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The Journal of Allergy and Clinical... Jun 2024Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses.
BACKGROUND
Mesenchymal stem cells (MSCs) play important roles in therapeutic applications by regulating immune responses.
OBJECTIVE
To investigate the safety and efficacy of allogenic human bone marrow-derived clonal MSCs (hcMSCs) in subjects with moderate to severe atopic dermatitis (AD).
METHODS
The study included a phase I open-label trial followed by a phase II randomized, double-blind, placebo-controlled trial that involved 72 subjects with moderate to severe AD.
RESULTS
In phase I, intravenous (IV) administration of hcMSCs at two doses (1×10 and 5×10 cells/kg) was safe and well-tolerated in 20 subjects. Since there was no difference between the two dosage groups (P=0.9), it was decided to administer low-dose hcMSCs only for phase II. In phase II, subjects receiving three weekly IV infusions of hcMSCs at 5x10 cells/kg showed a higher proportion of an eczema area and severity index (EASI)-50 response at week 12 compared to the placebo group (P=0.038). The differences between groups in the dermatology life quality index and pruritus numerical-rating scale scores were not statistically significant. Most adverse events were mild or moderate and resolved by the end of the study period.
CONCLUSIONS
Our findings demonstrate that hcMSCs treatment resulted in a significantly higher rate of achieving EASI-50 at 12 weeks compared to the control group in subjects with moderate to severe AD. The safety profile of hcMSCs treatment was acceptable. Further larger-scale studies are necessary to confirm these preliminary findings.
PubMed: 38944393
DOI: 10.1016/j.jaci.2024.06.013 -
Journal of Advanced Research Jun 2024The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular...
INTRODUCTION
The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-γ (IFN-γ) is a key inducer for the expression of immunosuppressive molecular profiles; however, the mechanism underlying this effect is unknown.
OBJECTIVES
To elucidate the regulation mechanism and biological functions of N-methyladenosine (mA) modification in the immunosuppressive functions by the IFN-γ-licensing MSCs.
METHODS
Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-γ-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/mA/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression.
RESULTS
We identified that IFN-γ increased the mA methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-γ-induced promotion of mA modification. IFN-γ activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an mA-YTHDF1-dependent manner; this effect further impacted the immunosuppressive capacity of IFN-γ licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-γ licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models.
CONCLUSION
Our results showed that mA modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA mediated by WTAP-YTHDF1 is involved in the regulation of IFN-γ licensing MSCs immunosuppressive abilities, and shed a light to enhance the clinical therapeutic potential of IFN-γ-licensing MSCs.
PubMed: 38944238
DOI: 10.1016/j.jare.2024.06.019 -
Seminars in Cancer Biology Jun 2024
PubMed: 38944133
DOI: 10.1016/j.semcancer.2024.06.002 -
Bone Jun 2024Recent research has revealed several important pathways of epigenetic regulation leading to transcriptional changes in bone cells. Rest Corepressor 2 (Rcor2) is a...
Recent research has revealed several important pathways of epigenetic regulation leading to transcriptional changes in bone cells. Rest Corepressor 2 (Rcor2) is a coregulator of Lysine-specific histone demethylase 1 (Lsd1), a demethylase linked to osteoblast activity, hematopoietic stem cell differentiation and malignancy of different neoplasms. However, the role of Rcor2 in osteoblast differentiation has not yet been examined in detail. We have previously shown that Rcor2 is highly expressed in mesenchymal stromal cells (MSC) and particularly in the osteoblastic lineage. The role of Rcor2 in osteoblastic differentiation in vitro was further characterized and we demonstrate here that lentiviral silencing of Rcor2 in MC3T3-E1 cells led to a decrease in osteoblast differentiation. This was indicated by decreased alkaline phosphatase and von Kossa stainings as well as by decreased expression of several osteoblast-related marker genes. RNA-sequencing of the Rcor2-downregulated MC3T3-E1 cells showed decreased repression of Rcor2 target genes, as well as significant upregulation of majority of the differentially expressed genes. While the heterozygous, global loss of Rcor2 in vivo did not lead to a detectable bone phenotype, conditional deletion of Rcor2 in limb-bud mesenchymal cells led to a moderate decrease in cortical bone volume. These findings were not accentuated by challenging bone formation by ovariectomy or tibial fracture. Furthermore, a global deletion of Rcor2 led to decreased white adipose tissue in vivo and decreased the capacity of primary cells to differentiate into adipocytes in vitro. The conditional deletion of Rcor2 led to decreased adiposity in fracture callus. Taken together, these results suggest that epigenetic regulation of mesenchymal stromal cell differentiation is mediated by Rcor2, which could thus play an important role in defining the MSC fate.
PubMed: 38944098
DOI: 10.1016/j.bone.2024.117180 -
International Journal of Biological... Jun 2024Pulmonary hypertension (PH) is a fatal disease with no existing curative drugs. NF-E2-related factor 2 (NRF2) a pivotal molecular in cellular protection, was...
Pulmonary hypertension (PH) is a fatal disease with no existing curative drugs. NF-E2-related factor 2 (NRF2) a pivotal molecular in cellular protection, was investigated in PH models to elucidate its role in regulating abnormal phenotypes in pulmonary artery cells. We examined the expression of NRF2 in PH models and explored the role of NRF2 in regulating abnormal phenotypes in pulmonary artery cells. We determined the expression level of NRF2 in lung tissues of PH model decreased significantly. We found that NRF2 was reduced in rat pulmonary artery endothelial cells (rPAEC) under hypoxia, while it was overexpressed in rat pulmonary artery smooth muscle cells (rPASMC) under hypoxia. Next, the results showed that knockdown NRF2 in rPAEC promoted endothelial-mesenchymal transformation and upregulated reactive oxygen species level. After the rPASMC was treated with siRNA or activator, we found that NRF2 could accelerate cell migration by affecting MMP2/3/7, and promote cell proliferation by regulating PDGFR/ERK1/2 and mTOR/P70S6K pathways. Therefore, the study has shown that the clinical application of NRF2 activator in the treatment of pulmonary hypertension may cause side effects of promoting the proliferation and migration of rPASMC. Attention should be paid to the combination of NRF2 activators.
PubMed: 38944076
DOI: 10.1016/j.ijbiomac.2024.133514 -
International Journal of Biological... Jun 2024Electrospun nanofibers exhibit a significant potential in the synthesis of nanostructured materials, thereby offering a promising avenue for enhancing the efficacy of...
Electrospun nanofibers exhibit a significant potential in the synthesis of nanostructured materials, thereby offering a promising avenue for enhancing the efficacy of wound care. The present study aimed to investigate the wound-healing potential of two biomacromolecules, PCL-Gelatin nanofiber adhered with bone marrow-derived mesenchymal stem cells (BMSCs). Characterisation of the nanofiber revealed a mean fiber diameter ranging from 200 to 300 nm, with distinctive elemental peaks corresponding to polycaprolactone (PCL) and gelatin. Additionally, BMSCs derived from bone marrow were integrated into nanofibers, and their wound-regenerative potential was systematically evaluated through both in-vitro and in-vivo methodologies. In-vitro assessments substantiated that BMSC-incorporated nanofibers enhanced cell viability and crucial cellular processes such as adhesion, and proliferation. Subsequently, in-vivo studies were performed to demonstrate the wound-healing efficacy of nanofibers. It was observed that the rate of wound healing of BMSCs incorporated nanofibers surpassed both, nanofiber and BMSCs alone. Furthermore, histomorphological analysis revealed accelerated re-epithelization and improved wound contraction in BMSCs incorporated nanofiber group. The fabricated nanofiber incorporated with BMSCs exhibited superior wound regeneration in animal model and may be utilised as a wound healing patch.
PubMed: 38944073
DOI: 10.1016/j.ijbiomac.2024.133447 -
International Journal of Biological... Jun 2024Nanocellulose (NC) is a promising biopolymer for various biomedical applications owing to its biocompatibility and low toxicity. However, it faces challenges in tissue...
Nanocellulose (NC) is a promising biopolymer for various biomedical applications owing to its biocompatibility and low toxicity. However, it faces challenges in tissue engineering (TE) applications due to the inconsistency of the microenvironment within the NC-based scaffolds with target tissues, including anisotropy microstructure and biomechanics. To address this challenge, a facile swelling-induced nanofiber alignment and a novel in situ biomineralization reinforcement strategies were developed for the preparation of NC-based scaffolds with tunable anisotropic structure and mechanical strength for guiding the differentiation of bone marrow-derived mesenchymal stem cells for potential TE application. The bacterial cellulose (BC) and cellulose nanofibrils (CNFs) based scaffolds with tunable swelling anisotropic index in the range of 10-100 could be prepared by controlling the swelling medium. The in situ biomineralization efficiently reinforced the scaffolds with 2-4 times and 10-20 times modulus increasement for BC and CNFs, respectively. The scaffolds with higher mechanical strength were superior in supporting cell growth and proliferation, suggesting the potential application in TE application. This work demonstrated the feasibility of the proposed strategy in the preparation of scaffolds with mechanical anisotropy to induce cells-directed differentiation for TE applications.
PubMed: 38944070
DOI: 10.1016/j.ijbiomac.2024.133515 -
Clinical Neurology and Neurosurgery Jun 2024Tumors located within the Meckel's cave (MC) pose a significant surgical challenge. Although several corridors to access this complex region have been described, the...
OBJECTIVE
Tumors located within the Meckel's cave (MC) pose a significant surgical challenge. Although several corridors to access this complex region have been described, the endoscopic transpterygoid approach (ETPA) and the endoscopic transorbital superior eyelid approach (ETOA) have emerged in recent years, as viable alternatives to traditional microsurgical transcranial approaches (MTA). To date, there is a limited literature on surgical series considering endoscopic-assisted approaches to the MC.
METHODS
We conducted a retrospective analysis of patients with primary MC tumors treated at our Institution between 2015 and 2022, specifically those managed via the ETPA assisted by intraoperative Endoscopic Diving Technique (EDT). Lesion resection extent was evaluated using pre- and post-intervention radiological images and surgical videos. Moreover, a literature review on ETPA was performed.
RESULTS
This series comprises 7 patients affected by 4 trigeminal schwannomas, 1 benign notochordal cell tumor, 1 dermoid cyst and 1 mesenchymal tumor. In 71 % of cases, trigeminal neuralgia was the presenting symptom. Post-operative clinical improvement was observed in all but one case. Notably, 85.7 % of patients achieved total or near-total resection (NTR), with the remaining case undergoing subtotal resection (STR). No significant intraoperative complications occurred, and no recurrences were observed during the mean follow-up period of 41 months.
CONCLUSIONS
In selected cases, the ETPA offers a direct and safe path to lesions located into the MC. This approach circumvents complications and constraints associated with ETOA or MTA. Moreover, the use of the EDT reduces manipulation of critical neurovascular structures, enhancing the efficacy of the ETPA.
PubMed: 38944020
DOI: 10.1016/j.clineuro.2024.108382 -
Biomedicine & Pharmacotherapy =... Jun 2024Adipose-derived mesenchymal stromal cells (AD-MSCs) are an essential issue in modern medicine. Extensive preclinical and clinical studies have shown that mesenchymal...
Adipose-derived mesenchymal stromal cells (AD-MSCs) are an essential issue in modern medicine. Extensive preclinical and clinical studies have shown that mesenchymal stromal/stem cells, including AD-MSCs, have specific properties (ability to differentiate into other cells, recruitment to the site of injury) of particular importance in the regenerative process. Ongoing research aims to elucidate factors supporting AD-MSC culture and differentiation in vitro. Angiopoietin-like proteins (ANGPTLs), known for their pleiotropic effects in lipid and glucose metabolism, may play a significant role in this context. Regeneration is a complex and dynamic process controlled by many factors. ANGPTL6 (Angiopoietin-related growth factor, AGF), among many activities modulated the biological activity of stem cells. This study examined the influence of synthesized AGF-derived peptides, designated as AGF9 and AGF27, on AD-MSCs. AGF9 and AGF27 enhanced the viability and migration of AD-MSCs and acted as a chemotactic factor for these cells. AGF9 stimulated chondrogenesis and lipid synthesis during AD-MSCs differentiation, influenced AD-MSCs cytokine secretion and modulated transcriptome for such basic cell activities as migration, transport of molecules, and apoptosis. The ability of AGF9 to modulate the biological activity of AD-MSCs warrants the consideration of this peptide a noteworthy therapeutic agent that deserves further investigation for applications in regenerative medicine.
PubMed: 38943988
DOI: 10.1016/j.biopha.2024.117052 -
Current Research in Translational... Jun 2024Hydrogels are commonly used as carriers for cell delivery due to their similarities to the extracellular matrix. A contraction-suppressed full-thickness wound model was...
Hydrogels are commonly used as carriers for cell delivery due to their similarities to the extracellular matrix. A contraction-suppressed full-thickness wound model was used to evaluate the therapeutic potential of Pluronic F127 (PF127) hydrogel loaded with adipose-derived stromal vascular fraction (AdSVF), mesenchymal stem cells (AdMSC), and conditioned media (AdMSC-CM) for the repair of wounds in a rabbit model. The experimental study was conducted on forty-eight healthy adult New Zealand white rabbits randomly divided into eight groups with six animals each and treated with AdSVF, AdMSC, and AdMSC-CM as an injectable or topical preparation. The healing potential of different adipose-derived cell-based and cell-free therapeutics was evaluated based on percentage wound healing, period of epithelialization, epidermal thickness, scar evaluation, histopathology analysis, histochemical evaluation, immunohistochemistry (collagen type I), and hydroxyproline assay by comparing with the positive and negative control. Collagen density analysis using different staining methods, immunohistochemistry, and hydroxyproline assay consistently showed that delivering AdMSC and AdMSC-CM in PF127 hydrogel enhanced epithelialization, collagen production, and organization, contributing to improved tissue strength and quality. Even though allogeneic AdSVF was found to promote wound healing in rabbits, it has a lower potential than AdMSC and AdMSC-CM. The wound healing potential of AdMSC and AdMSC-CM was enhanced when loaded in PF127 hydrogel and applied topically. Even though wounds treated with AdMSC outperformed AdMSC-CM, a significant difference in the healing quality was not observed in most instances, indicating almost similar therapeutic potential. The findings indicate that the wound healing potential of AdMSC and AdMSC-CM was enhanced when loaded in PF127 hydrogel and applied topically. These treatments promoted collagen production, tissue organization, and epidermal regeneration, ultimately improving overall healing outcomes.
PubMed: 38943898
DOI: 10.1016/j.retram.2024.103458