MSCs biomimetic ultrasonic phase change nanoparticles promotes cardiac functional recovery after acute myocardial infarction.

Acute Myocardial Infarction (AMI) has seen rising cases, particularly in younger people, leading to public health concerns. Standard treatments, like coronary artery recanalization, often don't fully repair the heart's microvasculature, risking heart failure. Advances show that Mesenchymal Stromal Cells (MSCs) transplantation improves cardiac function after AMI, but the harsh microenvironment post-AMI impacts cell survival and therapeutic results. MSCs aid heart repair via their membrane proteins and paracrine extracellular vesicles that carry microRNA-125b, which regulates multiple targets, preventing cardiomyocyte death, limiting fibroblast growth, and combating myocardial remodeling after AMI. This study introduces ultrasound-responsive phase-change bionic nanoparticles, leveraging MSCs' natural properties. These particles contain MSC membrane and microRNA-125b, with added macrophage membrane for stability. Using Ultrasound Targeted Microbubble Destruction (UTMD), this method targets the delivery of MSC membrane proteins and microRNA-125b to AMI's inflamed areas. This aims to enhance cardiac function recovery and provide precise, targeted AMI therapy.

Transcriptomic profiling of human mesenchymal stem cells using a pulsed electromagnetic-wave motion bioreactor system for enhanced osteogenic commitment and therapeutic potentials.

Traditional bioreactor systems involve the use of three-dimensional (3D) scaffolds or stem cell aggregates, limiting the accessibility to the production of cell-secreted biomolecules. Herein, we present the use a pulse electromagnetic fields (pEMFs)-assisted wave-motion bioreactor system for the dynamic and scalable culture of human bone marrow-derived mesenchymal stem cells (hBMSCs) with enhanced the secretion of various soluble factors with massive therapeutic potential. The present study investigated the influence of dynamic pEMF (D-pEMF) on the kinetic of hBMSCs. A 30-min exposure of pEMF (10V-1Hz, 5.82 G) with 35 oscillations per minute (OPM) rocking speed can induce the proliferation (1 × 105 â†’ 4.5 × 105) of hBMSCs than static culture. Furthermore, the culture of hBMSCs in osteo-induction media revealed a greater enhancement of osteogenic transcription factors under the D-pEMF condition, suggesting that D-pEMF addition significantly boosted hBMSCs osteogenesis. Additionally, the RNA sequencing data revealed a significant shift in various osteogenic and signaling genes in the D-pEMF group, further suggesting their osteogenic capabilities. In this research, we demonstrated that the combined effect of wave and pEMF stimulation on hBMSCs allows rapid proliferation and induces osteogenic properties in the cells. Moreover, our study revealed that D-pEMF stimuli also induce ROS-scavenging properties in the cultured cells. This study also revealed a bioactive and cost-effective approach that enables the use of cells without using any expensive materials and avoids the possible risks associated with them post-implantation.

Efficiently directing differentiation and homing of mesenchymal stem cells to boost cartilage repair in osteoarthritis via a nanoparticle and peptide dual-engineering strategy.

Mesenchymal stem cells (MSCs) are expected to be useful therapeutics in osteoarthritis (OA), the most common joint disorder characterized by cartilage degradation. However, evidence is limited with regard to cartilage repair in clinical trials because of the uncontrolled differentiation and weak cartilage-targeting ability of MSCs after injection. To overcome these drawbacks, here we synthesized CuO@MSN nanoparticles (NPs) to deliver Sox9 plasmid DNA (favoring chondrogenesis) and recombinant protein Bmp7 (inhibiting hypertrophy). After taking up CuO@MSN/Sox9/Bmp7 (CSB NPs), the expressions of chondrogenic markers were enhanced while hypertrophic markers were decreased in response to these CSB-engineered MSCs. Moreover, a cartilage-targeted peptide (designated as peptide W) was conjugated onto the surface of MSCs via a click chemistry reaction, thereby prolonging the residence time of MSCs in both the knee joint cavity of mice and human-derived cartilage. In a surgery-induced OA mouse model, the NP and peptide dual-modified W-CSB-MSCs showed an enhancing therapeutic effect on cartilage repair in knee joints compared with other engineered MSCs after intra-articular injection. Most importantly, W-CSB-MSCs accelerated cartilage regeneration in damaged cartilage explants derived from OA patients. Thus, this new peptide and NPs dual engineering strategy shows potential for clinical applications to boost cartilage repair in OA using MSC therapy.

Stiff extracellular matrix drives the differentiation of mesenchymal stem cells toward osteogenesis by the multiscale 3D genome reorganization.

Extracellular matrix (ECM) stiffness is a major driver of stem cell fate. However, the involvement of the three-dimensional (3D) genomic reorganization in response to ECM stiffness remains unclear. Here, we generated comprehensive 3D chromatin landscapes of mesenchymal stem cells (MSCs) exposed to various ECM stiffness. We found that there were more long-range chromatin interactions, but less compartment A in MSCs cultured on stiff ECM than those cultured on soft ECM. However, the switch from compartment B in MSCs cultured on soft ECM to compartment A in MSCs cultured on stiff ECM included genes encoding proteins primarily enriched in cytoskeleton organization. At the topologically associating domains (TADs) level, stiff ECM tends to have merged TADs on soft ECM. These merged TADs on stiff ECM include upregulated genes encoding proteins enriched in osteogenesis, such as SP1, ETS1, and DCHS1, which were validated by quantitative real-time polymerase chain reaction and found to be consistent with the increase of alkaline phosphatase staining. Knockdown of SP1 or ETS1 led to the downregulation of osteogenic marker genes, including COL1A1, RUNX2, ALP, and OCN in MSCs cultured on stiff ECM. Our study provides an important insight into the stiff ECM-mediated promotion of MSC differentiation towards osteogenesis, emphasizing the influence of mechanical cues on the reorganization of 3D genome architecture and stem cell fate.

Material-driven immunomodulation and ECM remodeling reverse pulmonary fibrosis by local delivery of stem cell-laden microcapsules.

Recent progress in stem cell therapy has demonstrated the therapeutic potential of intravenous stem cell infusions for treating the life-threatening lung disease of pulmonary fibrosis (PF). However, it is confronted with limitations, such as a lack of control over cellular function and rapid clearance by the host after implantation. In this study, we developed an innovative PF therapy through tracheal administration of microfluidic-templated stem cell-laden microcapsules, which effectively reversed the progression of inflammation and fibrotic injury. Our findings highlight that hydrogel microencapsulation can enhance the persistence of donor mesenchymal stem cells (MSCs) in the host while driving MSCs to substantially augment their therapeutic functions, including immunoregulation and matrix metalloproteinase (MMP)-mediated extracellular matrix (ECM) remodeling. We revealed that microencapsulation activates the MAPK signaling pathway in MSCs to increase MMP expression, thereby degrading overexpressed collagen accumulated in fibrotic lungs. Our research demonstrates the potential of hydrogel microcapsules to enhance the therapeutic efficacy of MSCs through cell-material interactions, presenting a promising yet straightforward strategy for designing advanced stem cell therapies for fibrotic diseases.

Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis.

Introduction: Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). Method: A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. Results: 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). Conclusion: MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.

A Liquid Band-Aid with Mesenchymal Stem Cell-Derived Exosomes for Wound Healing in Mice.

INTRODUCTION/OBJECTIVE: This study aimed to examine the effect of a human umbilical cord mesenchymal stem cell-derived exosome (hUC-MSC-Exo) liquid band-aid on wound healing in mice. METHODS: hUC-MSC-Exos were prepared from the supernatant via ion exchange chromatography. The composition ratio of the chitosan liquid band-aid was optimized to form a film and encapsulate hUC-MSC-Exo. The biological effects of chitosan exosome liquid band-aid on human umbilical vein endothelial cells (HUVECs) were observed, and its anti-bacterial properties were tested. BALB/c mice with back skin injury were randomly divided into chitosan exosome liquid band-aid group (CS-Exo), chitosan liquid band-aid group (CS), and normal saline control group (Con), and wound healing was evaluated post-treatment. Skin tissue samples posttreatment were collected for H&E staining. RESULTS: The hUC-MSC-Exo was prepared and characterized. The optimum conditions for film formation were 1% chitosan solution and 15% poloxamer 407/poloxamer 188 (pH 5.0 ~ 7.0). The chitosan exosome liquid band-aid promoted HUVEC proliferation and migration and markedly inhibited Escherichia coli and Staphylococcus aureus growth in vitro. In vivo, the wound healing rate in the CS-Exo group was higher than that in the Con and CS groups. Fourteen days post-treatment, the wounds completely healed, and hair grew normally, which was consistent with H&E results. Mouse weights in each group did not change significantly after administration, indicating that the chitosan exosome liquid band-aid had no obvious toxic side effects. CONCLUSION: Local chitosan exosome liquid band-aid application can promote wound healing in mice, and the mechanism could be related to hUC-MSC-Exo-induced vascular endothelial cell proliferation and migration.

Bone marrow mesenchymal stem cell and mononuclear cell combination therapy in patients with type 2 diabetes mellitus: a randomized controlled study with 8-year follow-up.

BACKGROUND: To investigate the long-term effects of combining bone marrow mesenchymal stem cells (MSCs) with mononuclear cells (MCs) in the treatment of type 2 diabetes mellitus (T2DM). METHODS: T2DM patients were divided into the combination group (Dual MSC + MC, n = 33), the mononuclear cell group (MC-Only, n = 32) and the control group (Control, n = 31). All groups were treated with insulin and metformin. The Dual MSC + MC group additionally received MSC and MC infusion and the MC-Only group additionally received MC infusion. The patients were followed up for 8 years. The primary endpoint was the C-peptide area under the curve (C-p AUC) at 1 year. This study was registered with clinicaltrial.gov (NCT01719640). RESULTS: A total of 97 patients were included and 89 completed the follow-up. The area under the curve of C-peptide of the Dual MSC + MC group and the MC-Only group was significantly increased (50.6% and 32.8%, respectively) at 1 year. After eight years of follow-up, the incidence of macrovascular complications was 13.8% (p = 0.009) in the Dual MSC + MC group and 21.4% (p = 0.061) in the MC-Only group, while it was 44.8% in the Control group. The incidence of diabetic peripheral neuropathy (DPN) was 10.3% (p = 0.0015) in the Dual MSC + MC group, 17.9% (p = 0.015) in the MC-Only group, and 48.3% in the Control group. CONCLUSIONS: The combination of MSC and MC therapy can reduce the incidence of chronic diabetes complications and improves metabolic control with mild side effects in T2DM patients.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis.

BACKGROUND: Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM: To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. METHODS: Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS: The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 µM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION: Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Innovative mesenchymal stem cell treatments for fatty liver disease.

The incidence of non-alcoholic fatty liver disease (NAFLD) and alcohol-associated liver disease (ALD) is increasing year by year due to changes in the contemporary environment and dietary structure, and is an important public health problem worldwide. There is an urgent need to continuously improve the understanding of their disease mechanisms and develop novel therapeutic strategies. Mesenchymal stem cells (MSCs) have shown promise as a potential therapeutic strategy in therapeutic studies of NAFLD and ALD. NAFLD and ALD have different triggers and their specific mechanisms of disease progression are different, but both involve disease processes such as hepatocellular steatosis and potential fibrosis, cirrhosis, and even hepatocellular carcinoma. MSCs have metabolic regulatory, anti-apoptotic, antioxidant, and immunomodulatory effects that together promote liver injury repair and functional recovery, and have demonstrated positive results in preclinical studies. This editorial is a continuum of Jiang et al's review focusing on the advantages and limitations of MSCs and their derivatives as therapeutics for NAFLD and ALD. They detail how MSCs attenuate the progression of NAFLD by modulating molecular pathways involved in glucolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. Based on recent advances, we discuss MSCs and their derivatives as therapeutic strategies for NAFLD and ALD, providing useful information for their clinical application.

Mesenchymal stem cells in wound healing: A bibliometric analysis as a powerful research tool.

Bibliographic analysis is still very rarely used in experimental basic study papers. The comprehensive bibliometric analysis of scientific literature on research progress and challenges in stem cell therapy for diabetic chronic wounds, which was conducted in the work of Shi et al can be a case study and a source of valuable information for writing reviews and experimental papers in this field. Basic experimental studies on a role of mesenchymal stem cells (MSCs) in wound healing that are published in 2023-2024, such as Zhang et al in 2023, Hu et al in 2023, Wang et al in 2023 are certainly also subjects for applying this powerful tool to analyze current research, challenges and perspectives in this field. This is due to the fact that these studies have addressed a great variety of aspects of the application of MSCs for the treatment of chronic wounds, such as using both the cells themselves and their various products: Sponges, hydrogels, exosomes, and genetic constructions. Such a wide variety of directions in the field of study and biomedical application of MSCs requires a deep understanding of the current state of research in this area, which can be provided by bibliometric analysis. Thus, the use of such elements of bibliographic analysis as publication count by year and analysis of top-10 keywords calculated independently or cited from bibliometric analysis studies can be safely recommended for every basic study manuscripts, primarily for the "Introduction" section, and review.

Mechanism of mesenchymal stem cells in liver regeneration: Insights and future directions.

Mesenchymal stem cells (MSCs) are a prevalent source for stem cell therapy and play a crucial role in modulating both innate and adaptive immune responses. Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides in liver cells and involves immune system activation, leading to histological changes, tissue damage, and clinical symptoms. A recent publication by Jiang et al, highlighted the potential of MSCs to mitigate in NAFLD progression by targeting various molecular pathways, including glycolipid metabolism, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In this editorial, we comment on their research and discuss the efficacy of MSC therapy in treating NAFLD.

Tuneable Recombinant Spider Silk Protein Hydrogels for Drug Release and 3D Cell Culture.

Hydrogels are useful drug release systems and tissue engineering scaffolds. However, synthetic hydrogels often require harsh gelation conditions and can contain toxic by-products while naturally derived hydrogels can transmit pathogens and in general have poor mechanical properties. Thus, there is a need for a hydrogel that forms under ambient conditions, is non-toxic, xeno-free, and has good mechanical properties. A recombinant spider silk protein-derived hydrogel that rapidly forms at 37 °C is recently developed. The temperature and gelation times are well-suited for an injectable in situ polymerising hydrogel, as well as a 3D cell culture scaffold. Here, it is shown that the diffusion rate and the mechanical properties can be tuned by changing the protein concentration and that human fetal mesenchymal stem cells encapsulated in the hydrogels show high survival and viability. Furthermore, mixtures of recombinant spider silk proteins and green fluorescent protein (GFP) form gels from which functional GFP is gradually released, indicating that bioactive molecules are easily included in the gels, maintain activity and can diffuse through the gel. Interestingly, encapsulated ARPE-19 cells are viable and continuously produce the growth factor progranulin, which is detected in the cell culture medium over the study period of 31 days.

HUC-MSC-derived exosomes repaired the damage induced by hydroquinone to 16HBE cells via miR-221/PTEN pathway.

Mesenchymal stem cell - originated exosomes (MSC-exo) are promising non-cellular treatment agents for various diseases. The present study aimed to explore whether human umbilical cord MSC - originated exosomes (HUC-MSC-exo) have the function of protecting human cells (16HBE) against the damage caused by HQ and the related mechanism. HUC-MSC-exo was isolated with differential gradient ultracentrifugation method and characterized by using transmission electron microscope (TEM). 16HBE cells were used as the tool cells and co-cultured with HUC-MSC-exo. Confocal laser scanning microscope was employed to confirm the ingestion of HUC-MSC-exo by 16HBE. Cell proliferation, migration, oxidative stress, DNA and chromosome damages of 16HBE were analyzed under HQ stress, and the role of miR-221/PTEN axis was investigated. Our data showed that under HQ stress, different groups of cells exhibited significantly decreased proliferation and migration abilities, and significant oxidative stress, DNA and chromosome damage effects. HUC-MSC-exo could alleviate the cytotoxic, oxidative stress and genotoxic damage effects of HQ on 16HBE cells. Mechanistically, HQ exposure up-regulated the level of miR-221 and down-regulated PTEN, while HUC-MSC-exo could significantly reduce the level of miR-221 and promote PTEN expression, which was involved in alleviating the toxic effects of HQ on 16HBE cells. Our data indicates that HUC-MSC-exo can alleviate the oxidative stress, cytotoxic and genotoxic effects of HQ on 16HBE cells via miR-221/PTEN pathway, and it may be a promising agent for protecting against the toxicity of HQ.

Bone marrow mesenchymal stem cells-derived exosomal miR-381 alleviates lung ischemia-reperfusion injury by activating Treg differentiation through inhibiting YTHDF1 expression.

AIM: Our study aimed to investigate whether BMSCs-derived exosomal miR-381 promotes Treg cell differentiation in lung ischemia-reperfusion injury (LIRI), and the underlying mechanism. METHODS: The in vitro and in vivo models of LIRI were established by hypoxia/reoxygenation (H/R) treatment and lung ischemia/reperfusion (I/R) surgery, respectively. BMSCs-derived exosomes were isolated and identified by western blot, nanoparticle tracking analysis, and transmission electron microscopy. Cell viability, proliferation, and apoptosis were assessed by CCK-8, EdU, and flow cytometry assay, respectively. IL-18 secretion level in lung microvascular endothelial cells (LMECs) and lung tissue homogenate was examined by ELISA. Treg cell differentiation was determined using flow cytometry. The relationships between miR-381, YTHDF1, and IL-18 were investigated using dual-luciferase reporter gene, RIP, and/or RNA pull-down assays. MeRIP assay was employed to determine m6A modification of IL-18 mRNA in LMECs. The ubiquitination level of Foxp3 protein in CD4+ T cells was analyzed by Co-IP assay. RESULTS: BMSCs-derived exosomes reduced LMECs injury and increased Treg cell differentiation in LIRI, whereas miR-381 inhibition in BMSCs weakened these impacts. Mechanistically, miR-381 inhibited IL-18 translation in LMECs by inhibiting YTHDF1 expression via binding to its 3'-UTR. As expected, YTHDF1 overexpression in LMECs abolished the effects of miR-381-overexpressed exosomes on LMECs injury and Treg cell differentiation. Moreover, LMECs-secreted IL-18 inhibited Treg cell differentiation by promoting the ubiquitination degradation of Foxp3 protein. CONCLUSION: BMSCs-derived exosomal miR-381 suppressed IL-18 translation in LMECs through binding to YTHDF1 3'-UTR, thus suppressing the ubiquitination degradation of Foxp3 in CD4+ T cells, which promoted Treg cell differentiation and mitigated LIRI development.

Emerging technologies in regenerative medicine: The future of wound care and therapy.

Wound healing, an intricate biological process, comprises orderly phases of simple biological processed including hemostasis, inflammation, angiogenesis, cell proliferation, and ECM remodeling. The regulation of the shift in these phases can be influenced by systemic or environmental conditions. Any untimely transitions between these phases can lead to chronic wounds and scarring, imposing a significant socio-economic burden on patients. Current treatment modalities are largely supportive in nature and primarily involve the prevention of infection and controlling inflammation. This often results in delayed healing and wound complications. Recent strides in regenerative medicine and tissue engineering offer innovative and patient-specific solutions. Mesenchymal stem cells (MSCs) and their secretome have gained specific prominence in this regard. Additionally, technologies like tissue nano-transfection enable in situ gene editing, a need-specific approach without the requirement of complex laboratory procedures. Innovating approaches like 3D bioprinting and ECM bioscaffolds also hold the potential to address wounds at the molecular and cellular levels. These regenerative approaches target common healing obstacles, such as hyper-inflammation thereby promoting self-recovery through crucial signaling pathway stimulation. The rationale of this review is to examine the benefits and limitations of both current and emerging technologies in wound care and to offer insights into potential advancements in the field. The shift towards such patient-centric therapies reflects a paradigmatic change in wound care strategies.

Progression of mesenchymal stem cell regulation on imbalanced microenvironment after spinal cord injury.

Spinal cord injury (SCI) results in significant neural damage and inhibition of axonal regeneration due to an imbalanced microenvironment. Extensive evidence supports the efficacy of mesenchymal stem cell (MSC) transplantation as a therapeutic approach for SCI. This review aims to present an overview of MSC regulation on the imbalanced microenvironment following SCI, specifically focusing on inflammation, neurotrophy and axonal regeneration. The application, limitations and future prospects of MSC transplantation are discussed as well. Generally, a comprehensive perspective is provided for the clinical translation of MSC transplantation for SCI.

Steroidogenic differentiation of human amniotic membrane-derived mesenchymal stem cells into a progesterone-/androgen-producing cell lineage by SF-1 and an estrogen-producing cell lineage by WT1-KTS.

Background: Sex steroid hormones, primarily synthesized by gonadal somatic cells, are pivotal for sexual development and reproduction. Mice studies have shown that two transcription factors, steroidogenic factor 1 (SF-1) and Wilms' tumor 1 (WT1), are involved in gonadal development. However, their role in human gonadal somatic differentiation remains unclear. We therefore aimed to investigate the roles of SF-1 and WT1 in human gonadal steroidogenic cell differentiation. Methods: Using a transient lentivirus-mediated gene expression system, we assessed the effects of SF-1 and WT1 expression on the steroidogenic potential of human amniotic membrane-derived mesenchymal stem cells (hAmMSCs). Results: SF-1 and WT1-KTS, a splice variant of WT1, played distinct roles in human steroidogenic differentiation of hAmMSCs. SF-1 induced hAmMSC differentiation into progesterone- and androgen-producing cell lineages, whereas WT1-KTS promoted hAmMSC differentiation into estrogen-producing cell lineages. Conclusion: Our findings revealed that SF-1 and WT1-KTS play important roles in human gonadal steroidogenic cell differentiation, especially during ovarian development. These findings may pave the way for future studies on human ovarian differentiation and development.

Mesenchymal stem cells suppress inflammation by downregulating interleukin-6 expression in intestinal perforation animal model.

Introduction: Intestinal perforation has significant fatality due to sepsis contamination and prolonged inflammation. Studies showed that mesenchymal stem cells (MSCs) secreted cytokines and growth factors to reduce inflammation. This study aims to reveal the role of MSCs in controlling inflammation in intestinal perforation wound healing by measuring interleukin-6 (IL-6) and leukocytes in injured tissue. Materials and methods: A total of 48 rat models with a 10-mm longitudinal incision at the small intestine were divided into four groups: sham, control, Treatment group 1 (T1) injected with MSC doses of 1.5×106 cells and Treatment group 2 (T2) with 3×106 cells. IL-6 expressions were determined using western blot analysis, whereas the leukocyte infiltrations were assessed using the histopathological examination. All variables were evaluated on day 3 and 7. Results: Leukocyte infiltration is significantly lower in T1 and T2 compared to control group in day 3 and 7 (P<0.05), while there were no differences between the two treatment groups. The expression of IL-6 was found to be significantly lower in the T1 and T2 groups compared to the control group on days 3 and 7 (P<0.05), with no significant differences observed between the two treatment groups. Conclusion: MSCs administration in rats with intestinal perforation reduced inflammation by controlling leukocyte infiltration and IL-6 expression.

Darvadstrocel for complex perianal fistulas in Crohn's disease: A systematic review and meta-analysis.

BACKGROUND: Local injection of darvadstrocel, a suspension of expanded adipose-derived allogenic mesenchymal stem cells, has been used for treatment-refractory perianal fistulas in Crohn's disease (CD). OBJECTIVE: This study aimed to investigate efficacy and safety of darvadstrocel for complex perianal fistulas in CD. METHODS: A systematic search was conducted through April 2024 in relevant databases for observational studies evaluating darvadstrocel. A random-effects meta-analysis model was used to calculate the pooled effect sizes (proportions or incidence rates [IRs]) with 95% confidence intervals (CIs) of effectiveness and safety outcomes. The risk of bias was evaluated using the Joanna Briggs Institute Critical Appraisal Tool. The I2 value assessed heterogeneity. Sensitivity and subgroup analyses were also conducted. RESULTS: Twelve studies were included with 595 patients. The pooled rate of patients achieving clinical remission, defined as fistula healing, was 68.1% at month 6 (95% CI 63.4-72.7) and 77.2% (95% CI 70.1-83.8) at month 12. Combined remission, defined as clinical remission and absence of collections >2 cm confirmed by magnetic resonance imaging, was reported in 60.6% and in 69.7% of patients at months 6 and 12, respectively. The rate of patients with treatment failure, defined as no clinical remission at the last follow-up (mean 18.7 months; SD 9.9), was 34.5%. Failure rate was independent of follow-up time (p = 0.85). For effectiveness outcomes, between-study heterogeneity was negligible. Subgroup analysis indicated that none of the covariates modified the treatment effect. Pooled IRs per 100 patient-years of adverse events (AE), serious AEs, perianal abscesses, and reoperations were 19.6, 3.2, 16.9 and 7.1, respectively. CONCLUSION: Evidence from observational studies supports the efficacy and safety of darvadstrocel for complex perianal fistulas in CD. Studies have reported high fistula healing rates that can be sustained long-term in most patients, with negligible between-study heterogeneity, as well as a favorable safety profile.