Marrow Mesenchymal Stem Cell Transplantation Research Articles

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.

Combination Therapy of Bone Marrow Mesenchymal Stem Cell Transplantation and Electroacupuncture for the Repair of Intrauterine Adhesions in Rats: Mechanisms and Functional Recovery.

Transplantation of bone marrow mesenchymal stem cells (BMSCs) has demonstrated promising clinical utility in the treatment of endometrial injury and the restoration of fertility. However, since the efficacy of BMSCs after transplantation is not stable, it is very important to find effective ways to enhance the utilisation of BMSCs. Electroacupuncture (EA) has some positive effects on the chemotaxis of stem cells and diseases related to uterine injury. In this study, we established the intrauterine adhesion (IUA) model of the Sprague-Dawley rat using lipopolysaccharide infection and mechanical scratching. Phosphate-buffered saline, BMSCs alone, and BMSCs combined with EA were randomly administered to the rats. Fluorescent cell labelling showed the migration of transplanted BMSCs. H&E staining, Masson staining, Western blot, immunohistochemistry, ELISA, and qRT-PCR were utilised to detect changes in endometrial morphology and expressions of endometrial receptivity-related factors, endometrial pro-inflammatory factors, and fibrosis factors. Finally, we conducted a fertility test to measure the recovery of uterine function. The results showed that EA promoted transplanted BMSCs to migrate into the injured uterus by activating the SDF-1/CXCR4 axis. Endometrial morphology showed the most significant improvement in the BMSC + EA group. The expressions of endometrial pro-inflammatory factors and fibrosis indexes in the BMSC + EA group were lower than those in the model and BMSC groups. Further studies revealed that the expression of endometrial receptivity-related factors and the number of embryos implanted on day 8 of gestation increased in the BMSC + EA group compared with the model group and the BMSC group.

A self-amplifying loop of TP53INP1 and P53 drives oxidative stress-induced apoptosis of bone marrow mesenchymal stem cells

Bone marrow mesenchymal stem cell (BMSC) transplantation is a promising regenerative therapy; however, the survival rate of BMSCs after transplantation is low. Oxidative stress is one of the main reasons for the high apoptosis rate of BMSCs after transplantation, so there is an urgent need to explore the mechanism of oxidative stress-induced apoptosis of BMSCs. Our previous transcriptome sequencing results suggested that the expression of P53-induced nuclear protein 1 (TP53INP1) and the tumor suppressor P53 (P53) was significantly upregulated during the process of oxidative stress-induced apoptosis of BMSCs. The present study further revealed the role and mechanism of TP53INP1 and P53 in oxidative stress-induced apoptosis in BMSCs. Overexpression of TP53INP1 induced apoptosis of BMSCs, knockdown of TP53INP1 alleviated oxidative stress apoptosis of BMSCs. Under oxidative stress conditions, P53 is regulated by TP53INP1, while P53 can positively regulate the expression of TP53INP1, so the two form a positive feedback loop. To clarify the mechanism of feedback loop formation. We found that TP53INP1 inhibited the ubiquitination and degradation of P53 by increasing the phosphorylation level of P53, leading to the accumulation of P53 protein. P53 can act on the promoter of the TP53INP1 gene and increase the expression of TP53INP1 through transcriptional activation. This is the first report on a positive feedback loop formed by TP53INP1 and P53 under oxidative stress. The present study clarified the formation mechanism of the positive feedback loop. The TP53INP1–P53 positive feedback loop may serve as a potential target for inhibiting oxidative stress-induced apoptosis in BMSCs.

Bone Marrow Mesenchymal Stem Cell-Derived Exosomes Ameliorate Aging-Induced BTB Impairment in Porcine Testes by Activating Autophagy and Inhibiting ROS/NLRP3 Inflammasomes via the AMPK/mTOR Signaling Pathway.

As a pivotal player in spermatogenesis, the blood-testis barrier (BTB) made from junction apparatus coexisting in Sertoli cells (SCs) is impaired with an increase in age and ultimately induces spermatogenic dysfunction or even infertility. It has been corroborated that bone marrow mesenchymal stem cell (BMSC) transplantation can efficiently repair and regenerate the testicular function. As vital mediators of cell-to-cell communication, MSC-derived exosomes (Exos) can directly serve as therapeutic agents for tissue repair and regeneration. However, the therapeutic value of BMSC-Exos in aging-induced BTB damage remains to be confirmed. In this study, we explored that the old porcine testes had defective autophagy, which aggravated BTB disruption in SCs. BMSC-Exos could decrease ROS production and NLRP3 inflammasome activation but enhanced autophagy and tight junction (TJ) function in D-gal-triggered aging porcine SCs and mouse model testes, according to in vitro and in vivo experiments. Furthermore, rapamycin, NAC, MCC950, and IL-1Ra restored the TJ function in D-gal-stimulated aging porcine SCs, while BMSC-Exos' stimulatory effect on TJ function was inhibited by chloroquine. Moreover, the treatment with BMSC-Exos enhanced autophagy in D-gal-induced aging porcine SCs by means of the AMPK/mTOR signal transduction pathway. These findings uncovered through the present study that BMSC-Exos can enhance the BTB function in aging testes by improving autophagy via the AMPK/mTOR signaling pathway, thereby suppressing ROS production and NLRP3 inflammasome activation.

Bone marrow mesenchymal stem cell transplantation protects rats from myocardial infarction by regulating TXNIP/NLRP3 pathway-mediated inflammation and fibrosis

Bone marrow mesenchymal stem cell transplantation protects rats from myocardial infarction by regulating TXNIP/NLRP3 pathway-mediated inflammation and fibrosis

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization.

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

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.

Transplantation of MiR-28-5p-Modified BMSCs Promotes Functional Recovery After Spinal Cord Injury

Traumatic spinal cord injury (TSCI) is a prevalent central nervous system condition that imposes a significant burden on both families and society, affecting more than 2 million people worldwide. Recently, there has been increasing interest in bone marrow mesenchymal stem cell (BMSC) transplantation as a promising treatment for spinal cord injury (SCI) due to their accessibility and low immunogenicity. However, the mere transplantation of BMSCs has limited capacity to directly participate in the repair of host spinal cord nerve function. MiR-28-5p, identified as a key differentially expressed miRNA in spinal cord ischemia–reperfusion injury, exhibits differential expression and regulation in various neurological diseases. Nevertheless, its involvement in this process and its specific regulatory mechanisms in SCI remain unclear. Therefore, this study aimed to investigate the potential mechanisms through which miR-28-5p promotes the neuronal differentiation of BMSCs both in vivo and in vitro. Our results indicate that miR-28-5p may directly target Notch1, thereby facilitating the neuronal differentiation of BMSCs in vitro. Furthermore, the transplantation of lentivirus-mediated miR-28-5p-overexpressed BMSCs into SCI rats effectively improved footprint tests and Basso, Beattie, and Bresnahan (BBB) scores, ameliorated histological morphology (hematoxylin–eosin [HE] and Nissl staining), promoted axonal regeneration (MAP2 and growth-associated protein 43 [GAP43]), and facilitated axonal remyelination (myelin basic protein [MBP]). These findings may suggest that miR-28-5p-modified BMSCs could serve as a therapeutic target to enhance the behavioral and neurological recovery of SCI rats.

Let-7a promotes periodontal bone regeneration of bone marrow mesenchymal stem cell aggregates via the Fas/FasL-autophagy pathway.

Periodontal bone regeneration using bone marrow mesenchymal stem cell (BMMSC) transplantation is a promising method; however, the method for osteogenic differentiation of BMMSCs needs to be improved. In this research, we sought to identify the roles of let-7a in the osteogenesis of BMMSCs and to provide a potential method for periodontal bone regeneration. Our previous study revealed that Fas/FasL is a target of let-7a. In this study, we demonstrated that let-7a overexpression significantly enhanced BMMSC-CAs osteogenesis both invitro and invivo. Mechanistically, upregulation of Fas/FasL using the rfas/rfaslg plasmid obstructed the osteogenesis of BMMSCs by inhibiting autophagy. Furthermore, we confirmed that overexpression of let-7a activated autophagy and alleviated the inhibited osteogenesis by the autophagy inhibitor 3-MA and the rfas/rfaslg plasmid of BMMSCs. In general, our findings showed that let-7a promoted the osteogenesis of BMMSCs through the Fas/FasL-autophagy pathway, suggesting that the application of let-7a in BMMSC-CAs based periodontal bone regeneration could be a promising strategy.

Electroacupuncture combined with bone marrow mesenchymal stem cell transplantation promotes repair of thin endometrium by regulating SDF-1/CXCR4 signaling

It is to explore, based on stromal cell derived factor 1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) signal axis, whether the electroacupuncture (EA) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation can promote thin endometrium regeneration and improve endometrial receptivity, so as to further study its mechanisms underlying improvement of promoting BMSCs homing to repair thin endometrium. Thirty matured female SD rats were randomly divided into normal control , model , BMSCs transplantation (BMSCs), BMSCs+AMD3100 (a specific antagonist of CXCR4, BMSCs+AMD3100), BMSCs+EA, and BMSCs+EA+AMD3100 groups, with 5 rats in each group. The thin endometrial model was established by intrauterine injection of 95% ethanol during the period of estrus. Rats of the model group received intravenous injection of PBS solution (tail vein) on day 1, 3 and 7 of modeling and intraperitoneal injection of normal saline once daily for 3 estrous cycles. Rats of the BMSCs group received intravenous injection of BMSCs suspension on day 1,3 and 7 of modeling, and those of the BMSCs+EA group received BMSCs transplantation and EA stimulation. EA (2 Hz/15 Hz, 1 mA) was applied to "Guanyuan" (CV4) and bilateral "Sanyinjiao"(SP9), "Zigong" (EX-CA1) for 15 min, once daily for 3 estrous cycles. Rats of the BMSCs+AMD3100 group received intravenous injection of BMSCs suspension (1×106/mL) and intraperitoneal injection of AMD3100 (5 mg/kg), and those of the BMSCs+EA+AMD3100 group received administration of BMSCs, AMD3100 and EA, with both groups being once daily for 3 estrous cycles. H.E. staining was used to observe histopathological changes of endometrium tissues, and immunohistochemistry was used to detect the expressions of cytokeratin (CK19) and vimentin in endometrium (for evaluating the damage and repair of endometrium). The expression levels of homeobox A10 (HOXA10), leukemia inhibitory factor (LIF), SDF-1 and CXCR4 proteins were detected by Western blot, and those of SDF-1 and CXCR4 mRNAs in the endometrium detected by real-time PCR. In comparison with the normal control group, the number of endometrial glands, the immunoactivity of CK19 and vimentin, the expression leve-ls of HOXA10, LIF and CXCR4 proteins and CXCR4 mRNA were significantly down-regulated (P<0.01), and the expression levels of SDF-1 protein and mRNA significantly up-regulated (P<0.05) in the model group. Compared with the model group, the number of endometrial glands, the immunoactivity of CK19 and vimentin, and the expression levels of HOXA10, LIF, CXCR4 proteins and CXCR4 mRNA in the BMSCs group, and the number of endometrial glands, the immunoactivity of CK19 and vimentin, the expression levels of HOXA10, LIF, CXCR4 proteins and CXCR4 mRNA, and SDF-1 protein and mRNA in the BMSCs+EA group were significantly up-regulated (P<0.05, P<0.01). Compared to the BMSCs group, the number of endometrial glands, and the expression levels of LIF, CXCR4 proteins and CXCR4 mRNA in the BMSCs+EA group were up-regulated (P<0.01, P<0.05)； the number of endometrial glands, the immunoactivity of CK19 and vimentin, the expression levels of HOXA10, LIF, CXCR4 proteins and CXCR4 mRNA in the BMSCs+AMD3100 group were down-regulated (P<0.01). Compared to the BMSCs+EA group, the number of endometrial glands, the immunoactivity of CK19 and vimentin, the expression levels of HOXA10, LIF, CXCR4 proteins and CXCR4 mRNA in the BMSCs+EA+AMD3100 group were down-regulated (P<0.01). Results of H.E. staining showed thin endometrium with absence of epithelial cells, and sparse glands and blood vessels, with smaller glandular cavity in the model group, which was relative milder in BMSCs and BMSCs+EA groups. EA can promote the transfer of transplanted BMSCs to the damaged site through SDF-1/CXCR4 signaling related stem cell homing, thereby promoting thin endometrial regeneration, repairing endometrial injury, and improving endometrial tolerance in rats with thin endometrium.

Screening of the best time window for MSC transplantation to treat acute myocardial infarction with SDF-1α antibody-loaded targeted ultrasonic microbubbles: An in vivo study in miniswine.

The present study aimed to screen the best time window for the transplantation of bone marrow mesenchymal stem cells (MSCs) after acute myocardial infarction (MI) through targeted ultrasound microbubbles loaded with SDF-1α antibody. Thirty-six MI miniswine were randomly divided into six experimental groups according to the duration after infarction (1 day, 3 days, 1 week, 2 weeks, 3 weeks, and 4 weeks after infarction). MSCs were labeled with BrdU and then injected through the coronary artery in the stem cell transplantation group to detect the number of transplanted MSCs at different time points after MI. Three miniswine were randomly selected as the control group (sham operation: open chest without ligation of the coronary artery). All SDF-1α groups and control groups were injected with a targeted microbubble ultrasound contrast agent. The values of the myocardial perfusion parameters (A, β, and A × β) were determined. A T, β T, and (A × β)T varied with time and peaked 1 week after MI (P < 0.05). The number of transplanted stem cells in the myocardium through coronary injection of MSCs at 1 week was the greatest and consistent with the changing tendency of A T, β T, and (A × β)T (r = 0.658, 0.778, 0.777, P < 0.05). β T(X), (A × β)T(X), and the number of transplanted stem cells was used to establish the regression equation as follows: Y = 36.11 + 17.601X; Y = 50.023 + 3.348X (R 2 = 0.605, 0.604, P < 0.05). The best time window for transplanting stem cells was 1 week after MI. The myocardial perfusion parameters of the SDF-1α targeted contrast agent can be used to predict the number of transplanted stem cells in the myocardial tissue.

#2733 TRANSPLANTATION OF MESENCHYMAL STEM CELLS - NEW FOCUS OF IMMUNE CORRECTION IN TREATMENT OF LUPUS NEPHRITIS

Abstract Background and Aims Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by the production of organ-specific autoantibodies to components of cell nucleus, immune complex lesions of the connective tissue, and the development of irreversible damage of internal organs. Chronic relapsing course of SLE, resistance to steroid and immunosuppressive therapy, toxic effects of drugs determine the need of search for new therapeutic approaches. Objective To evaluate the efficacy and safety of bone marrow mesenchymal stem cell (MSC) transplantation with high-dose immunosuppressive therapy (HIST) in SLE patients. Method A total amount of 15 patients with a diagnosis of SLE (ACR criteria) refractory to classical immunosuppressive therapy was examined. Patients were divided into 2 groups: patients from the main group underwent MSCs transplantation with HIST (n = 10), while the control group was observed on the background of traditional immunosuppressive therapy without cell transplantation (n = 5). Both groups were comparable in age, gender of patients, duration and severity of the disease. The SELENA-SLEDAI was used to determine SLE activity. Cytokines were examined by ELISA (IL-1Β, IL-4, IL-10, TNF-Α), antibodies to double-stranded DNA (anti-dsDNA) and anti-nuclear antibodies (ANA) by indirect immunofluorescence. Morphological examination of kidney included Masson-trichrome histochemistry for collagen fibers, silvering reaction for elastic and reticulin fibers, immunofluorescent and immunohistochemical methods. The safety assessment included registration of various adverse events during and after transplantation. Statistical analysis was carried out by Kruskal-Wallis test using STATISTICA 6.1. Results Monitoring the effectiveness of autologous stem cell transplantation in SLE patients showed a significant 2-fold decrease in activity by SELENA-SLEDAI score from 14.67±1.15 to 7.33±1.15 points after 12 months (p = 0.03). In the control group, this indicator remained unchanged and amounted to 15.0±0.87 points despite ongoing immunosuppressive therapy. Clinical efficacy was noted in all patients receiving HIST and MSC transplantation, which was confirmed by a significant decrease in daily proteinuria from 2,48±0,77 to 1,06±0,56 g/l, a decrease in the value of antibodies to DNA (from 443,28±547,53 to 187,8±146,60) and blood cytokines (significantly for TNF-Α), and an increase in the level of complement (though insignificantly). According to kidney biopsy data, after MSC transplantation with HIST, positive dynamics consisted in an increase in the number of reticulin fibers in the vascular loops of the glomeruli, as well as a decrease in the immune inflammatory process in the vascular loops of the glomeruli by immunofluorescence analysis for the spectrum of antibodies (Figure 1). In most patients of the main group, the doses of methylprednisolone and immune suppressants were reduced. Chills during transplantation was registered in one patient; no other unwanted adverse events were identified. Conclusion MSC transplantation in combination with HIST is significantly more effective than traditional immunosuppressive therapy in SLE according to clinical and laboratory data. The method is safe, allows decreasing signs of autoimmune aggression and can be used in cases of refractoriness, low efficiency or intolerance of standard therapy for SLE.

Bone marrow-derived mesenchymal stem cells transplantation downregulates pancreatic NF-κB and pro-inflammatory cytokine profile in rats with type I and type II-induced diabetes: a comparison study

AbstractDiabetes mellitus (DM) is a set of metabolic diseases defined by a persistently high blood sugar level. Mesenchymal stem cells (MSCs) are a novel potential therapeutic intervention in treatments of various diseases, which is also referred to as regenerative medicine. We aimed to compare the pro-inflammatory cytokines’ levels during bone marrow mesenchymal stem cells (BM-MSCs) transplantation in rats with induced type I (T1D) and type II diabetes (T2D). Thirty-five male Sprague dawley rats were divided into: Group I: the healthy control group, group II: untreated rats with streptozotocin (STZ)-induced T1D (65 mg/kg), group III: BM-MSCs treated rats with STZ-induced T1D, group IV: untreated rats with high-fat diet (HFD)/STZ-induced T2D (40 mg/kg), group V: BM-MSCs-treated rats with HFD/STZ-induced T2D. Biochemical, histopathological and immunohistochemical studies were applied. Our results showed that transplantation reduced hyperglycemia and increased insulin levels in both induced T1D and T2D. Also, reductions in the levels of inflammatory markers were noticed after transplantation that was coincided with nuclear factor-kappa B (NF-кB) immunohistochemical results; which showed negative or moderate cytoplasmic reactivity in treated groups III and V. These results indicated the ability of BM-MSCs transplantation to modulate the pro-inflammatory cytokine profile during treatment of both T1D and T2D.

Bone marrow mesenchymal stem cell transplantation alleviates radiation-induced myocardial fibrosis through inhibition of the TGF-β1/Smad2/3 signaling pathway in rabbit model

Backgroundand purpose: Radiotherapy (RT) is an effective treatment for most malignant chest tumors. However, radiation-induced myocardial fibrosis (RIMF) is a serious side effect of RT. Currently, due to the mechanism of RIMF has not been fully elucidated, there is a lack of effective therapeutic approach. In this study, we aimed to investigate the role and possible mechanisms of bone marrow mesenchymal stem cells (BMSCs) in the therapy of RIMF. Materials and methodsTwenty-four New Zealand white rabbits were allotted into four groups (n = 6). Rabbits in the Control group received neither irradiation nor treatment. A single dose of 20 Gy heart X-irradiation was applied to the RT group, RT + PBS group and RT + BMSCs group. Rabbits in the RT + PBS group and RT + BMSCs group were injected with 200 μL PBS or 2 × 106 cells via pericardium puncture 24 h following irradiation, respectively. Echocardiography was used to test the cardiac function; Then the heart samples were collected, and processed for histopathological, Western blot and immunohistochemistry investigations. ResultsIt was observed that BMSCs have therapeutic effect on RIMF. Compared with the Control group, inflammatory mediators, oxidative stress and apoptosis were significantly increased, meanwhile, cardiac function was remarkably decreased in the RT group and RT + PBS group. However, in the BMSCs group, BMSCs significantly improved cardiac function, decreased inflammatory mediators, oxidative stress and apoptosis. Furthermore, BMSCs remarkably reduced the expression level of TGF-β1 and the phosphorylated-Smad2/3. ConclusionsIn conclusion, our research indicates BMSCs have the potential to alleviate RIMF through TGF-β1/Smad2/3 and would be a new therapeutic approach for patients with myocardial fibrosis.

Young human PRP promotes the rejuvenation of aged bone marrow mesenchymal stem cells and the therapeutic effect on ischemic heart disease

Bone marrow mesenchymal stem cell (BMSC) transplantation is an effective treatment for ischemic heart disease, but its effectiveness is limited in aging populations due to decreased viability and injury resistance of autologous BMSCs. The purpose of this study was to compare the differences between platelet-rich plasma (PRP) derived from young and aged donors, and to investigate whether it is possible to enhance the viability of elderly human BMSCs (hBMSCs) using PRP, and to apply the rejuvenated hBMSCs for the treatment of ischemia. The key growth factors in PRP, including IGF-1, EGF, and PDGF-BB, were found to have significant differences between young and old individuals. Our results showed that PRP could enhance the proliferation, cloning, and rejuvenation of aged hBMSCs, with a superior effect observed when using PRP derived from younger donors. In the SD rat infarct model, the application of hBMSCs optimized with PRP resulted in a smaller infarct area compared to the control group (NC-Old). Specifically, the infarct area in the group treated with hBMSCs cultured with PRP from young donors (YPRP-Old) was smaller than that in the group treated with PRP from older donors (OPRP-Old). The survival rate of hBMSCs after transplantation, the number of neovascularization in the infarct area of SD rats and the recovery of cardiac function were all higher in the YPRP-Old group than the OPRP-Old group, and both groups were better than the group treated with aged hBMSCs alone. In conclusion, PRP may provide a new stem cell transplantation therapy option for ischemic diseases.

Andrographolide-treated bone marrow mesenchymal stem cells-derived conditioned medium protects cardiomyocytes from injury by metabolic remodeling.

Bone marrow mesenchymal stem cells (BMSCs) transplantation therapy providing a great hope for the recovery of myocardial ischemic hypoxic injury. However, the microenvironment after myocardial injury is not conducive to the survival of BMSCs, which limits the therapeutic application of BMSCs. Our previous study has confirmed that the survival of BMSCs cells in the glucose and serum deprivation under hypoxia (GSDH) is increased after Andrographolide (AG) pretreatment, but whether this treatment could improve the effect of BMSCs in repairing of myocardial injury has not been verified. We first treated H9C2 with GSDH to simulate the microenvironment of myocardial injury in vitro, then we pretreated rat primary BMSCs with AG, and collected conditioned medium derived from BMSCs (BMSCs-CM) and conditioned medium derived from AG-pretreated BMSCs (AG-BMSCs-CM) after GSDH treatment. And they were used to treat H9C2 cells under GSDH to further detect oxidative stress and metabolic changes. The results showed that AG-BMSCs-CM could be more advantageous for cardiomyocyte injury repair than BMSCs-CM, as indicated by the decrease of apoptosis rate and oxidative stress. The changes of mitochondria and lipid droplets results suggested that AG-BMSCs-CM can regulate metabolic remodeling of H9C2 cells to repair cell injury, and that AMPK was activated during this process. This study demonstrates, for the first time, the protective effect of AG-BMSCs-CM on GSDH-induced myocardial cell injury, providing a potential therapeutic strategy for clinical application.

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway.

Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.

Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway. Neural Regen Res. 2023 May;18(5)1067–1075

Despite the fact that a number of therapeutic modalities have shown promise in the treatment of spinal cord injury (SCI), focusing solely on one aspect of recovery will not lead to successful and useful regeneration in people. The current study targets an integrated approach of neuroprotection and rehabilitation strategies to treat spinal cord injury, increasing nerve regeneration and functional recovery through functional sensorimotor training and cell transplantation. Sun et al., 2022 investigated the synergistic effect of exercise training and bone marrow mesenchymal stem cell transplantation which could promote active recovery in a mice model of thoracic contusive spinal cord injury.

Aspirin reverses inflammatory suppression of chondrogenesis by stabilizing YAP.

Bone marrow mesenchymal stem cells (BMMSCs) transplantation methods are promising candidates for osteoarthritis (OA) treatment. However, inflammatory factors (such as TNF-α) that occur at cell transplantation sites are critical factors that impair the effectiveness of the treatment. Previous studies have shown that aspirin (AS) had a regulatory role in stem cell differentiation. However, little is known about the role of AS on the chondrogenesis of BMMSCs. The purpose of this study is to explore the protective role of AS against the negative effects of TNF-α on BMMSC chondrogenesis. In this study, we investigated the effects of AS and TNF-α on BMMSCs chondrogenesis by performing the Alcian Blue staining, safranin O-fast green staining, haematoxylin and eosin staining, and immunohistochemical staining, as well as real-time RT-PCR and western blot assays. Our results demonstrated that TNF-α inhibited chondrogenic differentiation of BMMSCs by disrupting the balance of cartilage metabolism and promoting oxidative stress in BMMSCs, while AS treatment attenuated these effects. Furthermore, a detailed molecular mechanistic analysis indicated that Yes-associated protein (YAP) played a critical regulatory role in this process. In addition, AS treatment mitigated the progression of cartilage degeneration in a mouse destabilization of the medial meniscus (DMM) model. AS alleviated the inhibitory effect of TNF-α on chondrogenesis of BMMSCs by stabilizing YAP, which may provide new therapeutic strategies for OA treatment.