Stem cell-based therapies have emerged as a promising frontier in the treatment of gastrointestinal disorders, offering potential solutions for challenges posed by conventional treatments. This review comprehensively examines recent advancements in cell-based therapeutic strategies, particularly focusing on stem cell applications, immunotherapy, and cellular therapies for digestive diseases. It highlights the successful differentiation of enteric neural progenitors from pluripotent stem cells and their application in animal models, such as Hirschsprung disease. Furthermore, the review evaluates clinical trials and experimental studies demonstrating the potential of stem cells in regenerating damaged tissues, modulating immune responses, and promoting healing in conditions like Crohn's disease and liver failure. By addressing challenges, such as scalability, immunogenicity, and ethical considerations, the review underscores the translational opportunities and obstacles in realizing the clinical potential of these therapies. Concluding with an emphasis on future directions, the study provides insights into optimizing therapeutic efficacy and fostering innovations in personalized medicine for digestive disorders.

Steroid-refractory acute graft-versus-host disease (SR-AGVHD) presents a significant barrier to successful outcomes following allogeneic hematopoietic cell transplantation (HCT), despite advancements in GVHD prophylaxis and management. While ruxolitinib therapy has shown improved response rates, survival benefits remain elusive. This review explores the definitions and proposed distinct pathophysiology and treatment landscape of SR-AGVHD. Emerging therapies offer potential, yet further research is critical to better define steroid-refractory populations, improve treatment precision with biomarkers, and overcome resistance, particularly in ruxolitinib-refractory cases.

Patients with systemic lupus erythematosus (SLE) with inadequate responses to standard therapies have unmet therapeutic needs. The immunomodulatory, proangiogenic, and antifibrotic properties of mesenchymal stromal cells support their use in treating patients with SLE. We aimed to assess the safety of a single intravenous infusion of allogeneic umbilical cord-derived mesenchymal stromal cells in patients with severe SLE.

This prospective, single-centre, open-label, dose-escalation, Bayesian phase 1 study was done at the Saint-Louis University Hospital (Paris, France). Eligible patients were aged 18-70 years, were diagnosed with SLE according to American College of Rheumatology criteria with positive antinuclear antibodies, had a baseline Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI) score of 6 or more, and had disease that was refractory to first and second line SLE therapies. Patients were to receive a single intravenous infusion of 1 × 106, 2 × 106, or 4 × 106 umbilical cord-derived mesenchymal stromal cells per kg (manufactured from a single umbilical cord) in cohorts of five patients per dose, starting at 2 × 106 cells per kg. The primary endpoint was the rate of treatment-related severe adverse events (grade ≥3) in the first 10 days after infusion of umbilical cord-derived mesenchymal stromal cells. People with lived experience were involved in study design, patient enrolment, and dissemination of the study findings. This study is registered with ClinicalTrials.gov, NCT03562065, and the EU Clinical Trials Register, EudraCT2017-001400-29.

From May 14, 2019, to March 6, 2023, 29 patients were screened for eligibility, eight of whom were enrolled in the study. Enrolment was terminated early after inclusion of eight patients and no patients received the 1 × 106 dose of umbilical cord-derived mesenchymal stromal cells. Seven (88%) of eight participants were cisgender women and one (13%) was a cisgender man. The median age was 35 years (range 26-57) and the median SLE disease duration was 12 years (5-19). All patients received at least 2 × 106 cells per kg (range 2 × 106 to 4 × 106). No severe adverse events and three infusion-related adverse events (two grade 1 and one grade 2) occurred in two patients in the first 10 days after infusion. After 12·4 months (range 12-13) of follow-up, no treatment-related severe adverse events and three non-treatment-related severe adverse events occurred in one patient after relapse.

Our results suggest that a single infusion of 2 × 106 cells per kg or 4 × 106 cells per kg of allogeneic umbilical cord-derived mesenchymal stromal cells was safe in patients with severe SLE. Placebo-controlled trials are needed to confirm clinical efficacy and the role of B-cell modifications in clinical benefit.

Fondation du Rein, Alliance Maladies Rares AFM-Téléthon, Direction de la Recherche Clinique et de l'Innovation AP-HP, and ANR eCellFrance.

Periodontitis, the main cause of tooth loss in adults, is a public health concern; its incidence increases with age, and its prevalence increases with increasing life expectancy of the population. Innovative therapies such as cell therapy represent promising future solutions for guided tissue regeneration. However, these therapies may be associated with fears and mistrust from the general public. The aim of this study was to estimate the acceptability of an advanced therapy medicinal product combining allogeneic mesenchymal stromal cells from adipose tissue with a natural fibrin hydrogel in the treatment of periodontitis.

The methodology was based on a qualitative study conducted through semi-structured interviews with patients followed for periodontitis in the Oral Medicine Department of the Toulouse University Hospital, Toulouse, France. Qualitative studies are essential methodologies to understand the patterns of health behaviours, describe illness experiences, and design health interventions in a humanistic and person-centred way of discovering.

Eleven interviews (with 4 men and 7 women) were required to reach thematic saturation. Analysis allowed 4 main themes to emerge: (1) perception of new treatments, science, and caregivers; (2) conditions that the treatment must meet; (3) patient perception of the disease; and (4) factors related to the content of the treatment.

Patients find cell therapy for periodontitis to be acceptable. If they express a need to be informed about the benefit/risk ratio, they are not particularly worried about side effects of the treatment, for either allogeneic or blood-derived products. Periodontitis is a prototypical model of chronic inflammatory pathology and is multitissular, with hard- and soft-tissue lesions. In a patient-centred approach, the success of cell therapy will require a bilateral, informed decision, taking into account potential therapeutic effectiveness and patient expectations for regeneration.

Trabecular meshwork (TM) cell therapy has been proposed as a next-generation treatment for elevated intraocular pressure (IOP) in glaucoma, the most common cause of irreversible blindness. Using a magnetic cell steering technique with excellent efficiency and tissue-specific targeting, we delivered two types of cells into a mouse model of glaucoma: either human adipose-derived mesenchymal stem cells (hAMSCs) or induced pluripotent cell derivatives (iPSC-TM cells). We observed a 4.5 [3.1, 6.0] mmHg or 27% reduction in intraocular pressure (IOP) for nine months after a single dose of only 1500 magnetically-steered hAMSCs, explained by increased outflow through the conventional pathway and associated with an higher TM cellularity. iPSC-TM cells were also effective, but less so, showing only a 1.9 [0.4, 3.3] mmHg or 13% IOP reduction and increased risk of tumorigenicity. In both cases, injected cells remained detectable in the iridocorneal angle three weeks post-transplantation. Based on the locations of the delivered cells, the mechanism of IOP lowering is most likely paracrine signaling. We conclude that magnetically-steered hAMSC cell therapy has potential for long-term treatment of ocular hypertension in glaucoma.

A novel magnetic cell therapy provided effective intraocular pressure reduction in a mouse model, motivating future translational studies.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing β cells within pancreatic islets, the specialized endocrine cell clusters of the pancreas. Islet transplantation has emerged as a β cell replacement therapy, involving the infusion of cadaveric islets into a patient's liver through the portal vein. This procedure offers individuals with T1D the potential to restore glucose control, reducing or even eliminating the need for exogenous insulin therapy. However, it does not address the underlying autoimmune condition responsible for T1D. The need for systemic immunosuppression remains the primary barrier to making islet transplantation a more widespread therapy for patients with T1D. Here, we review recent progress in addressing the key limitations of islet transplantation as a viable treatment for T1D. Concerns over systemic immunosuppression arise from its potential to cause severe side effects, including opportunistic infections, malignancies, and toxicity to transplanted islets. Recognizing the risks, the Edmonton protocol (2000) marked a shift away from glucocorticoids to prevent β cell damage specifically. This transition led to the development of combination immunosuppressive therapies and the emergence of less toxic immunosuppressive and anti-inflammatory drugs. More recent advances in islet transplantation derive from islet encapsulation devices, biomaterial platforms releasing immunomodulatory compounds or surface-modified with immune regulating ligands, islet engineering and co-transplantation with accessory cells. While most of the highlighted studies in this review remain at the preclinical stage using mouse and non-human primate models, they hold significant potential for clinical translation if a transdisciplinary research approach is prioritized.

Interest in Current Good Manufacturing Practices (cGMP)-grade extracellular vesicles (EVs) is expanding. Some obstacles in this new but rapidly growing field include a lack of standardization and scalability. This review focuses on automated biomanufacturing of EVs in conditioned media collected from cultured mesenchymal stromal cells (MSCs). Different automated cell culture systems are discussed, including factors affecting EV quantity and quality, isolating EVs manufactured in an automated system, and validations needed. The ultimate goal when manufacturing cGMP-grade EVs is to identify a specific application and characterize the EV population in detail. This is achieved by validating every step of the process, choosing appropriate release criteria, and assuring batch-to-batch consistency. Due to the lack of standards in the field, it is critical to ensure that the cGMP-grade EVs meet FDA standards pertaining to identity, reproducibility, sterility, safety, purity, and potency. A closed-system automated bioreactor can be a valuable tool to generate cGMP-EVs in a scalable, economical, and reproducible manner.

This meta-analysis aimed to pool the existing evidence to determine the clinical efficacy and safety of mesenchymal stem cells (MSC) in patients with non-unions.

A systematic search in PubMed and Scopus was performed until October 2024 to gather pertinent studies. The inclusion criteria included participants with non-unions, the intervention of MSC administration, a comparator of standard treatment (bone graft), and outcomes focused on healing rate, healing time, or side effects. The Jadad score Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias in randomized and non-randomized studies, respectively. Moreover, GRADE criteria were used to assess the quality of evidence. Using a random effects model, odds ratios (OR) with 95% confidence intervals (CIs) were calculated for healing and complication rates, while standardized mean differences (SMD) with their 95% CIs were used to assess the impact of MSC therapy on bone union time.

Twenty-one studies, with 866 patients, were included. The bone healing rates were 44% at 3 months, 73% at 6 months, 90% at 9 months, and 86% at 12 months, eventually reaching 91% after 12 months of follow-up. MSC therapy, with or without scaffolds, was linked to higher odds of bone healing rate at 3 and 6 months, compared to bone grafts as the standard care (OR = 1.69). The time to union following the treatment was 6.30 months (95%CI: 86-96%), with patients treated with MSC/Scaffold experiencing a shorter time compared to MSC alone (5.85 vs. 6.36 months). MSC therapy significantly decreased bone union time (SMD:-0.54 months, 95% CI: -0.75 to -0.33). The complication rate was 1% (MSC/Scaffold: 0%, MSC alone: 2%), with MSC alone or MSC/Scaffold showing a lower risk than the standard care (OR = 0.41, 95% CI: 0.22-0.78).

MSC is a potential adjunct therapy for patients with non-union fractures.

Not applicable.

The long-term effect of adipose-derived mesenchymal stromal cells (ASC) on restoring radiation-induced salivary gland hypofunction in patients with previous head and neck cancer has not been validated in larger settings.

The study was a 12-month follow-up of a randomized trial, including patients with hyposalivation. Patients were randomized to receive allogeneic ASC or placebo in the submandibular glands. The primary endpoint was unstimulated whole saliva (UWS) followed by stimulated whole saliva, patient-reported outcomes (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire, Head and Neck Module, and the xerostomia questionnaire), and safety.

Of the 120 enrolled patients, 117 (97.5%) were assessed at 12 months. Treatment with ASC did not increase UWS compared with placebo: Increase in UWS was 0.02 mL/minute [95% confidence interval (CI), 0.01-0.04] in the ASC group and 0.02 mL/minute (95% CI, 0-0.03) in the placebo group (P = 0.56). ASC reduced the symptom burden for dry mouth with -10.07 units (95% CI, -13.39 to -6.75) compared with -4.15 units (95% CI, -7.46 to -0.84) in the placebo group (P = 0.01). Compared with placebo, ASC did not improve sticky saliva (-9.27 vs. -4.55 units; P = 0.13), swallowing (-4.50 vs. 3.49 units; P = 0.5), or xerostomia (-3.12 vs. -2.74 units; P = 0.82). Treatment was safe and associated with a transient immune response.

Intraglandular ACS therapy in the submandibular glands significantly relieved subjective dry mouth symptoms. Both ASC and placebo increased UWS, but ASC did not prove superior to placebo in restoring salivary gland function, based on the salivary flow rate.

Stress urinary incontinence (SUI) is a prevalent pelvic floor dysfunction in women post-pregnancy. Currently, conservative treatment options have low success rates, while surgical interventions often result in multiple complications. The altered state of the extracellular matrix (ECM) is a pivotal factor in the onset of various diseases and likely plays a significant role in the pathogenesis of SUI, particularly through changes in collagen and elastin levels. Recent advances in mesenchymal stem cells (MSCs) therapy have shown considerable promise in treating SUI by modulating ECM remodeling, thereby enhancing the supportive tissues of the female pelvic floor. MSCs exhibit substantial potential in enhancing urethral sphincter function, modulating connective tissue architecture, and stimulating fibroblast activity. They play a pivotal role in the reconstruction and functional recovery of the ECM by influencing various signaling pathways, including TGF-β/SMAD, JAK/STAT, Wnt/β-catenin, PI3K/AKT, and ERK/MAPK. We have reviewed the advancements in MSC-mediated ECM metabolism in SUI and, by integrating the functions of ECM in other diseases and how MSCs can ameliorate conditions through their impact on ECM metabolism, we have projected the future trajectory of SUI treatment development.

Mesenchymal stem cells (MSCs) have emerged as a promising tool for regenerative medicine due to their multipotency and immunomodulatory properties. According to recent research, exposing MSCs to super-low-intensity microwave radiation can have a significant impact on how they behave and operate. This review provides an overview of the most recent studies on the effects of microwave radiation on MSCs with power densities that are much below thermal values. Studies repeatedly show that non-thermal mechanisms affecting calcium signaling, membrane transport, mitochondrial activity, along ion channel activation may increase MSC proliferation, differentiation along mesodermal lineages, paracrine factor secretion, and immunomodulatory capabilities during brief, regulated microwave exposures. These bioeffects greatly enhance MSC regeneration capability in preclinical models of myocardial infarction, osteoarthritis, brain damage, and other diseases. Additional study to understand microwave treatment settings, biological processes, and safety assessments will aid in the translation of this unique, non-invasive strategy of activating MSCs with microwave radiation to improve cell engraftment, survival, and tissue healing results. Microwave-enhanced MSC treatment, if shown safe and successful, might have broad relevance as a novel cell-based approach for a variety of regenerative medicine applications.

To visualize and analyze the trends and hotspots of efferocytosis and inflammation via bibliometric methods.

Relevant articles and reviews from 2006 to 2023 were retrieved from the Web of Science Core Collection. The data were processed with CiteSpace, and some graphs were generated with Microsoft Excel (version 2016), VOSviewer, Scimago Graphica, Bibliometrix and R Studio.

A total of 1,003 papers were included, revealing a significant upward trend in efferocytosis and inflammation research. The United States (456, 45.46%), China (164, 16.35%) and the United Kingdom (99, 9.87%) were the three countries with the highest numbers of publications. Harvard University (84, 6.74%) contributes the most out of the top 5 institutions. Among the researchers in this field, Serhan CN was the author with the highest number of articles in the field (35, 3.49%), and deCathelineau AM first named "efferocytosis" in 2003. Keyword analysis identified "activation," "tam receptors," "docosahexaenoic acid" "systemic lupus erythematosus," "myocardial infarction" and "alveolar macrophages" as core topics, indicating a concentrated trend in the mechanism of physiological state and inflammatory diseases such as autoimmune, cardiovascular, and pulmonary diseases. The latest surge words "inflammation resolution" and "cancer" in the keyword heatmap indicate future research directions.

Research on the association between efferocytosis and inflammation has been a promising field. Key areas of focus include the crucial role of efferocytosis on tissue homeostasis and the pathogenesis of nontumorous inflammatory diseases. Future research will likely continue to explore these frontiers, with an emphasis on understanding efferocytosis in the context of chronic diseases and cancer, as well as developing novel therapeutic strategies.

Postmenopausal osteoporosis is a common degenerative disease, with suboptimal clinical outcomes. The targets of current therapeutic agents are both nonspecific and diverse. We synthesized a novel nanoparticle (NP), ALN@BMSCM@PLGA-TK-PEG-SS31. After intravenous injection, the NP evaded immune phagocytosis, targeted bone tissue, and efficiently downregulated bone reactive oxygen species (ROS) generation. The core PLGA-TK-PEG-SS31 NP was ∼100 nm in diameter. The TK chemical bond breaks on exposure to ROS, releasing the novel mitochondrion-targeting peptide SS31. Outer bone marrow mesenchymal stem cell membranes (BMSCMs) were used to coat the NP with surface proteins to ensure membrane functionality. The circulation time was prolonged and immune phagocytosis was evaded. Embedding the DSPE-PEG-ALN lipid within the cell membrane enhanced the bone-targeting ability of the NP. Our results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 exerted dual effects on bone tissue in vitro, significantly inhibiting RANKL-induced osteoclastogenesis in the presence of H2O2 and promoting osteogenic differentiation in BMSCs. In a mouse model of ovariectomy-induced osteoporosis, ALN@BMSCM@PLGA-TK-PEG-SS31 significantly ameliorated oxidative stress and increased bone mass with no notable systemic side effects. These results suggest that ALN@BMSCM@PLGA-TK-PEG-SS31 is a promising treatment for osteoporosis.

In clinical trials, mesenchymal stromal/stem cells (MSCs) have consistently demonstrated safety. However, demonstration of efficacy has been inconsistent and many MSC trials have failed to meet their efficacy endpoint. This disappointing reality is reflected by the limited number MSC therapies approved by regulatory agencies, despite the large number of MSC trials registered on clinicaltrials.gov. Notably, there has been a recent approval of an MSC therapy for pediatric graft-vs.-host disease in the United States, marking the first MSC therapy approved by the U.S. Food and Drug Administration. This review provides a background of the history and potential therapeutic value of MSCs, an overview of MSC products with regulatory approval, and a summary of registered MSC trials. It concludes with a discussion on current and ongoing challenges and questions surrounding MSC therapy that remains to be resolved before becoming available for routine clinical use outside of clinical trials.

Defining the mechanism of immune modulation by mesenchymal stromal cells (MSCs) from distinct anatomical tissues is of great translational interest. The human cornea is an immunologically privileged organ, and the mechanism of immunoregulation of cornea-derived MSCs (cMSCs) is currently unknown. We investigated cMSCs derived from the corneas of 5 independent human donorS for their fitness and mechanism of action in suppressing T cells. cMSCs display the immunophenotype CD45-CD73+CD105+CD90+CD44+ and robust in vitro growth. 30-plex secretome analysis identified that cMSCs innately secrete specific molecules in a dose-dependent manner. cMSCs do not express or upregulate costimulatory but do upregulate coinhibitory molecules upon stimulation with interferon γ (IFNγ). cMSCs inhibit T-cell proliferation in contact-dependent co-cultures, which can be predicted by a unique secretome signature. In addition, co-culturing in a 2-chamber transwell system has demonstrated that cMSCs also inhibit T-cell proliferation in a non-contact-dependent manner. Mechanistic analysis has demonstrated that activated T cells effectively induce indoleamine 2,3-dioxygenase (IDO) but not other enzymes of the tryptophan metabolic pathway in cMSCs. Silencing of IDO in cMSCs reduces their fitness to suppress T cells. These results provide evidence that in cMSCs, one of the principal mechanisms of immunosuppression on T cells is through IDO. These results suggest that MSCs derived from the human cornea display immunoregulatory properties and, thus, may play a role in maintaining the immune-privileged niche of the cornea.

Osteoarthritis (OA) is a common chronic musculoskeletal disease with heterogeneous clinical manifestations and variable responses to different treatments. Unfortunately, there is no effective disease modifying therapy at present that can alter the natural course of the disease. Cell therapy based on mesenchymal stromal cells (MSCs) may offer an attractive therapeutic option for OA with their multiple modes of action, particularly immune-regulatory and regenerative capacities.

In this narrative review, updates on mode of action based on patient's data, factors that can influence the efficacy of MSC treatment, current status in clinical application of MSCs as seen from randomized, controlled OA trials are introduced as well as the author's perspectives in the future of MSCs as OA therapeutics.

Symptomatic relief is not sufficient to justify the high cost associated with culture-expanded stem cells. Its advantages and efficacy over simple and low risk/cost modalities should be seriously reevaluated. Also, as the short-term strategy, efforts should be made to lower the cost of MSC therapy. In the future, multiomics technology may help to predict that subgroup of patients who will favorably respond to stem cell treatment, which would enhance the cost effectiveness and therapeutic benefit of MSC therapy.

The liver plays a crucial role in regulating lipid metabolism. Our study examined the impact of Exosomes derived from adipose mesenchymal stem cells (ADSCs-Exo) on lipid metabolism following liver ischemia-reperfusion injury (IRI) combined with partial hepatectomy. We developed a miniature swine model for a minimally invasive hemi-hepatectomy combined with liver IRI. In this study, we administered PBS, ADSCs-Exo, and adipose-derived stem cells (ADSCs) individually through the portal vein. Before and after surgery, we evaluated various factors including hepatocyte ultrastructure, lipid accumulation in liver tissue, and expression levels of genes and proteins associated with lipid metabolism. In addition, we measured serum and liver tissue levels of high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (CHOL). TEM and oil red O stain indicated a significant reduction in liver steatosis following ADSCs-Exo treatment, which also elevated serum levels of HDL, LDL, TG, and CHOL. Additionally, ADSCs-Exo have been shown to significantly decrease serum concentrations of HDL, LDL, TG, and CHOL in the liver (p < 0.05). Finally, ADSCs-Exo significantly downregulated lipid synthesis-related genes and proteins, including SREBP-1, SREBP-2, ACC1, and FASN (p < 0.05), while upregulating lipid catabolism-related genes and proteins, such as PPAR-α and ACOX1 (p < 0.05). ADSCs-Exo as a cell-free therapy highlights its therapeutic potential in hepatic lipid metabolism abnormalities.

Promising therapeutic strategies are being explored to replace or regenerate the neuronal populations that are lost in patients with neurodegenerative disorders. Several research groups have attempted direct reprogramming of astrocytes into neurons by manipulating the expression of polypyrimidine tract-binding protein 1 (PTBP1) and claimed putative converted neurons to be functional, which led to improved disease outcomes in animal models of several neurodegenerative disorders. However, a few other studies reported data that contradict these claims, raising doubt about whether PTBP1 suppression truly reprograms astrocytes into neurons and the therapeutic potential of this approach. This review discusses recent advances in regenerative therapeutics including stem cell transplantations for central nervous system disorders, with a particular focus on Parkinson's and Alzheimer's diseases. We also provide a perspective on this controversy by considering that astrocyte heterogeneity may be the key to understanding the discrepancy in published studies, and that certain subpopulations of these glial cells may be more readily converted into neurons.

Advances in ultrasound and prenatal diagnosis are leading an expansion in the options for parents whose fetus is identified with a congenital disease. Obstetric diseases such as pre-eclampsia and fetal growth restriction may also be amenable to intervention to improve maternal and neonatal outcomes. Advanced Medicinal Therapeutic Products such as stem cell, gene, enzyme and protein therapies are most commonly being investigated as the trajectory of treatment for severe genetic diseases moves toward earlier intervention. Theoretical benefits include prevention of in utero damage, smaller treatment doses compared to postnatal intervention, use of fetal circulatory shunts and induction of immune tolerance. New systematic terminology can capture adverse maternal and fetal adverse events to improve safe trial conduct. First-in-human clinical trials are now beginning to generate results with a focus on safety first and efficacy second. If successful, these trials will transform the care of fetuses with severe early-onset congenital disease.

Lung transplantation is hindered by low donor lung utilization rates. Infectious complications are reasons to decline donor grafts due to fear of post-transplant primary graft dysfunction. Mesenchymal stem cells are a promising therapy currently investigated in treating lung injury. Full-term amniotic fluid-derived lung-specific mesenchymal stem cell treatment may regenerate damaged lungs. These cells have previously demonstrated inflammatory mediation in other respiratory diseases, and we hypothesized that treatment would improve donor lung quality and postoperative outcomes.

In a transplantation model, donor pigs were stratified to either the treated or the nontreated group. Acute respiratory distress syndrome was induced in donor pigs and harvested lungs were placed on ex vivo lung perfusion (EVLP) before transplantation. Treatment consisted of 3 doses of 2 × 106 cells/kg: one during EVLP and 2 after transplantation. Donors and recipients were assessed on clinically relevant parameters and recipients were followed for 3 days before evaluation for primary graft dysfunction (PGD).

Repeated injection of the cell treatment showed reductions in inflammation seen through lowered immune cell counts, reduced histology signs of inflammation, and decreased cytokines in the plasma and bronchoalveolar lavage fluid. Treated recipients showed improved pulmonary function, including increased PaO2/FiO2 ratios and reduced incidence of PGD.

Repeated injection of lung-specific cell treatment during EVLP and post transplant was associated with improved function of previously damaged lungs. Cell treatment may be considered as a potential therapy to increase the number of lungs available for transplantation and the improvement of postoperative outcomes.

The aim of this study was to assess the safety and efficacy of human umbilical cord mesenchymal stromal cells (hUC-MSCs) patch used as an adjuvant therapy in fetal myelomeningocele (MMC) surgery in the ovine model.

hUC-MSCs were isolated from human umbilical cords (UC) using the explant method, cultured and characterized. hUC-MSCs were then embedded in a fibrin patch. MMC were surgically created at 75 days of gestation and repaired at 89 days of gestation in sheep fetuses. Two groups were compared: the hUC-MSCs group in which MMC was repaired using a cellular patch and the control group, in which MMC was repaired using an acellular patch. Safety was evaluated by clinical ewes' monitoring during gestation, and clinical and histological examinations of lambs after birth. Efficacy was assessed by clinical neurological evaluation at 2 and 24 h of life using the sheep locomotor rating scale and by histological analyses.

Among the 17 operated lambs, nine were born alive: six in the hUC-MSCs group and three in the control group. Overall fetal loss was 47% (8/17) without differences between the two groups. No fever was reported in ewes. No tumors were detected in clinical and histological examinations in the lambs. At 24 h of life, mean Sheep Locomotor Rating score was higher in the hUC-MSCs group than in the control group: 15.0 versus 2.0 (p = 0.07). Histological analyses showed a higher large neurons density in the hUC-MSCs group in comparison with the control group: 9.9 versus 6.3/mm2 of gray matter (p = 0.04). Lambs in the hUC-MSCs group had lower fibrosis around the spinal cord and at the level of the MMC scar: 70.9 versus 253.7 μm (p = 0.10) and 691.3 versus 1684.4 μm (p = 0,18), respectively.

Ovine fetal repair of MMC using human UC-MSCs seems to be an effective and safe procedure.

Spinocerebellar ataxia (SCA) is a heterogeneous disorder characterized by impaired balance and coordination caused by cerebellar dysfunction. The absence of treatments approved by the U.S. Food and Drug Administration for SCA has driven the investigation of alternative therapeutic strategies, including stem cell therapy. Mesenchymal stem cells (MSCs), known for their multipotent capabilities, have demonstrated significant potential in treating SCA. This review examines how MSCs may promote neuronal growth, enhance synaptic connectivity, and modulate brain inflammation. Recent findings from preclinical and clinical studies are also reviewed, emphasizing the promise of MSC therapy in addressing the unmet needs of SCA patients. Furthermore, ongoing clinical trials and future directions are proposed to address the limitations of the current approaches.

A limited number of tissues can spontaneously regenerate following injury, and even fewer can regenerate to a state comparable to mature, healthy adult tissue. Mesenchymal stem cells (MSCs) were first described in the 1960s-1970s by Friedenstein et al as a small population of bone marrow cells with osteogenic potential and abilities to differentiate into chondrocytes. In 1991, Arnold Caplan coined the term "mesenchymal cells" after identifying these cells as a theoretical precursor to bone, cartilage, tendon, ligament, marrow stroma, adipocyte, dermis, muscle, and connective tissues. MSCs are derived from periosteum, fat, and muscle. Another attractive property of MSCs is their immunoregulatory and regenerative properties, which result from crosstalk with their microenvironment and components of the innate immune system. Collectively, these properties make MSCs potentially attractive for various therapeutic purposes. MSCs offer potential in sports medicine, aiding in muscle recovery, meniscal tears, and tendon and ligament injuries. In joint disease, MSCs have the potential for chondrogenesis and reversing the effects of osteoarthritis. MSCs have also demonstrated potential application to the treatment of degenerative disc disease of the cervical, thoracic, and lumbar spine.

There is limited data on third-party umbilical cord blood (UCB) or mesenchymal stem cell (MSC) transplantation-assisted haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in pediatric patients.

To evaluate the efficacy and safety of UCB and MSC transplantation-assisted haplo-HSCT in pediatric patients with acute leukemia (AL).

Observational study.

Clinical data of 152 children with AL undergoing haplo-HSCT at the Children's Hospital of Soochow University between January 2020 and June 2022 were collected. The patients were divided into the haplo-HSCT + UCB group (n = 76), haplo-HSCT + MSC group (n = 31), and haplo-HSCT group (n = 45). Hematopoietic reconstruction time, complications within 30 days after transplantation, and survival and recurrence at 3 years after transplantation were compared among the groups.

Multivariate analysis revealed that haplo-HSCT with MSC and human leukocyte antigen (HLA) matching ⩾6/10 were independent factors reducing engraftment syndrome (ES) incidence. There were no significant differences among the groups in the hematopoietic reconstruction time or incidence of complications within 30 days after transplantation (p > 0.05). Overall survival, relapse-free survival, cumulative incidence of relapse, cumulative incidence of hematological relapse, and 3-year transplant-related mortality were not significantly different (p > 0.05). The incidence of adverse reactions in the haplo-HSCT + UCB group was 97.3% within 4 h after UCB infusion, with a particularly high occurrence rate of 94.7% for hypertension. No transfusion-related adverse reactions occurred after the transfusion of umbilical cord MSC in the haplo-HSCT + MSC group.

MSC-assisted haplo-HSCT can reduce ES incidence after transplantation in pediatric patients with AL. UCB infusion is associated with a high incidence of reversible hypertension. However, no adverse reactions were observed in umbilical cord MSC transfusion.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, leading to significant disability through neurodegeneration. Despite advances in the understanding of MS pathophysiology, effective treatments remain limited. Mesenchymal stem cells (MSCs) have gained attention as a potential therapeutic option due to their immunomodulatory and regenerative properties. This review examines MS pathogenesis, emphasizing the role of immune cells, particularly T cells, in disease progression, and explores MSCs' therapeutic potential. Although preclinical studies in animal models show MSC efficacy, challenges such as donor variability, culture conditions, migratory capacity, and immunological compatibility hinder widespread clinical adoption. Strategies like genetic modification, optimized delivery methods, and advanced manufacturing are critical to overcoming these obstacles. Further research is needed to validate MSCs' clinical application in MS therapy.

Cellular therapies utilizing regulatory T cells (Tregs) have flourished in the autoimmunity space as a new pillar of medicine. These cells have shown a great promise in the treatment of such devastating conditions as type 1 diabetes mellitus (T1DM), systemic lupus erythematosus (SLE) and graft versus host disease (GVHD). Novel treatment protocols, which utilize Tregs-mediated suppressive mechanisms, are based on the two main strategies: administration of immunomodulatory factors affecting Tregs or adoptive cell transfer (ACT). ACT involves extraction, in vitro expansion and subsequent administration of Tregs that could be either of autologous or allogeneic origin. Rheumatoid arthritis (RA) is another autoimmune candidate where this treatment approach is being considered. RA remains an especially challenging adversary since it is one of the most frequent and debilitating conditions among all autoaggressive disorders. Noteworthy, Tregs circulating in RA patients' blood have been proven defective and unable to suppress inflammation and joint destruction. With this knowledge, adoptive transfer of compromised autologous Tregs in the fledgling clinical trials involving RA patients should be reconsidered. In this article we hypothesize that incorporation of healthy donor allogeneic Tregs may provide more lucid and beneficial results.

To assess the safety and efficacy of an allogeneic adipose-derived mesenchymal stem cell preparation (MAG200) in the treatment of knee osteoarthritis over 12 months.

A single-centre, double-blind, ascending dose, randomised controlled trial. 40 participants with moderate knee osteoarthritis were randomised to receive a single intra-articular injection of MAG200 (dose cohorts:10, 20, 50, 100 ​× ​106 ​cells) or placebo. Primary objectives were safety and efficacy according to a compound responder analysis of minimal clinically important difference in pain (numerical pain rating scale [NPRS]) and function (Knee Injury and Osteoarthritis Outcome Score - Function in Daily Living subscale [KOOSADL]) at month 12. Secondary efficacy outcomes included changes from baseline in patient reported outcome measures and evaluation of disease-modification using quantitative MRI.

Treatment was well tolerated with no treatment-related serious adverse events. MAG200 cohorts reported a greater proportion of responders than placebo and demonstrated clinical and statistically significant improvement in pain and clinically relevant improvement in all KOOS subscales. MAG200 demonstrated a reproducible treatment effect over placebo, which was clinically relevant for pain in the 10 ​× ​106 dose cohort (mean difference NPRS:-2.25[95%CI:-4.47,-0.03, p ​= ​0.0468]) and for function in the 20 ​× ​106 and 100 ​× ​106 dose cohorts (mean difference KOOSADL:10.12[95%CI:-1.51,21.76, p ​= ​0.0863] and 10.81[95%CI:-1.42,23.04, p ​= ​0.0810] respectively). A trend in disease-modification was observed with improvement in total knee cartilage volume in MAG200 10, 20, and 100 ​× ​106 dose cohorts, with progression of osteoarthritis in placebo, though this was not statistically significant. No clear dose response was observed.

This early-phase study provides supportive safety and efficacy evidence to progress MAG200 to later-stage trial development.

ACTRN12617001095358/ACTRN12621000622808.

Mesenchymal Stem Cells (MSCs) are of interest in the clinic because of their immunomodulation capabilities, capacity to act upstream of inflammation, and ability to sense metabolic environments. In standard physiologic conditions, they play a role in maintaining the homeostasis of tissues and organs; however, there is evidence that they can contribute to some autoimmune diseases. Gaining a deeper understanding of the factors that transition MSCs from their physiological function to a pathological role in their native environment, and elucidating mechanisms that reduce their therapeutic relevance in regenerative medicine, is essential. We conducted a Systematic Review and Meta-Analysis of human MSCs in preclinical studies of autoimmune disease, evaluating 60 studies that included 845 patient samples and 571 control samples. MSCs from any tissue source were included, and the study was limited to four autoimmune diseases: multiple sclerosis, rheumatoid arthritis, systemic sclerosis, and lupus. We developed a novel Risk of Bias tool to determine study quality for in vitro studies. Using the International Society for Cell & Gene Therapy's criteria to define an MSC, most studies reported no difference in morphology, adhesion, cell surface markers, or differentiation into bone, fat, or cartilage when comparing control and autoimmune MSCs. However, there were reported differences in proliferation. Additionally, 308 biomolecules were differentially expressed, and the abilities to migrate, invade, and form capillaries were decreased. The findings from this study could help to explain the pathogenic mechanisms of autoimmune disease and potentially lead to improved MSC-based therapeutic applications.

Hypoxic ischemic encephalopathy (HIE) remains a leading cause of neonatal mortality and lifelong disability across the world. While therapeutic hypothermia (HT) is beneficial, it is only partially protective and adjuvant treatments that further improve outcomes are urgently needed. In high-income countries where HT is standard care, novel treatments are tested in conjunction with HT. Mesenchymal stromal cells (MSC) represent a paradigm shift in brain protection, uniquely adapting to the host cellular microenvironment. MSC have low immunogenicity and potent paracrine effects stimulating the host tissue repair and regeneration and reducing inflammation and apoptosis. Preclinical studies in perinatal brain injury suggest that MSC are beneficial after hypoxia-ischemia (HI) and most preclinical studies of MSC with HT show protection. Preclinical and early phase clinical trials have shown that allogenic administration of MSC to neonates with perinatal stroke and HIE is safe and feasible but further safety and efficacy studies of HT with MSC in these populations are needed. Combination therapies that target all stages of the evolution of injury after HI (eg HT, melatonin and MSC) show promise for improving outcomes in HIE.

Peritoneal dialysis is an important part of end-stage kidney disease replacement therapy. However, prolonged peritoneal dialysis can result in peritoneal fibrosis and ultrafiltration failure, forcing patients to withdraw from peritoneal dialysis treatment. Therefore, there is an urgent need for some effective measures to alleviate the occurrence and progression of peritoneal fibrosis. Mesenchymal stem cells play a crucial role in immunomodulation and antifibrosis. Numerous studies have investigated the fact that mesenchymal stem cells can ameliorate peritoneal fibrosis mainly through the paracrine pathway. It has been discovered that mesenchymal stem cells participate in the improvement of peritoneal fibrosis involving the following signaling pathways: TGF-β/Smad signaling pathway, AKT/FOXO signaling pathway, Wnt/β-catenin signaling pathway, TLR/NF-κB signaling pathway. Additionally, in vitro experiments, mesenchymal stem cells have been shown to decrease mesothelial cell death and promote proliferation. In animal models, mesenchymal stem cells can enhance peritoneal function by reducing inflammation, neovascularization, and peritoneal thickness. Mesenchymal stem cell therapy has been demonstrated in clinical trials to improve peritoneal function and reduce peritoneal fibrosis, thus improving the life quality of peritoneal dialysis patients.

Despite the effectiveness of insulin injections in managing hyperglycemia in type 1 diabetes mellitus (T1DM), they fall short in addressing autoimmunity and regenerating damaged islets. This review aims to explore the potential and prospects of emerging treatment modalities for T1DM, including mesenchymal stem cells (MSCs), MSC-derived exosomes, gene therapy, islet allotransplantation, pancreatic islet cell transplantation, and teplizumab. We review emerging treatment modalities for T1DM, highlighting several promising strategies with varied mechanisms and outcomes. Mesenchymal stem cells demonstrate potential in modulating the immune response and preserving or restoring beta-cell function, although variability in sources and administration routes necessitates further standardization. Similarly, MSC-derived exosomes show promise in promoting beta-cell regeneration and immune regulation, supported by early-stage studies showing improved glucose homeostasis in animal models, albeit with limited clinical data. Gene therapy, utilizing techniques like CRISPR-Cas9, offers targeted correction of genetic defects and immune modulation; however, challenges in precise delivery and ensuring long-term safety persist. Islet allotransplantation and pancreatic islet cell transplantation have achieved some success in restoring insulin independence, yet challenges such as donor scarcity and immunosuppression-related complications remain significant. Teplizumab, an anti-CD3 monoclonal antibody, has demonstrated potential in delaying T1DM onset by modulating immune responses and preserving beta-cell function, with clinical trials indicating prolonged insulin production capability. Despite significant progress, standardization, long-term efficacy, and safety continue to pose challenges across these modalities. Conclusion: While these therapies demonstrate significant potential, challenges persist. Future research should prioritize optimizing these treatments and validating them through extensive clinical trials to enhance T1DM management and improve patient outcomes.

Recently, the therapeutic potential of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) has been extensively studied in both human and veterinary medicine. EVs are nano-sized particles containing biological components commonly found in other biological materials. For that reason, EV isolation and characterization are critical to draw precise conclusions during their investigation. Research on EVs within veterinary medicine is still considered in its early phases, yet numerous papers were published in recent years. The conventional adult tissues for deriving MSCs include adipose tissue and bone marrow. Nonetheless, alternative sources such as synovial fluid, endometrium, gingiva, and milk have also been intermittently used. Fetal adnexa are amniotic membrane/fluid, umbilical cord and Wharton's jelly. Cells derived from fetal adnexa exhibit an intermediate state between embryonic and adult cells, demonstrating higher proliferative and differentiative potential and longer telomeres compared to cells from adult tissues. Summarized here are the principal and recent preclinical and clinical studies performed in domestic animals such as horse, cattle, dog and cat. To minimize the use of antibiotics and address the serious issue of antibiotic resistance as a public health concern, they will undoubtedly also be utilized in the future to treat infections in domestic animals. A number of concerns, including large-scale production with standardization of EV separation and characterization techniques, must be resolved for clinical application.

Mesenchymal stem cells (MSCs) may be effective in treating connective tissue disease and associated organ damage, leveraging their anti-inflammatory and immunoregulatory effects. Moreover, MSCs may possess the ability to produce antiapoptotic, proliferative, growth, angiogenic, and antifibrotic factors. Among MSCs, adipose-derived MSCs (ASCs) stand out for their relative ease of harvesting and abundance. Additionally, studies have indicated that compared with bone marrow-derived MSCs, ASCs have superior immunomodulatory, proangiogenic, antiapoptotic, and antioxidative properties. However, relatively few reviews have focused on the efficacy of ASC therapy in treating connective tissue disease (CTD) and interstitial lung disease (ILD). Therefore, this review aims to evaluate evidence from preclinical studies that investigate the effectiveness of MSC therapy, specifically ASC therapy, in managing CTD and ILD. Moreover, we explore the outcomes of documented clinical trials. We also introduce an innovative approach involving the utilization of pharmacologically primed ASCs in the CTD model to address the current challenges associated with ASC therapy.

To investigate the effect of nasal mucosa-derived ectodermal mesenchymal stem cells (NM-EMSCs) on the inflammatory state of rats with chronic rhinosinusitis (CRS) and the underlying therapeutic mechanism.

NM-EMSCs were isolated and extracted to construct a rat model of CRS. Fifteen Sprague‒Dawley (SD) rats were randomly divided into three groups: CK + NS group rats were injected locally with saline in the nasal mucosa; CRS + NS group rats were injected locally with saline in the nasal mucosa; and CRS + EMSCs group rats were injected locally with NM-EMSCs in the nasal mucosa. One rat from the CRS + EMSCs group was randomly euthanized at 2, 4, and 6 days after injection, and the nasal mucosa tissues were collected for HE staining, Masson's trichrome staining, and periodic acid-Schiff staining.

NM-EMSCs specifically expressing CD73, CD105, and CD90 were successfully isolated from the nasal mucosa of rats and were able to differentiate into adipocytes, osteoblasts, and chondrocytes. After saline and NM-EMSC injection, compared with those in the blank control CK + NS group, the nasal mucosa in the CRS + NS and CRS + EMSC groups exhibited obvious thickening, a large amount of inflammatory cell infiltration, and increased collagen and mucin distribution. Four days post-NM-EMSC injection, the thickening of the nasal mucosa in the CRS group was gradually alleviated, the inflammatory cell infiltration gradually decreased, and the distribution of collagen and mucin and the collagen-positive area gradually decreased. Moreover, only a small number of inflammatory cells were visible, and the distribution of mucins was limited to 6 days post-NM-EMSC injection.

NM-EMSCs effectively attenuated inflammation in the nasal mucosa of CRS model rats.

In the recent past, the formulation and development of nanocarriers has been elaborated into the broader fields and opened various avenues in their preclinical and clinical applications. In particular, the cellular membrane-based nanoformulations have been formulated to surpass and surmount the limitations and restrictions associated with naïve or free forms of therapeutic compounds and circumvent various physicochemical and immunological barriers including but not limited to systemic barriers, microenvironmental roadblocks, and other cellular or subcellular hinderances-which are quite heterogeneous throughout the diseases and patient cohorts. These limitations in drug delivery have been overcome through mesenchymal cells membrane-based precision therapeutics, where these interventions have led to the significant enhancements in therapeutic efficacies. However, the formulation and development of nanocarriers still focuses on optimization of drug delivery paradigms with a one-size-fits-all resolutions. As mesenchymal stem cell membrane-based nanocarriers have been engineered in highly diversified fashions, these are being optimized for delivering the drug payloads in more and better personalized modes, entering the arena of precision as well as personalized nanomedicine. In this Review, we have included some of the advanced nanocarriers which have been designed and been utilized in both the non-personalized as well as precision applicability which can be employed for the improvements in precision nanotherapeutics. In the present report, authors have focused on various other aspects of the advancements in stem cells membrane-based nanoparticle conceptions which can surmount several roadblocks and barriers in drug delivery and nanomedicine. It has been suggested that well-informed designing of these nanocarriers will lead to appreciable improvements in the therapeutic efficacy in therapeutic payload delivery applications. These approaches will also enable the tailored and customized designs of MSC-based nanocarriers for personalized therapeutic applications, and finally amending the patient outcomes.

Fibrosis is a pathological process, that could result in permanent scarring and impairment of the physiological function of the affected organ; this condition which is categorized under the term organ failure could affect various organs in different situations. The involvement of the major organs, such as the lungs, liver, kidney, heart, and skin, is associated with a high rate of morbidity and mortality across the world. Fibrotic disorders encompass a broad range of complications and could be traced to various illnesses and impairments; these could range from simple skin scars with beauty issues to severe rheumatologic or inflammatory disorders such as systemic sclerosis as well as idiopathic pulmonary fibrosis. Besides, the overactivation of immune responses during any inflammatory condition causing tissue damage could contribute to the pathogenic fibrotic events accompanying the healing response; for instance, the inflammation resulting from tissue engraftment could cause the formation of fibrotic scars in the grafted tissue, even in cases where the immune system deals with hard to clear infections, fibrotic scars could follow and cause severe adverse effects. A good example of such a complication is post-Covid19 lung fibrosis which could impair the life of the affected individuals with extensive lung involvement. However, effective therapies that halt or slow down the progression of fibrosis are missing in the current clinical settings. Considering the immunomodulatory and regenerative potential of distinct stem cell types, their application as an anti-fibrotic agent, capable of attenuating tissue fibrosis has been investigated by many researchers. Although the majority of the studies addressing the anti-fibrotic effects of stem cells indicated their potent capabilities, the underlying mechanisms, and pathways by which these cells could impact fibrotic processes remain poorly understood. Here, we first, review the properties of various stem cell types utilized so far as anti-fibrotic treatments and discuss the challenges and limitations associated with their applications in clinical settings; then, we will summarize the general and organ-specific mechanisms and pathways contributing to tissue fibrosis; finally, we will describe the mechanisms and pathways considered to be employed by distinct stem cell types for exerting anti-fibrotic events.

Hepatocellular carcinoma (HCC) is experiencing a concerning rise in both incidence and mortality rates. Current therapeutic strategies are limited in their effectiveness, largely due to the complex causes of the disease and significant levels of drug resistance. Given the latest developments in human umbilical cord mesenchymal stem cells (hUC-MSCs) research, there is a debate over the continued use of stem cell transplantation for treating tumors. Consequently, this study seeks to explore the role of hUC-MSCs in the management of HCC.

HUC-MSCs increased the number (10.75 ± 1.50) in the DEN/TCPOBOP-induced mice hepatoma model, compared with DMSO group (7.25 ± 1.71). Moreover, the liver index in hUC-MSCs group (0.21 ± 0.06) was greater than that in DMSO group (0.09 ± 0.01). Immunohistochemical (IHC) analysis revealed that while hUC-MSCs did not alter Foxp3 expression, they significantly stimulated Ki67 expression, indicative of increased tumor cellular proliferation. Additionally, immunofluorescence (IF) studies showed that hUC-MSCs increased CD8+ T cell counts without affecting macrophage numbers. Notably, granzyme B expression remained nearly undetectable. We observed that serum IL-18 levels were higher in the hUC-MSCs group (109.66 ± 0.38 pg/ml) compared to the DMSO group (91.14 ± 4.37 pg/ml). Conversely, IL-1β levels decreased in the hUC-MSCs group (63.00 ± 0.53 pg/ml) relative to the DMSO group (97.38 ± 9.08 pg/ml).

According to this study, hUC-MSCs promoted the growth of liver tumors. Therefore, we proposed that hUC-MSCs are not suitable for treating HCC, as they exhibit clinically prohibited abnormalities.

Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4.

BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover.

The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals.

EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.

Culture-derived mesenchymal stromal cells (MSCs) exhibit variable characteristics when manufactured using different methods, source material and culture media. The purpose of this multicenter study was to assess the impact on MSC expansion, gene expression and other characteristics when different laboratories expanded MSCs from cultures initiated with bone marrow-MSC aliquots derived from the same donor source material yet with different growth media.

Eight centers expanded MSCs using four human platelet lysate (HPL) and one fetal bovine serum (FBS) products as media supplements. The expanded cells were taken through two passages then assessed for cell count, viability, doubling time, immunophenotype, cell function, immunosuppression and gene expression. Results were analyzed by growth media and by center.

Center methodologies varied by their local seeding density, feeding regimen, inoculation density, base media and other growth media features (antibiotics, glutamine, serum). Doubling times were more dependent on center than on media supplements. Two centers had appropriate immunophenotyping showing all MSC cultures were positive for CD105, CD73, CD90 and negative for CD34, CD45, CD14, HLA-DR. MSCs cultured in media supplemented with FBS compared with HPL featured greater T-cell inhibition potential. Gene expression analysis showed greater impact of the type of media supplement (HPL versus FBS) than the manufacturing center. Specifically, nine genes were decreased in expression and six increased when combining the four HPL-grown MSCs versus FBS (false discovery rate [FDR] <0.01), however, without significant difference between different sources of HPL (FDR <0.01).

Local manufacturing process plays a critical role in MSC expansion while growth media may influence function and gene expression. All HPL and FBS products supported cell growth.

Stem cells of mesenchymal origin have good proliferative capacity when compared to other stem cell types. Dental pulp stem cells (DPSCs) are a variety of mesenchymal cells obtained from the pulpal tissue of teeth and are abundantly available and easy to obtain. DPSCs facilitate and improve the formation of new bone using different bone graft scaffolds. This present study aims to evaluate and compare the osteogenic potential of DPSCs on alloplastic and xenogeneic bone grafts.

Hydroxyapatite and beta-tricalcium bone graft and bovine bone graft were used in a triplicate manner in the laboratory. DPSCs were obtained from the pulpal tissue of extracted third molars in the laboratory. The cytotoxicity, osteogenic potential, and difference in the rate of proliferation of mesenchymal cells on the biomaterials were assessed.

Darker purple staining was seen in the case of hydroxyapatite/beta-tricalcium bone graft on MTT colorimetric assay stating that there was an increase in cell viability in hydroxyapatite/beta-tricalcium bone graft as compared to the bovine bone graft. Hydroxyapatite/beta-tricalcium bone graft showed more osteogenic potential as compared to the bovine bone graft as a higher degree of red staining was seen in Alizarin staining.

Higher cell viability and higher osteogenic proliferation and differentiation were seen on the hydroxyapatite/beta-tricalcium bone graft compared to the bovine bone scaffold.

Mesenchymal stromal cell (MSC)-based advanced therapy medicinal products (ATMPs) are being tried in a vast range of clinical applications. These cells can be isolated from different donor tissues by using several methods, or they can even be derived from induced pluripotent stem cells or embryonic stem cells. However, ATMP heterogeneity may impact product identity and potency, and, consequently, clinical trial outcomes. In this review, we discuss these topics and the need to establish minimal criteria regarding the manufacturing of MSCs so that these innovative therapeutics may be better positioned to contribute to the advancement of regenerative medicine.

Myocardial infarction (MI) stands out as a highly lethal disease that poses a significant threat to global health. Worldwide, heart failure resulting from MI remains a leading cause of human mortality. Mesenchymal stem cell (MSC) therapy has emerged as a promising therapeutic approach, leveraging its intrinsic healing properties. Nevertheless, pervasive issues, including a low cell retention rate, suboptimal survival rate, and incomplete differentiation of MSCs, present formidable challenges for further research. The introduction and advancement of biomaterials have offered a novel avenue for the exploration of MSC therapy in MI, marking considerable progress thus far. Notably, hydrogels, among the representative biomaterials, have garnered extensive attention within the biomedical field. This review delves into recent advancements, specifically focusing on the application of hydrogels to augment MSC therapy for cardiac tissue regeneration in MI.