Muse cells to osteochondral lesions.

Labeled MSCs were cultured and sorted into Muse and non-Muse (MSCs without Muse cells) groups. These cells were then formed into spheroids, and chondrogenic differentiation was assessed in vitro. Twenty-one immunocompromised mice were used as the in vivo models of osteochondral lesions. Live imaging, macroscopic evaluation, and histological and immunohistochemical analyses were conducted at the 4- and 8-week time points.

Muse cell spheroids were formed, which were larger and stained more intensely with toluidine blue than non-Muse spheroids, indicating better chondrogenic differentiation. Live imaging confirmed luminescence in all 4-week model knees, but only in a few knees at 8 weeks, suggesting cell persistence. Macroscopically and histologically, no significant differences were observed between the Muse and non-Muse groups at 4 and 8 weeks; however, both groups showed better cartilage repair than that of the vehicle group at 8 weeks. No collagen type II generation was observed in the repaired tissues.

The implantation of the spheroids of Muse and non-Muse cells resulted in better healing of osteochondral lesions than that of the controls, and Muse cells had a higher chondrogenic differentiation potential in vitro than non-Muse cells.

Corneal injuries are the major cause of blindness and visual impairment. Available treatments are limited by their efficacy and side effects. Mesenchymal stem cell-derived extracellular vesicles are presumed as functional equivalents and potential candidates for cell-free therapy. This study reports isolation and characterization of extracellular vesicles from human bone marrow mesenchymal stem cells and evaluates their role in mediating epithelial repair and apoptosis in cultured corneal epithelial cells through scratch assay, PCR, immunofluorescence, and flow cytometry in vitro. The isolated extracellular vesicles were spherical, < 150 nm in diameter, and characterized as CD9+, CD63+, CD81+, TSG101+, and Calnexin-. Further, these vesicles promoted corneal epithelial repair by enhancing proliferation and suppressed apoptosis by regulating the expression of BAD, P53, BCL-2, and cleaved CASPASE-3. Thus, our results suggest that BM-MSC-EVs might have the potential to be used for the treatment of injury-induced corneal epithelial defects. Clinical translation of this work would require further investigations.

To determine total protein content, antioxidant activity, and protective ability of lyophilized human gingival mesenchymal stem cells (hGMSCs)-secretome in hydrogen peroxide (H2O2) induced oxidative stress model.

Human GMSCs were cultured to obtain a conditioned medium (secretome), then lyophilized to produce lyosecretome. Total protein was determined by bicinchoninic acid assay (BCA) and SDS-PAGE to improve protein measurements. Antioxidant concentration was measured by ABTS assay, while the protective ability of lyosecretome against oxidative stress was determined by the metabolic activity of osteoblast cells. The study group was divided into a control group (culture medium) and a lyosecretome treatment group (0.0; 0.157, 0.313, 0.625, 1.25, 2.5, 5, and 10 mg/mL + H2O2).

Lyosecretome had a protein concentration of 2086.00 ± 0.20 μg/ml, with a molecular weight of 174, 74, 61, 55, and 26 kDa, which are thought to facilitate cell migration, as well as bind cytokines and growth factors. Lyosecretome also provided the highest antioxidant activity of 93.51% at a concentration of 4.8 mg/ml, with an IC50 value of 2.08 mg/ml. The highest cell metabolic activity (79.53 ± 2.41%) was shown in the 1.25 mg/ml lyosecretome treatment group. All concentrations of hGMSC-lyosecretome attenuate the adverse effect of H2O2-induced oxidative stress.

Lyosecretome obtained from hGMSCs can maintain metabolic activity in osteoblast cells as protection against H2O2 oxidative stress.

Contemporary trends reveal an escalating interest in regenerative medicine-based interventions for addressing refractory skin defects. Conventional wound healing treatments, characterized by high costs and limited efficacy, necessitate a more efficient therapeutic paradigm to alleviate the economic and psychological burdens associated with chronic wounds. Mesenchymal stem/stromal cells (MSCs) constitute cell-based therapies, whereas cell-free approaches predominantly involve the utilization of MSC-derived extracellular vesicles or exosomes, both purportedly safe and effective. Exploiting the impact of MSCs by paracrine signaling, exosomes have emerged as a novel avenue capable of positively impacting wound healing and skin regeneration. MSC-exosomes confer several advantages, including the facilitation of angiogenesis, augmentation of cell proliferation, elevation of collagen production, and enhancement of tissue regenerative capacity. Despite these merits, challenges persist in clinical applications due to issues such as poor targeting and facile removal of MSC-derived exosomes from skin wounds. Addressing these concerns, a three-dimensional (3D) platform has been implemented to emend exosomes, allowing for elevated levels, and constructing more stable granules possessing distinct therapeutic capabilities. Incorporating biomaterials to encapsulate MSC-exosomes emerges as a favorable approach, concentrating doses, achieving intended therapeutic effectiveness, and ensuring continual release. While the therapeutic potential of MSC-exosomes in skin repair is broadly recognized, their application with 3D biomaterial scenarios remains underexplored. This review synthesizes the therapeutic purposes of MSCs and exosomes in 3D for the skin restoration, underscoring their promising role in diverse dermatological conditions. Further research may establish MSCs and their exosomes in 3D as a viable therapeutic option for various skin conditions.

Aim: To assess the therapeutic potential of human umbilical cord mesenchymal stem cells (hUCMSCs) combined with porcine small intestinal submucosa (SIS) on full-thickness skin injuries in rats. Methods: We established full-thickness skin injury models in Sprague-Dawley rats, dividing them into blank control, SIS, hUCMSCs and hUCMSCs combined with SIS. We monitored wound healing, scores and area, and analyzed inflammatory cells, microvessel density and collagen fibers after 12 days. Results: The blank group showed no healing, forming a scar of 0.6 × 0.5 cm2, while SIS and hUCMSCs groups exhibited incomplete healing with 0.4 × 0.5 cm2 scabs. Wound healing was significantly better in the hUCMSCs combined with the SIS group. Conclusion: Local application of hUCMSCs combined with SIS enhances full-thickness skin injury wound healing in rats.

Cardiovascular diseases continue to challenge global health, demanding innovative therapeutic solutions. This review delves into the transformative role of mesenchymal stem cells (MSCs) in advancing cardiovascular therapeutics. Beginning with a historical perspective, we trace the development of stem cell research related to cardiovascular diseases, highlighting foundational therapeutic approaches and the evolution of cell-based treatments. Recognizing the inherent challenges of MSC-based cardiovascular therapeutics, which range from understanding the pro-reparative activity of MSCs to tailoring patient-specific treatments, we emphasize the need to refine the pro-regenerative capacity of these cells. Crucially, our focus then shifts to the strategies of the fourth generation of cell-based therapies: leveraging the secretomic prowess of MSCs, particularly the role of extracellular vesicles; integrating biocompatible scaffolds and artificial sheets to amplify MSCs' potential; adopting three-dimensional ex vivo propagation tailored to specific tissue niches; harnessing the promise of genetic modifications for targeted tissue repair; and institutionalizing good manufacturing practice protocols to ensure therapeutic safety and efficacy. We conclude with reflections on these advancements, envisaging a future landscape redefined by MSCs in cardiovascular regeneration. This review offers both a consolidation of our current understanding and a view toward imminent therapeutic horizons.

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future.

We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.

Oral submucous fibrosis (OSF) is a precancerous lesion characterized by fibrous tissue deposition, the incidence of which correlates positively with the frequency of betel nut chewing. Prolonged betel nut chewing can damage the integrity of the oral mucosal epithelium, leading to chronic inflammation and local immunological derangement. However, currently, the underlying cellular events driving fibrogenesis and dysfunction are incompletely understood, such that OSF has few treatment options with limited therapeutic effectiveness. Dental pulp stem cells (DPSCs) have been recognized for their anti-inflammatory and anti-fibrosis capabilities, making them promising candidates to treat a range of immune, inflammatory, and fibrotic diseases. However, the application of DPSCs in OSF is inconclusive. Therefore, this study aimed to explore the pathogenic mechanism of OSF and, based on this, to explore new treatment options.

A human cell atlas of oral mucosal tissues was compiled using single-cell RNA sequencing to delve into the underlying mechanisms. Epithelial cells were reclustered to observe the heterogeneity of OSF epithelial cells and their communication with immune cells. The results were validated in vitro, in clinicopathological sections, and in animal models. In vivo, the therapeutic effect and mechanism of DPSCs were characterized by histological staining, immunohistochemical staining, scanning electron microscopy, and atomic force microscopy.

A unique epithelial cell population, Epi1.2, with proinflammatory and profibrotic functions, was predominantly found in OSF. Epi1.2 cells also induced the fibrotic process in fibroblasts by interacting with T cells through receptor-ligand crosstalk between macrophage migration inhibitory factor (MIF)-CD74 and C-X-C motif chemokine receptor 4 (CXCR4). Furthermore, we developed OSF animal models and simulated the clinical local injection process in the rat buccal mucosa using DPSCs to assess their therapeutic impact and mechanism. In the OSF rat model, DPSCs demonstrated superior therapeutic effects compared with the positive control (glucocorticoids), including reducing collagen deposition and promoting blood vessel regeneration. DPSCs mediated immune homeostasis primarily by regulating the numbers of KRT19 + MIF + epithelial cells and via epithelial-stromal crosstalk.

Given the current ambiguity surrounding the cause of OSF and the limited treatment options available, our study reveals that epithelial cells and their crosstalk with T cells play an important role in the mechanism of OSF and suggests the therapeutic promise of DPSCs.

Myocardial infarction (MI) and its associated poor prognosis pose significant risks to human health. Nanomaterials hold great potential for the treatment of MI due to their targeted and controlled release properties, particularly biomimetic nanomaterials. The utilization of biomimetic strategies based on extracellular vesicles (EVs) and cell membranes will serve as the guiding principle for the development of nanomaterial therapy in the future. In this review, we present an overview of research progress on various exosomes derived from mesenchymal stem cells, cardiomyocytes, or induced pluripotent stem cells in the context of myocardial infarction (MI) therapy. These exosomes, utilized as cell-free therapies, have demonstrated the ability to enhance the efficacy of reducing the size of the infarcted area and preventing ischaemic reperfusion through mechanisms such as oxidative stress reduction, polarization modulation, fibrosis inhibition, and angiogenesis promotion. Moreover, EVs can exert cardioprotective effects by encapsulating therapeutic agents and can be engineered to specifically target the infarcted myocardium. Furthermore, we discuss the use of cell membranes derived from erythrocytes, stem cells, immune cells and platelets to encapsulate nanomaterials. This approach allows the nanomaterials to camouflage themselves as endogenous substances targeting the region affected by MI, thereby minimizing toxicity and improving biocompatibility. In conclusion, biomimetic nano-delivery systems hold promise as a potentially beneficial technology for MI treatment. This review serves as a valuable reference for the application of biomimetic nanomaterials in MI therapy and aims to expedite the translation of NPs-based MI therapeutic strategies into practical clinical applications.

Despite improvements in contemporary medical and surgical therapies, cardiovascular disease (CVD) remains a significant cause of worldwide morbidity and mortality; more specifically, ischemic heart disease (IHD) may affect individuals as young as 20 years old. Typically managed with guideline-directed medical therapy, interventional or surgical methods, the incurred cardiomyocyte loss is not always completely reversible; however, recent research into various stem cell (SC) populations has highlighted their potential for the treatment and perhaps regeneration of injured cardiac tissue, either directly through cellular replacement or indirectly through local paracrine effects. Different stem cell (SC) types have been employed in studies of infarcted myocardium, both in animal models of myocardial infarction (MI) as well as in clinical studies of MI patients, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), Muse cells, multipotent stem cells such as bone marrow-derived cells, mesenchymal stem cells (MSCs) and cardiac stem and progenitor cells (CSC/CPCs). These have been delivered as is, in the form of cell therapies, or have been used to generate tissue-engineered (TE) constructs with variable results. In this text, we sought to perform a narrative review of experimental and clinical studies employing various stem cells (SC) for the treatment of infarcted myocardium within the last two decades, with an emphasis on therapies administered through thoracic incision or through percutaneous coronary interventions (PCI), to elucidate possible mechanisms of action and therapeutic effects of such cell therapies when employed in a surgical or interventional manner.