Bone Marrow Mesenchymal Stem Cells Transplantation Research Articles

Human decidual mesenchymal stem cells obtained from early pregnancy attenuate bleomycin-induced lung fibrosis by inhibiting inflammation and apoptosis

BackgroundDecidual mesenchymal stem cells (DMSCs) are easily obtained and exhibit strong anti-inflammatory and anti-apoptotic effects. Compared with bone marrow mesenchymal stem cells (BMSCs), their role in cell transplantation after idiopathic pulmonary fibrosis remains unclear. We investigated whether the transplantation of BMSCs and DMSCs could alleviate pulmonary inflammation and fibrosis in a bleomycin-induced mouse model of pulmonary fibrosis. MethodsBMSCs and DMSCs were derived from healthy donors. The anti-inflammatory and anti-apoptotic effects on both cell types were evaluated in vitro. The function of DMSCs in MLE-12 cells and mouse lung fibroblasts was examined using additional transwell coculture experiments in vitro. Twenty-one days after MSC transplantation, we examined the inflammatory factors in the serum and bronchoalveolar lavage fluid, collagen content, pathology, fibrotic area, lung function, and micro-computed tomography of the lung tissue. ResultsDMSCs exhibited better anti-inflammatory and anti-apoptotic effects than BMSCs on MLE-12 cells in vitro. In addition, DMSCs inhibited tumor growth factor β-dependent epithelial-mesenchymal transition in MLE-12 cells and attenuated mouse lung fibroblasts fibrosis. Furthermore, transplantation of DMSCs in the mouse idiopathic pulmonary fibrosis model significantly attenuated pulmonary inflammation and lung fibrosis compared with BMSCs transplantation. ConclusionsDMSCs exhibited better efficacy in improving pulmonary inflammation and lung fibrosis than BMSCs. Thus, DMSCs are a potential therapeutic target for pulmonary fibrosis.

PHD2 shRNA-Modified Bone Marrow Mesenchymal Stem Cells Facilitate Periodontal Bone Repair in Response to Inflammatory Condition.

To investigate whether bone marrow mesenchymal stem cells (BMMSCs) modulate periodontal bone repair through the hydroxylase domain-containing protein 2 (PHD2)/hypoxia- inducible factor-1 (HIF-1) signalling pathway in response to inflammatory conditions. Osteogenic differentiation of PHD2 shRNA-modified BMMSCs and the possible mechanism were explored in an inflammatory microenvironment stimulated by porphyromonas gingivalis lipopolysaccharide (Pg-LPS) in vitro. The effect of PHD2 gene-modified BMMSCs on periodontal bone loss was evaluated with experimental periodontitis. Pg-LPS stimulation greatly impaired the osteogenic differentiation of BMMSCs, whereas the silence of PHD2 significantly enhanced the osteogenesis of BMMSCs. More importantly, increased level of vascular endothelial growth factor (VEGF) was detected under Pg-LPS stimulation, which was verified to be associated with the augmented osteogenesis. In experimental periodontitis, PHD2-modified BMMSCs transplantation elevated osteogenic parameters and the expression of VEGF in periodontal tissue. This study highlighted that PHD2 gene silencing could be a feasible approach to combat inflammatory bone loss by rescuing the dysfunction of seed cells.

Bone marrow derived mesenchymal stem cells restored GLUT1 expression in the submandibular salivary glands of ovariectomized rats

ObjectiveLoss of ovarian function in menopause is commonly associated with salivary gland dysfunction. The aim is to study the possible therapeutic effect of bone marrow mesenchymal stem cells (BM-MSCs) on the altered structure of the submandibular salivary glands (SMGs) of ovariectomized rats. DesignTwenty-four female, adult, Wistar rats were used and distributed into three groups (8 rats/group). The control group included sham-operated rats. The ovariectomized group consisted of rats with removed ovaries. The third group consisted of ovariectomized rats received injections, via tail, of MSCs extracted from bone marrow of 3-weeks-old rat hind limb (BM-MSC group). Four weeks after BM-MSC transplantation, the bone mineral density (BMD) of the femur was detected. The SMG was dissected and processed for histological, immunohistochemical, and histomorphometric analyses. ResultsThe ovariectomized rats depicted low BMD in the femur. The SMG acini revealed atrophy. The ductal and acinar cells depicted vacuolization and abnormal nuclear histology. GLUT1 immunostaining was decreased in SMG ducts. The BM-MSC group resumed the normal SMG histology and GLUT1 immunolabelling. ConclusionsBM-MSC therapy restored the normal SMG structure and GLUT1 immunostaining in the treated ovariectomized rats, suggesting improved glucose transporting function.

The Effect of Bone Marrow Mesenchymal Stem Cells on Nestin and Sox-2 Gene Expression and Spatial Learning (Percent Alternation Y-Maze Test) against AlCl3-Induced Alzheimer's-like Pathology in a Rat Model.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual cognitive impairment, including loss of synapses and nerve cells involved in learning, memory, and habit formation processes. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) are multipotent cells. Because of their self-renewable, differentiation, and immunomodulatory capabilities, they are commonly used to treat many disorders. Hence, the current study intends to examine the effect of BM-MSCs transplantation on Aluminum chloride (AlCl3)-induced cognitive problems, an experimental model resembling AD's hallmarks in rats. The study was conducted in 2022 at The Biomedical Laboratory Faculty of Medicine, Andalas University, Indonesia. Adult male Wistar rats (three groups: negative control; no intervention+treatment with PBS; positive control: AlCl3+treatment with aqua dest; AlCl3+BM-MSCs: AlCl3+treatment with BM-MSCs, n=5 each) were treated daily with AlCl3 orally for five days. Stem cells were intraperitoneally injected into rats at a dose of 1x106 cells/rat. The same quantity of phosphate-buffered saline was given to the control group. One month after stem cell injection, the rat brain tissue was removed and placed in the film bottles that had been created. The expression of neural progenitor cell markers, including nestin and sex-determining Y-box 2 (SOX-2), was analyzed using real-time polymerase chain reaction (RT-PCR). Rats' cognitive and functional memory were examined using Y-maze. Data were analyzed using SPSS software (version 26.0) with a one-way analysis of variance (ANOVA) test. The gene expression of nestin (29.74±0.42), SOX-2 (31.44±0.67), and percent alternation of Y-maze (67.04±2.28) increased in the AlCl3+BM-MSCs group compared to that in the positive control group. RT-PCR analysis indicated that nestin (P<0.001) and SOX-2 (P<0.001) were significantly enhanced in the AlCl3+BM-MSCs group compared to the positive control group. This group also indicated an increased percent alternation of Y-maze (P<0.001) in the AlCl3+BM-MSCs group compared to the positive control group. Due to its potential effects on cell therapy, BM-MSCs were found effective in a rat model of AD on the impairment of the rats' behavior and increased expression of neural progenitor cell markers.

Sclerostin Transduced Bone Marrow Mesenchymal Stem Cells Promote Fracture Healing in Rats Through the Wnt/β-Catenin Signal Pathway.

The prognosis of fracture is directly related to several factors. Due to the limitations of existing treatment strategies, there are still many fractures with poor healing. Bone marrow mesenchymal stem cells (BMSCs) have the potential to differentiate into osteoblasts and chondrocytes. Therefore, BMSC transplantation is promised as an effective method for treating bone fractures. We aim to explore whether silently expressing sclerostin gene (SOST) can promote bone formation through the SOST/Wnt/β-catenin signal pathway. We isolated rat BMSCs and the target gene (SOST shRNA) was transduced into them for osteogenic induction. The results showed that SOST significantly inhibited the proliferation and osteogenic differentiation of BMSCs during osteogenic induction, whereas silently expressing SOST not only increased the number of surviving BMSCs but also promoted the expression of osteogenesis-related proteins RUNX2, osteoprotegerin, Collagen I (COL-I), and bone morphogenetic protein-2 during osteogenic induction. The results of imaging examination in rats show that downregulating the expression of SOST can promote the formation of bony callus and the transformation of cartilage tissue into normal bone tissue, and then accelerate the healing of osteoporotic fracture. In addition, we also found that SOST silencing can activate the Wnt/β-catenin pathway to achieve these effects. In conclusion, SOST silencing can promote the proliferation and osteogenic differentiation of BMSCs in situ, and therefore may enhance the therapeutic efficiency of BMSC transplantation in OPF.

Stem cell grafts enhance endogenous extracellular vesicle expression in the stroke brain

Endogenous brain repair occurs following an ischemic stroke but is transient, thus unable to fully mount a neuroprotective response against the evolving secondary cell death. Finding a treatment strategy that may render robust and long-lasting therapeutic effects stands as a clinically relevant therapy for stroke. Extracellular vesicles appear to be upregulated after stroke, which may represent a candidate target for neuroprotection. In this study, we probed whether transplanted stem cells could enhance the expression of extracellular vesicles to afford stable tissue remodeling in the ischemic stroke brain. Aged rats were initially exposed to the established ischemic stroke model of middle cerebral artery occlusion then received intravenous delivery of either bone marrow-derived mesenchymal stem cell transplantation or vehicle. A year later, the animals were assayed for brain damage, inflammation, and extracellular vesicle expression. Our findings revealed that while core infarction was not reduced, the stroke animals transplanted with stem cells displayed a significant reduction in peri-infarct cell loss that coincided with downregulated Iba1-labeled inflammatory cells and upregulated CD63-positive extracellular vesicles that appeared to be co-localized with GFAP-positive astrocytes. Interestingly, grafted stem cells were not detected at one year post-transplantation period, suggesting that the extracellular vesicles likely originated within the host brain. That long-lasting functional benefits persisted in the absence of surviving transplanted stem cells, but with upregulation of endogenous extracellular vesicles, advances the concept that transplantation of stem cells acutely after stroke propels host extracellular vesicles to the ischemic brain, altogether promoting chronic brain remodeling.

Transplantation of Wnt5a-modified Bone Marrow Mesenchymal Stem Cells Promotes Recovery After Spinal Cord Injury via the PI3K/AKT Pathway.

Spinal cord injury (SCI) is a severe neurological condition that can lead to paralysis or even death. This study explored the potential benefits of bone marrow mesenchymal stem cell (BMSC) transplantation for repairing SCI. BMSCs also differentiate into astrocytes within damaged spinal cord tissues hindering the cell transplantation efficacy, therefore it is crucial to enhance their neuronal differentiation rate to facilitate spinal cord repair. Wnt5a, an upstream protein in the non-classical Wnt signaling pathway, has been implicated in stem cell migration, differentiation, and neurite formation but its role in the neuronal differentiation of BMSCs remains unclear. Thus, this study investigated the role and underlying mechanisms of Wnt5a in promoting neuronal differentiation of BMSCs both in vivo and in vitro. Wnt5a enhanced neuronal differentiation of BMSCs in vitro while reducing astrocyte differentiation. Additionally, high-throughput RNA sequencing revealed a correlation between Wnt5a and phosphoinositide 3-kinase (PI3K)/protein kinase B(AKT) signaling, which was confirmed by the use of the PI3K inhibitor LY294002 to reverse the effects of Wnt5a on BMSC neuronal differentiation. Furthermore, transplantation of Wnt5a-modified BMSCs into SCI rats effectively improved the histomorphology (Hematoxylin and eosin [H&E], Nissl and Luxol Fast Blue [LFB] staining), motor function scores (Footprint test and Basso-Beattie-Bresnahan [BBB]scores)and promoted neuron production, axonal formation, and remodeling of myelin sheaths (microtubule associated protein-2 [MAP-2], growth-associated protein 43 [GAP43], myelin basic protein [MBP]), while reducing astrocyte production (glial fibrillary acidic protein [GFAP]). Therefore, targeting the Wnt5a/PI3K/AKT pathway could enhance BMSC transplantation for SCI treatment.

Transplanted MSCs promote alveolar bone repair via hypoxia-induced extracellular vesicle secretion.

Mesenchymal stem cell (MSC) therapy is a potential strategy for promoting alveolar bone regeneration. This study evaluated the effects and mechanisms of transplanted MSCs on alveolar bone repair. Mouse alveolar bone defect model was treated using mouse bone marrow mesenchymal stem cell (BMSC) transplantation. The bone repair was evaluated by micro-CT and Masson staining. The conditioned medium of hypoxia-treated BMSCs was co-cultured with normal BMSCs invitro to detect the regulatory effect of transplanted MSCs on the chemotactic and migratory functions of host cells. The mechanisms were investigated using Becn siRNA transfection and western blotting. BMSC transplantation promoted bone defect regeneration. The hypoxic microenvironment induces BMSCs to release multiple extracellular vesicle (EV)-mediated regulatory proteins that promote the migration of host stem cells. Protein array analysis, western blotting, GFP-LC3 detection, and Becn siRNA transfection confirmed that autophagy activation in BMSCs plays a key role during this process. The local hypoxic microenvironment induces transplanted MSCs to secrete a large number of EV-mediated regulatory proteins, thereby upregulating the migration function of the host stem cells and promoting alveolar bone defect regeneration. This process depends on the autophagy-related mechanism of the transplanted MSCs.

METTL3 inhibits BMSC apoptosis and facilitates osteonecrosis repair via an m6A-IGF2BP2-dependent mechanism

Hypoxia-induced apoptosis of bone marrow mesenchymal stem cells (BMSCs) limits the efficacy of their transplantation for steroid-induced osteonecrosis of the femoral head (SONFH). As apoptosis and RNA methylation are closely related, exploring the role and mechanism of RNA methylation in hypoxic apoptosis of BMSCs is expected to identify new targets for transplantation of BMSCs for SONFH and enhance transplantation efficacy. We performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA-seq on a hypoxia-induced apoptosis BMSC model and found that the RNA methyltransferase-like 3 (METTL3) is involved in hypoxia-induced BMSC apoptosis. The expression of METTL3 was downregulated in BMSCs after hypoxia and in BMSCs implanted in osteonecrosis areas. Knockdown of METLL3 under normoxic conditions promoted apoptosis of BMSCs. In contrast, overexpression of METTL3 promoted the survival of BMSCs under hypoxic conditions, and overexpression of METTL3 promoted the survival of BMSCs in the osteonecrosis area and the repair of the osteonecrosis area. Regarding the mechanism, the m6A levels of the mRNAs of anti-apoptotic genes Bcl-2, Mcl-1, and BIRC5 were significantly increased upon the overexpression of METTL3 under hypoxic conditions, which promoted the binding of Bcl-2, Mcl-1, and BIRC5 mRNAs to IGF2BP2, enhanced the mRNA stability, and increased the protein expression of the three anti-apoptotic genes. In conclusion, overexpression of METTL3 promoted m6A modification of mRNAs of Bcl-2, Mcl-1, and BIRC5, promoted the binding of IGF2BP2 to the above-mentioned mRNAs, enhanced mRNA stability, inhibited hypoxia-induced BMSC apoptosis, and promoted repair of SONFH, thereby providing novel targets for transplantation of BMSCs for SONFH.

Application and advance in repair of spinal cord injury by transplantation of bone marrow mesenchymal stem cells

Objectives: To summarize retrospectively the application and advance of bone marrow mesenchymal stem cells (BMSCs) in the recovery of spinal cord injury (SCI). Methods: An online search at Pubmed between 2023 and 1967 was conducted to identify the related articles with the keywords “bone marrow mesenchymal stem cells, spinal cord injury”, and the language was limited to English. The identified articles were extensively reviewed, focusing on these aspects: the biological characteristics of BMSCs, the various experimental models and clinical studies on the repair of SCI by transplantation of BMSCs, the mechanisms of immigration and therapy, and the problems and prospects. Results: The various experimental models and clinical studies demonstrated that great advances were made in the repair of SCI by transplantation of BMSCs. After transplantation, BMSCs could immigrate to the position of the injured spinal cord, and partially differentiate into nerve-like cells and secrete neurotrophic factors, so as to promote the repair and regeneration of nervous tissue and recovery of neurological function. Conclusions: With the profound researches of transgenic treatment and associated cell transplantation, BMSCs can extend their application on the recovery of SCI owing to the self-renewing and multi-directional differentiation.

Combination of bone marrow mesenchymal stem cells and moxibustion restores cyclophosphamide-induced premature ovarian insufficiency by improving mitochondrial function and regulating mitophagy

BackgroundPremature ovarian insufficiency (POI) is a major cause of infertility. In this study, we aimed to investigate the effects of the combination of bone marrow mesenchymal stem cells (BMSCs) and moxibustion (BMSCs-MOX) on POI and evaluate the underlying mechanisms.MethodsA POI rat model was established by injecting different doses of cyclophosphamide (Cy). The modeling of POI and the effects of the treatments were assessed by evaluating estrous cycle, serum hormone levels, ovarian weight, ovarian index, and ovarian histopathological analysis. The effects of moxibustion on BMSCs migration were evaluated by tracking DiR-labeled BMSCs and analyzing the expression of chemokines stromal cell-derived factor 1 (Sdf1) and chemokine receptor type 4 (Cxcr4). Mitochondrial function and mitophagy were assessed by measuring the levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), ATP, and the mitophagy markers (Drp1, Pink1, and Parkin). Furthermore, the mitophagy inhibitor Mdivi-1 and the mitophagy activator CCCP were used to confirm the role of mitophagy in Cy-induced ovarian injury and the underlying mechanism of combination therapy.ResultsA suitable rat model of POI was established using Cy injection. Compared to moxibustion or BMSCs transplantation alone, BMSCs-MOX showed improved outcomes, such as reduced estrous cycle disorders, improved ovarian weight and index, normalized serum hormone levels, increased ovarian reserve, and reduced follicle atresia. Moxibustion enhanced Sdf1 and Cxcr4 expression, promoting BMSCs migration. BMSCs-MOX reduced ROS levels; upregulated MMP and ATP levels in ovarian granulosa cells (GCs); and downregulated Drp1, Pink1, and Parkin expression in ovarian tissues. Mdivi-1 significantly mitigated mitochondrial dysfunction in ovarian GCs and improved ovarian function. CCCP inhibited the ability of BMSCs-MOX treatment to regulate mitophagy and ameliorate Cy-induced ovarian injury.ConclusionsMoxibustion enhanced the migration and homing of BMSCs following transplantation and improves their ability to repair ovarian damage. The combination of BMSCs and moxibustion effectively reduced the excessive activation of mitophagy, which helped prevent mitochondrial damage, ultimately improving ovarian function. These findings provide a novel approach for the treatment of pathological ovarian aging and offer new insights into enhancing the efficacy of stem cell therapy for POI patients.Graphical abstract

Safety and Efficacy of Bone Marrow Mesenchymal Stem Cells in the Treatment of Ischemic Stroke: A Meta-Analysis.

We aimed to systematically evaluate the efficacy and safety of bone marrow mesenchymal stem cells (BMMSCs) in the treatment of ischemic stroke. Six Chinese and English databases were searched for related randomized controlled trials from the establishment of the databases to 28 February 2023. Two investigators performed screening and a comprehensive analysis and evaluated the quality of the studies. They extracted information from the included studies, and managed and analzsed the data using RevMan 5.4.1 software (The First College of Clinical Medical Science, China Three Gorges University). Finally, they performed meta and heterogeneity analyses and created a risk-of-bias map. A total of 13 high-quality articles were included. The National Institute of Health Stroke Scale (NIHSS) scores of the experimental group differed significantly from those of the control group at 3 months (I2 <50%, mean difference [MD] = -2.88, P < 0.001) after treatment. The Fugl-Meyer assessment (FMA) scores of the experimental group varied significantly from that of the control group at 1 month (I2 >50%, MD = 15.94, P < 0.001), 3 months (I2 >50%, MD = 12.71, P < 0.001), and 6 months (I2 >50%, MD = 13.76, P < 0.001) after treatment, and the overall difference (I2 >50%, MD = 14.38, P ≤ 0.001) was significant. The functional independence measure (FIM) scores were significantly different from that of the control group at 1 month (I2 >50%, MD = 20.04, P = 0.02), 3 months (I2 >50%, MD = 15.51, P < 0.001), and 6 months (I2 >50%, MD = 13.46, P = 0.03). There was no significant increase in adverse events compared with the traditional treatment regimen. To some extent, BMMSC transplantation can improve the neurological deficit, motor function, and daily living ability of patients with ischemic stroke.

NR4A1 PROMOTES OSTEOGENIC DIFFERENTIATION OF MESENCHYMAL STEM CELLS AND IMPROVES INFLAMMATION-INHIBITED BONE REGENERATION

Stem cell therapy is an effective means to address the repair of large segmental bone defects. However, the intense inflammatory response triggered by the implants severely impairs stem cell differentiation and tissue regeneration. High-dose transforming growth factor β1 (TGF-β1), the most locally expressed cytokine in implants, inhibits osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) and promotes tissue fibrosis, severely compromising the efficacy of stem cell therapy. Small molecule inhibitors of TGF-β1 can be used to ameliorate the osteogenic disorders caused by high concentrations of TGF-β1, but systemic inhibition of TGF-β1 function will cause strong adverse effects. How to find safe and reliable molecular targets to antagonize TGF-β1 remains to be elucidated. Orphan nuclear receptor Nr4a1, an endogenous inhibitory molecule of TGF-β1, suppresses tissue fibrosis, but its role in BMSC osteogenesis is unclear. We found that TGF-β1 inhibited Nr4a1 expression through HDAC4. Overexpression of Nr4a1 in BMSCs reversed osteogenic differentiation inhibited by high levels of TGF- β1. Mechanistically, RNA sequencing showed that Nr4a1 activated the ECM-receptor interaction and Hippo signaling pathway, which in turn promoted BMSC osteogenesis. In bone defect repair and fracture healing models, transplantation of Nr4a1-overexpressing BMSCs into C57BL/6J mice or treatment with the Nr4a1 agonist Csn-B significantly ameliorated inflammation-induced bone regeneration disorders. In summary, our findings confirm the endogenous inhibitory effect of Nr4a1 on TGF- β1 and uncover the effectiveness of Nr4a1 agonists as a therapeutic tool to improve bone regeneration, which provides a new solution strategy for the treatment of clinical bone defects and inflammatory skeletal diseases.

YTHDC1 Mitigates Apoptosis in Bone Marrow Mesenchymal Stem Cells by Inhibiting NfƙBiα and Augmenting Cardiac Function Following Myocardial Infarction.

The therapeutic efficacy of bone marrow mesenchymal stem cells (BMSCs) in myocardial infarction (MI) is hindered by poor cell survival. This study explored the role of N6-methyladenosine (m6A) regulation, specifically YTHDC1, in improving BMSC transplantation for MI. By screening m6A-related regulators in hypoxia and serum deprivation (HSD)-induced BMSC apoptosis, YTHDC1 was found to be downregulated. Overexpression of Ythdc1 in BMSCs reduced apoptosis markers, reactive oxygen species (ROS) release, and improved cell survival under HSD conditions. Conversely, Ythdc1 knockdown enhanced apoptosis. In rat MI models, transplantation of Ythdc1-overexpressing BMSCs improved cardiac function and reduced myocardial fibrosis. Mechanistically, YTHDC1 interacts with nuclear factor kappa B (NF-κB) inhibitor-alpha mRNA, suggesting its involvement in BMSC survival pathways. This study identifies YTHDC1 as a potential target to enhance BMSC efficacy in MI therapy.

Immunoregulatory paracrine effect of mesenchymal stem cells and mechanism in the treatment of osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease caused by chronic inflammation that damages articular cartilage. At present, the treatment of OA includes drug therapy to relieve symptoms and joint replacement therapy for advanced OA. However, these palliatives cannot truly block the progression of the disease from the immunological pathogenesis of OA. In recent years, bone marrow mesenchymal stem cell (BMSC) transplantation has shown great potential in tissue engineering repair. In addition, many studies have shown that BMSC paracrine signals play an important role in the treatment of OA through immune regulation and suppressing inflammation. At present, the mechanism of inflammation-induced OA and the use of BMSC transplantation in joint repair have been reviewed, but the mechanism and significance of BMSC paracrine signals in the treatment of OA have not been fully reviewed. Therefore, this article focused on the latest research progress on the paracrine effects of BMSCs in the treatment of OA and the related mechanisms by which BMSCs secrete cytokines to inhibit the inflammatory response, regulate immune balance, and promote cell proliferation and differentiation. In addition, the application potential of BMSC-Exos as a new type of cell-free therapy for OA is described. This review aimed to provide systematic theoretical support for the clinical application of BMSC transplantation in the treatment of OA.

Synergistic effects of electroacupuncture and bone marrow mesenchymal stem cell transplantation on rat intrauterine adhesion： an observation.

To investigate the effects of electroacupuncture(EA) combined with bone marrow mesen-chymal stem cells(BMSCs) transplantation on the endometrium of rats with intrauterine adhesions(IUA), so as to explore the possible mechanisms underlying their combined therapeutic effects. Forty adult female SD rats were randomly divided into control, model, cell, and combined groups. The IUA rat model was established using a dual injury method of mechanical scratching and lipopolysaccharide infection. After successful modeling, on days 1, 3, and 7, rats in the model group received tail vein injection of phosphate buffered solution, while rats in the cell group received tail vein injection of BMSCs suspension for BMSCs transplantation；and rats in the combined group received BMSCs transplantation combined with EA treatment (2 Hz/15 Hz, 1-2 mA), targeting the "Guanyuan"(CV4), bilateral "Zusanli"(ST36) and "Sanyinjiao"(SP6) for 20 min daily for 3 consecutive estrous cycles. After intervention, uterine tissue was collected from 5 rats in each group. Histological analysis was performed using hematoxylin and eosin staining to evaluate endometrial thickness and glandular number. Masson staining was used to assess endometrial fibrosis area. Immunohistochemistry was performed to detect the positive expressions of vascular endothelial growth factor(VEGF), proliferating cell nuclear antigen(PCNA), and estrogen receptor(ER). Western blot analysis was conducted to determine the protein expressions of homeobox A10(HoxA10) and leukemia inhibitory factor(LIF), both key regulators of endometrial receptivity. The remaining 5 rats in each group were co-housed with male rats, and the uterine function recovery was evaluated by assessing the number of embryo implantations. Compared with the control group, the model group showed thinning endometrium(P<0.001), decreased glandular number(P<0.001), increased endometrial fibrosis area(P<0.001), reduced positive expressions of VEGF, PCNA, ER, expressions of HoxA10 and LIF, and decreased embryo implantation number (P<0.001) on the injured side of the uterus. Compared with the model group, the combined group showed a reversal of the aforementioned indicators(P<0.001, P<0.01)；the cell group exhibited thicker endometrium(P<0.001) and reduced endometrial fibrosis area(P<0.001). Compared with the cell group, the combined group showed increased endometrial thickness(P<0.01), elevated glandular number(P<0.05), significantly decreased endometrial fibrosis area(P<0.05), enhanced positive expressions of VEGF, PCNA and ER, expressions of HoxA10 and LIF in the endometrium, and a significant increase in embryo implantation number (P<0.001, P<0.05, P<0.01) on the injured side of the uterus, indicating better results than the cell group. The combination of EA and BMSCs synergistically promotes the repair of damaged endometrium, improves endometrial morphology, reduces fibrosis levels, enhances vascular regeneration and matrix cell proliferation, improves endometrial receptivity, which ultimately facilitates embryo implantation.

Effects of Biodegradable Biomaterials Combined with Bone Marrow Mesenchymal Stem Cells Transplantation on Neurological Function in Rats with Ischemic Cerebral Infarction

The aim of this research was to explore the effects of degradable biomaterial self-polypeptide nanofiber scaffolds plus bone marrow mesenchymal stem cells (BMSCs) on the behavior and neurological function of rats with focal ischemic cerebral infarction (ICI). BMSCs were isolated and cultured. The self-assembling peptides and BMSCs were mixed to prepare self-assembling peptides/BMSCs (SAP/BMSCs) material. BMSCs and SAP/BMSCs were injected into the carotid artery of rats in Model group. The rats without ligation were used as Sham group. Longa 5 and modified neurological severity scores (mNSS) of each group were evaluated. The adhesive removal test and forelimb asymmetry test were used to examine the behavior of the rats. The brain tissues were collected, and the infarct size, neuronal apoptosis, and the protein expression of Nogo-A and lipoprotein a (LPA) in the hippocampus were detected by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining, TdT-mediated dUTP nick end labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), and Western blot. The results indicated that the fiber diameter of the self-polymerizing peptide material was about 12 nm, and the length was about 100-250 nm. The cells grew well after composite BMSCs. Compared with Sham group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, and neuronal apoptosis rate were increased, interleukin 6 (IL-6) and Tumor Necrosis Factor alpha (TNF-α) were raised, IL-10 was decreased, and Nogo-A and LPA protein was increased in Model group (P &lt; 0.05). As against Model group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, neuronal apoptosis rate, IL-6 and TNF-α were clearly decreased, and IL-10 was raised, and Nogo-A and LPA protein was clearly decreased in BMSCs and SAP/BMSCs groups (P &lt; 0.05). As against BMSCs group, Longa 5, mNSS score, adhesive removal time, forelimb asymmetry test score, cerebral infarction volume, and neuronal apoptosis rate were clearly decreased, and IL-6 and TNF-α were decreased, and IL-10 was raised, and Nogo-A and LPA protein was decreased in SAP/BMSCs group (P &lt; 0.05). Early transplantation of BMSCs can improve the neurobehavioral symptoms of ICI rats and inhibit neuronal apoptosis and inflammatory response. The effect of self-polymerizing peptide nanofiber scaffold plus BMSCs transplantation in ICI is superior to the transplantation of BMSCs alone.

Tauroursodeoxycholic Acid Inhibited Apoptosis and Oxidative Stress in H2O2-Induced BMSC Death via Modulating the Nrf-2 Signaling Pathway: the Therapeutic Implications in a Rat Model of Spinal Cord Injury

Spinal cord injury (SCI) is a prevalent and significant injury to the central nervous system, resulting in severe consequences. This injury is characterized by motor, sensory, and excretory dysfunctions below the affected spinal segment. Transplantation of bone marrow mesenchymal stem cells (BMSCs) has emerged as a potential treatment for SCI. However, the low survival as well as the differentiation rates of BMSCs within the spinal cord microenvironment significantly limit their therapeutic efficiency. Tauroursodeoxycholic acid (TUDCA), an active ingredient found in bear bile, has demonstrated its neuroprotective, antioxidant, and antiapoptotic effects on SCI. Thus, the present study was aimed to study the possible benefits of combining TUDCA with BMSC transplantation using an animal model of SCI. The results showed that TUDCA significantly enhanced BMSC viability and reduced apoptosis (assessed by Annexin V-FITC, TUNEL, Bax, Bcl-2, and Caspase-3) as well as oxidative stress (assessed by ROS, GSH, SOD, and MDA) both in vitro and in vivo. Additionally, TUDCA accelerated tissue regeneration (assessed by HE, Nissl, MAP2, MBP, TUJ1, and GFAP) and improved functional recovery (assessed by BBB score) following BMSC transplantation in SCI. These effects were mediated via the Nrf-2 signaling pathway, as evidenced by the upregulation of Nrf-2, NQO-1, and HO-1 expression levels. Overall, these results indicate that TUDCA could serve as a valuable adjunct to BMSC transplantation therapy for SCI, potentially enhancing its therapeutic efficacy.

Peripheral Blood Grafts Vs Bone Marrow Grafts in Young Acute Myeloid Leukemia Patients with HLA-Matched Sibling Donors Undergoing Myeloablative Conditioning

In allogeneic hematopoietic cell transplantation (allo-HSCT), graft source has been changed from bone marrow grafts (Bone marrow stem cell, BMSC) to peripheral blood grafts (Peripheral blood stem cell, PBSC) mobilized by granulocyte colony-stimulating factor. PBSC transplantation is known to have numerous advantages over BMSC, including faster engraftment, improved survival outcomes, and for the donor, the elimination of invasive marrow harvesting procedure under general anesthesia. However, previous studies regarding graft source included various hematologic malignancies and lacked consistency in conditioning intensity and disease status at allo-HSCT. Still, there are limited data on the comparison of graft sources specifically in patients with acute myeloid leukemia (AML) undergoing myeloablative conditioning. In this background, we conducted an analysis to investigate the impact of graft source on transplant outcomes in AML patients who underwent HLA A, B, C, DR-matched sibling donor (MSD) HSCT with myeloablative conditioning. This study was a retrospective, single-center study for patients with AML who received first allo-HSCT from 2002 to 2022. We included the patients aged &amp;lt; 60 at the time of allo-HSCT, in a state of complete remission (CR) or CR with incomplete hematologic recovery, from a MSD, and underwent myeloablative conditioning. We classified the patients into three groups: the BMSC graft group (BMSC group), the PBSC graft group without antithymocyte globulin (ATG) (PBSC/ATG- group), and the PBSC graft group with ATG (PBSC/ATG+ group). Patients who received both PBSC and BMSC grafts were excluded from the analysis. We examined the differences in overall survival (OS), relapse-free survival (RFS) among these three groups. A total of 480 patients were included in this analysis, with 234 patients in the BMSC group, 66 patients in the PBSC/ATG+ group, and 180 patients in the PBSC/ATG- group. BMSC transplantation was mostly performed before 2010, whereas PBSC transplantation started in 2007, and allo-HSCT with ATG administration were conducted after 2014. In the PBSC/ATG+ group, the median ATG dose was 2.5 mg/kg (Interquartile range, IQR: 1.6-2.5). The BMSC group tended to be younger at the time of HSCT (median 38 years [31-46]) compared to the other groups (median age of PBSC/ATG+ group: 44 years [37-51], PBSC/ATG- group: 46 years [39-51], p&amp;lt;0.01). Of total patients in the three groups, there was only 1 case of neutrophil engraftment failure (in the PBSC/ATG- group) and 5 cases of platelet engraftment failure (3 in the BMSC group and the other 2 in the PBSC/ATG- group). BMSC patients demonstrated superior OS compared to PBSC patients, with the most pronounced difference was observed over PBSC/ATG- group (Figure A). Similar trends were presented in relapse-free survival (RFS) as well. After adjusting for other covariates through multivariate Cox modeling, the difference caused by the graft source remained significant, particularly in terms of RFS (Figure B). The hazard ratios for RFS of PBSC comparing to BMSC were as follows; PBSC/ATG+: 1.64 [1.04-2.58], PBSC/ATG-: 1.95 [1.45-2.63]. In conclusion, Despite the clear differences in allo-HSCT era between groups, even BMSC patients underwent allo-HSCT at an earlier time, patients receiving BMSC grafts showed superior survival compared to those receiving PBSC grafts in young AML patients undergoing MSD myeloablative allo-HSCT. Parallel evaluation of the transplant outcomes between BMSC and PBSC would be crucial for assessing the advantages and disadvantages of PBSC and BMSC grafts in this setting.

Bone Marrow Mesenchymal Stem Cells Alleviate Acute Severe Pancreatitis and Promote Lung Repair via Inhibiting NLRP3 Inflammasome in Rat.

Acute severe pancreatitis (SAP) is a severe acute abdominal disease, which can lead to pancreatic infection and necrosis as well as distant organ damage. Bone marrow mesenchymal stem cells (BMSCs) can exert anti-inflammatory effect on SAP, while NLRP3 inflammasomes play an important role in the inflammatory response. This study aimed to investigate whether BMSCs exert anti-inflammatory effect on SAP by inhibiting NLRP3 inflammasome. The rat SAP model was established. Serum amylase, lipase and inflammatory factor levels were measured by ELISA, and the level of tissue injury was assessed by HE staining. The expression of NLRP3 inflammasome was detected by PCR, Western Blot and immunohistochemistry. ML385 was used to block Nrf2 pathway, aiming to investigate whether Nrf2 pathway was involved in the therapeutic effect of BMSCs on SAP by regulating NLRP3 inflammasome expression. In SAP rats, NLRP3 inflammasome was activated, which became more evident over time. After transplantation of BMSCs, the NLRP3 inflammasome expression decreased at both mRNA and protein levels, the serum levels of amylase, lipase and inflammatory factors decreased, and the pathological scores of the pancreas and lung were both improved. After blocking the Nrf2 pathway, the NLRP3 inflammasome expression increased in the injured pancreas and lung, and the inflammation deteriorated, which inhibited the therapeutic effects of BMSCs on SAP. The therapeutic effect of BMSC on SAP is at least partially ascribed to the inhibition of NLRP3 inflammasome, and Nrf2 pathway mediates the therapeutic effect of BMSC on SAP by inhibiting NLRP3 inflammasome.