Injection Of Mesenchymal Stem Cells Research Articles

Overexpression of Nrf2 in Mesenchymal Stem Cells Promotes Migration and Invasion of B- Acute Lymphoblastic Leukemia Cells

Background and objective:B -Acute lymphoblastic leukemia (B-ALL) is one of the most difficult cancers to treat in adults, especially recurrence and drug resistance are still the biggest challenges for B-ALL. In recent years, a new concept has been proposed, that is, the interaction between bone marrow microenvironment and leukemic cells can reduce the sensitivity of leukemic cells to chemotherapy. The components of bone marrow microenvironment (BMM) have been shown to mediate the occurrence and development of leukemia. There is growing evidence that leukemic cells teach the bone marrow microenvironment, change its function and establish leukemia protective interactions with stromal cells and immune cells. Bone marrow mesenchymal stem cells (Bone marrow mesenchymal stem cells, BM-MSCs) are stromal cells in leukemia microenvironment, which can promote the progression of leukemia under certain conditions. Nuclear factor erythroid related factor 2 (Nrf2) is an important transcription factor and a regulator of cellular antioxidant response, which regulates the expression of genes encoding antioxidant enzymes to prevent various oxidative changes. It has been confirmed that the high expression of Nrf2 in leukemic cells is related to drug resistance and poor prognosis of leukemia. However, the interaction mechanism of Nrf2 overexpression in MSCs on B-cell acute lymphoblastic leukemia (B-ALL) cells is not clear. We will for the first time propose the mechanism of Nrf2 overexpression in MSCs on the migration and invasion of B-ALL leukemic cells. Methods :Bone marrow nucleated cells were detected in 16 patients with complete remission (B-ALL/CR), 12 patients with relapsed/refractory (B-ALL/R/R) ALL and 10 normal controls. The expression of Nrf2 was detected byreal-time PCR and Western Blot. In vitro cell experiments, real-time PCR and Western Blot were used to detect the expression of Nrf2 in mesenchymal stem cells (MSCs) alone and in the co-culture of MSCs and cell lines (Nalm-6/RS4:11) express the situation Mouse model experiment in vivo, transwell chamber experiment in vitro, three-dimensional (3D) cell culture model, lentivirus transfection, WB and PCR were used to explore the possible mechanism of Nrf2 overexpression in mesenchymal stem cells on the migration and invasion of B-ALL cells. Results: In clinical samples, the expression of Nrf2 in B-ALL-R/R group was significantly higher than that in ALL-CR group and normal control group, suggesting that the expression of Nrf2 was closely related to the recurrence and drug resistance of ALL. In vitro cell experiment, the expression level of Nrf2 in MSCs co-cultured with cell line (NALM-6/RS4:11) was higher than that in MSC cultured alone(P < 0.05). By regulating the overexpression of Nrf2 in MSCs, it can significantly promote the growth, proliferation, migration and invasion of leukemia cells, and promote the expression of CXCR4 in tumor tissues. We further regulated the expression of Nrf2 in MSCs. The results showed that it significantly promoted the migration and invasion of NALM-6/RS4:11 cells. We concluded that the overexpression of Nrf2 in MSCs promotes the migration and invasion of leukemic cells by activating the activity of SDF-1-CXCR4 axis. In vivo experiments, we used tail vein injection of MSCs and B-ALL leukemia cells to explore the protective effect of Nrf2 overexpression in mesenchymal stem cells on leukemia cells and promote extramedullary infiltration of leukemia. The results showed that the infiltration degree of extramedullary organs of mice after combined infusion of two kinds of cells was significantly higher than that of leukemia cells alone, and the survival time of mice was significantly shortened after combined infusion. After statistical treatment, the difference was statistically significant (P < 0.05). Conclusion:The expression of Nrf2 in MSCs may be a key component in mediating the interaction between MSCs and ALL cells. This result may provide a new entry point for deepening all disease progression mechanisms and finding more promising targeted therapies.On the other hand, activation of PI3K/AKTERK1/2 signaling pathway in B-ALL cells further promoted the evolution of B-ALL. This may provide new ideas for findingpotential therapeutic targets for B-ALL extramedullary infi ltration, and help to further solve the current problem of B-ALL relapse and refractory.

Effect of Intra-ovarian Injection of Mesenchymal Stem Cells or its Conditioned Media on Repeated OPU-IVEP Outcomes in Jersey Heifers and Its Relationship with Follicular Fluid Inflammatory Markers.

Repeated Ovum Pick Up (OPU) could have a detrimental effect on ovarian function, reducing In Vitro Embryo Production (IVEP). The present study examined the therapeutic effect of adipose-derived Mesenchymal Stem Cells (MSCs) or its Conditioned Medium (ConM) on ovarian trauma following repeated OPU. Resolvin E1 (RvE1) and Interleukin-12 (IL-12) were investigated as biomarkers. Jersey heifers (n=8) experienced 11 OPU sessions including 5 pre-treatment and 6 treatment sessions. Heifers received intra-ovarian administration of MSCs or ConM (right ovary) and Dulbecco's Modified Phosphate Buffer Saline (DMPBS; left ovary) after OPU in sessions 5 and 8 and 2 weeks after session 11. The concentrations of RvE1 and IL-12 in follicular fluid was evaluated on sessions 1, 5, 6, 9, and 4 weeks after session 11. Following each OPU session, the IVEP parameters were recorded. Intra-ovarian administration of MSCs, ConM, and DMPBS did not affect IVEP parameters (p>0.05). The concentration of IL-12 in follicular fluid increased at the last session of pre-treatment (Session 5; p<0.05) and remained elevated throughout the treatment period. There was no correlation between IL-12 and IVEP parameters (p>0.05). However, RvE1 remained relatively high during the pre-treatment and decreased toward the end of treatment period (p<0.05). This in turn was associated with decline in some IVEP parameters (p<0.05). Intra-ovarian administration of MSCs or ConM during repeated OPU did not enhance IVEP outcomes in Bos taurus heifers. The positive association between RvE1 and some of IVEP parameters could nominate RvE1 as a promising biomarker to predict IVEP parameters following repeated OPU.

Therapeutic effects and potential mechanisms of endoscopic submucosal injection of mesenchymal stem cells on chronic atrophic gastritis

Previous studies have demonstrated the rejuvenating and restorative actions of mesenchymal stem cells (MSCs) in multiple diseases, but their role in reversing chronic atrophic gastritis (CAG) is not well understood owing to their low efficiency in homing to the stomach. In this work, we investigated the therapeutic effect of umbilical cord-derived MSCs (UC-MSCs) on CAG by endoscopic submucosal injection and preliminarily explored possible mechanisms in vitro. MSCs and normal saline (NS) were injected into the submucosa of the stomach in randomly grouped CAG rabbits. Therapeutic effects on serum indices and histopathology of the gastric mucosa were analyzed in vivo at 30 and 60 days after MSCs injection. GES-1 cells were co-cultured with MSCs in vitro using a Transwell system and cell viability, proliferation, and migration ability were detected. Additionally, in view of the potential mechanisms, the relative protein expression levels of apoptosis, autophagy and inflammation in vitro were explored by Western Blotting. We found that submucosal injection of MSCs up-regulated serum indices (G-17, PGI and PGI/PGII) and alleviated histopathological damage to the gastric mucosa in CAG rabbits. Co-culture of GES-1 cells with MSCs improved cell viability, proliferation, and migration ability, while suppressing apoptosis. We also observed a reduction in the expression of apoptosis indicators, including Bax and cleaved caspase-3, in GES-1 cells after co-culture with MSCs in vitro. Our findings suggest that submucosal injection of MSCs is a promising approach for reversing CAG, and attenuating apoptosis plays a potential role in this process.

MORPHOLOGICAL FEATURES OF THE REPARATIVE PROCESS IN THE PLASTIC SECTION OF THE MUSCLE-APONEUROTIC DEFECT IN THE EXPERIMENT USING STEM CELLS

Abstract. Anterior abdominal wall hernia repair is one of the most common procedures in general surgery. Very often, the parameters of the quality of life of operated patients with ventral hernias of the anterior abdominal wall during the fi rst year after the operation, according to a number of criteria, are signifi cantly better with alloplastic with polypropylene mesh, in contrast to the use of hernioplasty with the use of inert suture material. Hernias of the anterior abdominal wall (ventral hernias) most often occur after surgical intervention on the organs of the abdominal cavity and are considered postoperative complications arising in anatomically weak areas and under the infl uence of mechanical factors. The goal of the work. To experimentally investigate the eff ect of mesenchymal stem cells on the regeneration of muscle fi bers and their reparative properties in the area of postoperative wounds. When modeling a muscle- aponeurotic defect of the anterior abdominal wall with plasticity with own tissues and plasticity with an allograft in combination with injections of mesenchymal stem cells. The study was conducted on 38 white rats of both sexes, the initial weight of each animal was 215±12 g, the experimental animals were kept in the same conditions with full compliance with bioethical norms. All animals of groups 1 and 2 were experimentally modeled a muscle- aponeurotic defect of the anterior abdominal wall by an acute method up to 2.5 cm in diameter, followed by layer-by-layer suturing of this defect with a continuous wraparound single-row suture, «Vicryl» 3/0 with a barb was used as suture material with a needle In the 2nd group, plastic surgery was performed using the «on lay» technique with polypropylene mesh and suture material «Vicryl» 3/0 with a barbed needle, and mesenchymal stem cell injections were additionally performed. At the plastic site of the muscle- aponeurotic defect, the tissue of the anterior abdominal wall was taken in full layers for further histological examination. Histological examination of the wound tissues of animals of the control group 10 days after surgery showed that the wound defect was fi lled with granulation tissue at an early stage of maturation. After 30 days, the wound defect was fi lled with young loose connective tissue, in which there were sporadic islands of granulation tissue. In the area of the wound defect of 2 groups of experimental animals, after 10 days we detected maturing granulation tissue. Visually, the area of the lesion itself decreased. On the 30th day of the study, there was no granulation tissue, the wound defect was fi lled with fully matured newly formed and vascularized connective tissue. During the histological examination, it was found that as a result of the combined use of polypropylene mesh and stem cells, the regeneration of the wound defect is intensifi ed and its healing is accelerated.

Transplantation of bone marrow-derived mesenchymal stem cells ameliorated dopamine system impairment in a D-galactose-induced brain ageing in rats.

Ageing is the primary risk factor for Parkinson's disease. Progressive motor and coordination decline that occurs with ageing has been linked to nigrostriatal dysfunction. Few studies have investigated the efficacy of mesenchymal stem cells in ameliorating the structural and functional alterations in the ageing nigrostriatal system. This study is the first to evaluate the effects of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose- induced rat model of nigrostriatal ageing. BMMSCs were intravenously injected once every 2 weeks for 8 weeks. The transplanted cells survived, migrated to the brain, and differentiated into dopaminergic neurones and astrocytes. BMMSC transplantation improved locomotor activity, restored dopaminergic system function, preserved atrophic dopaminergic neurones in the substantia nigra, exerted antioxidative effects, and restored neurotrophic factors. Our findings demonstrate the efficacy of BMMSC injection in a nigrostriatal ageing rat model, and suggest that these cells may provide an effective therapeutic approach for the ageing nigrostriatal system.

Autologous mesenchymal stem cell therapy for diabetic men with erectile dysfunction. Is it promising? A pilot study.

to assess safety and efficacy of autologous mesenchymal bone marrow stem cell injection in penile cavernosal tissue for erectile dysfunction therapy in diabetic men. The subjects of this study were diabetic men suffering erectile dysfunction, non-responding to maximum dose of oral PDE5I. Mesenchymal bone marrow stem cells were aspirated and injected after preparation in both corpora cavernosa at 3, 9 o'clock position. Erectile function was assessed by the International Index of Erectile Function and penile Doppler study, before and after 6 months after injection. 4 patients out of 10 achieve hard erection adequate for satisfactory coitus, and 2 patients achieved penile hardness with addition of pharmacological therapy with sildenafil 100mg. Peak systolic velocity increased significantly in 4 patients (2 arteriogenic and 2 mixed erectile dysfunction), from 12∼22 cm/s to 32∼69 cm/s. Variations in end-diastolic velocity increased substantially in 2 patients with venogenic insufficiency alone at follow-up from 4∼5 cm /s to -4∼-3 cm/s. Despite promising stem cell treatment efficacy for patients with erectile dysfunction, more clinical studies and researches are still warranted.

Umbilical Cord Mesenchymal Stem Cells Overexpressing Heme Oxygenase-1 Promotes Symptoms Recovery in Cystitis Rats by Alleviating Neuroinflammation.

Interstitial cystitis/bladder pain syndrome (IC/BPS) seriously reduces the patient's quality of life, yet current therapies only provide partial relief. In the spinal dorsal horn (SDH), neuroinflammation plays a pivotal role in the development of IC. Injection of human umbilical cord mesenchymal stem cells (hUMSCs) to reduce inflammation is an effective strategy, and heme oxygenase-1 (HO-1) exhibits anti-nociceptive effect in neuroinflammatory pain. This study aimed to test the therapeutic effects of hUMSCs overexpressing HO-1 on cyclophosphamide-induced cystitis rat model. Cystitis rats were transplanted with altered cells and then assessed for 3 weeks. A series of behavioral measurements would be trial including suprapubic mechanical allodynia, depressive-like behaviors, micturition frequency, and short-term memory function. Additionally, western blot, immunofluorescence staining, and ELISA kit test for anti-inflammation effect. HUMSCs were capable of being transduced to overexpress HO-1. Injection of hUMSCs overexpressing HO-1 was more effective than hUMSCs alone in alleviating behavioral symptoms in rats. Furthermore, hUMSCs overexpressing HO-1 inhibited the activation of glial and TLR4/p65/NLRP3 pathway, decreased the levels of pro-inflammatory cytokines in the SDH region. Surprisingly, it markedly increased anti-inflammatory cytokine IL-10, reduced MDA content, and protected GSH concentrations in local environment. Our results suggest that injecting hUMSCs overexpressing HO-1 intrathecally can significantly promote functional outcomes in cystitis rats by reducing neuroinflammation, at least, partly through downregulating TLR4/p65/NLRP3 signaling pathway in the SDH region. This cell therapy affords a new strategy for IC/BPS treatment.

Clinical evaluation of intralesional umbilical cord-derived mesenchymal stem cells, conditioned medium and triamcinolone acetonide injection for keloid treatment: A pilot study.

Topical keloid therapy is performed with triamcinolone acetonide (TA) intralesional injection. However, the recurrence rate is high with various side effects. Mesenchymal stem cells (MSCs) have high proliferative abilities and reduce the activity and proliferation of fibroblast cells in keloids. To overcome the costs and limitations, conditioned medium (CM) is used. This study aims to evaluate feasibility of intralesional injection of umbilical cord MSC (UC-MSC) and conditioned medium (UC-CM) compared to TA for keloid therapy. Twenty-four patients with keloids who met the inclusion criteria were included, randomized into three treatment groups and then got assessed for the sociodemographic data, keloid volume, histopathology (type 1:3 collagen ratio), interleukin-10 (IL-10) levels and Patient and Observer Scar Assessment Scale (POSAS) score during visits. Largest volume regression occurred in the UC-MSC group, followed by UC-CM and then the TA group (UC-MSC: 45.32% ± 2.61%; UC-CM: 43.61% ± 3.67%; TA: 28.34% ± 3.81%; p = 0.003). Similar pattern was also observed in increase in IL-10 levels, the decrease in POSAS scores and the reduction of type 1:3 collagen ratio. Hence, UC-MSC and UC-CM are promisingly more effective than TA for keloid therapy, showcasing their superiority in reducing keloid volume, symptoms and type 1:3 collagen ratio, as well as increasing the levels of IL-10.

Integrin beta1 mediates the effect of telocytes on mesenchymal stem cell proliferation and migration in the treatment of acute lung injury.

Co-transplantation of mesenchymal stem cells (MSCs) with telocytes (TCs) was found to have therapeutic effects, although the mechanism of intercellular communication is still unknown. Our current studies aim at exploring the potential molecular mechanisms of TCs interaction and communication with MSCs with a focus on integrin beta1 (ITGB1) in TCs. We found that the co-culture of MSCs with ITGB1-deleted TCs (TCITGB1-ko ) changed the proliferation, differentiation and growth dynamics ability of MSC in responses to LPS or PI3K inhibitor. Changes of MSC proliferation and apoptosis were accompanied with the dysregulation of cytokine mRNA expression in MSCs co-cultured with TCITGB1-ko during the exposure of PI3Kα/δ/β inhibitor, of which IL-1β, IL-6 and TNF-α increased, while IFN-γ, IL-4 and IL-10 decreased. The responses of PI3K p85, PI3K p110 and pAKT of MSCs co-cultured with TCITGB1-ko to LPS or PI3K inhibitor were opposite to those with ITGB1-presented TCs. The intraperitoneal injection of TCITGB1-ko , TCvector or MSCs alone, as well as the combination of MSCs with TCITGB1-ko or TCvector exhibited therapeutic effects on LPS-induced acute lung injury. Thus, our data indicate that telocyte ITGB1 contributes to the interaction and intercellular communication between MSCs and TCs, responsible for influencing other cell phenomes and functions.

Unstable angina due to extrinsic coronary compression secondary to a gigantic pulmonary artery aneurysm: An uncommon etiology

Unstable angina due to extrinsic coronary compression secondary to a gigantic pulmonary artery aneurysm: An uncommon etiology

Injection of rat mesenchymal stem cells leads to their homing and differentiation in the liver in a blunt liver trauma model

Injection of rat mesenchymal stem cells leads to their homing and differentiation in the liver in a blunt liver trauma model

Bidirectional Feto-Maternal Traffic of Donor Mesenchymal Stem Cells Following Transamniotic Stem Cell Therapy (TRASCET)

PurposeTransamniotic stem cell therapy (TRASCET) with mesenchymal stem cells (MSCs) has emerged experimentally as a potential treatment for different congenital diseases and maternal diseases of pregnancy. The broad applicability of TRASCET is predicated on hematogenous routing of donor MSCs via the placenta. We investigated whether donor MSC kinetics includes bidirectional traffic between the fetus and mother. MethodsEight time-dated dams had their fetuses (n = 96) divided in 4 groups on gestational day 17 (E17, term = E21). Groups populating one uterine horn received intra-amniotic injections (50 μL) of either donor amniotic fluid-derived MSCs (2×106 cells/mL) labelled with a firefly luciferase reporter gene (MSC-injected, n = 32), or of acellular luciferase (luciferase-injected, n = 26). Contra-lateral (CL) horn fetuses received no injection (MSC-CL, n = 20 and luciferase-CL, n = 18). At term, samples from 11 fetal anatomical sites from CL fetuses, along with placentas from all fetuses and maternal blood were screened for luciferase activity via microplate luminometry. ResultsOverall survival was 95 % (91/96). When controlled by the acellular injection, positive luciferase activity was observed in the placentas of all MSC-injected fetuses, confirming viability of the donor cells at term. When controlled by the acellular injection group, MSC-CL fetuses showed positive luciferase activity in the bone marrow, peripheral blood, brain and skin (p = <0.001–0.048). No luciferase activity was detected in any maternal blood sample. ConclusionAmniotic fluid-derived MSCs can traffic between the fetus and mother in both directions after simple intra-amniotic injection, in a healthy rat model. This phenomenon must be considered in TRASCET performed in twin/multiple pregnancies. Level of evidenceN/A (animal and laboratory study).

Subconjunctival injection of human umbilical cord mesenchymal stem cells alleviates experimental allergic conjunctivitis via regulating T cell response

BackgroundT helper 2 (Th2) cells are thought to play critical roles in allergic conjunctivitis (AC). They release inflammatory cytokines to promote an allergic response in AC. Due to individual heterogeneity and long-term chronic management, current therapies do not always effectively control AC. Mesenchymal stem cells (MSCs) have been shown to be effective in treating allergy-related disorders, but it is unclear how exactly the Th2-mediated allergic response is attenuated. This study aims to elucidate the therapeutic effect and mechanism of the human umbilical cord MSCs (hUCMSCs) in a mouse model of experimental AC (EAC).MethodsA mouse EAC model was established by inoculating short ragweed (SRW) pollen. After the SRW pollen challenge, the mice received a single subconjunctival or tail vein injection of 2 × 106 hUCMSCs, or subconjunctival injection of hUCMSCs conditioned medium (hUCMSC-CM), and dexamethasone eye drops was used as positive control; subsequent scratching behavior and clinical symptoms were assessed. Immunostaining and flow cytometry were carried out to show allergic reactions and the activation of CD4 + T cell subsets in the conjunctiva and cervical lymph nodes (CLNs). Gene expression was determined by RNA-seq and further verified by qRT-PCR and Western blot. Co-culture assays were performed to explore the regulatory role of hUCMSCs in the differentiation of CD4 + naive T cells (Th0) into Th2 cells.ResultsSubconjunctival administration of hUCMSCs resulted in fewer instances of scratching and lower inflammation scores in EAC mice compared to the tail vein delivery, hUCMSC-CM and control groups. Subconjunctival administration of hUCMSCs reduced the number of activated mast cells and infiltrated eosinophils in the conjunctiva, as well as decreased the number of Th2 cells in CLNs. After pretreatment with EAC mouse serum in vitro to mimic the in vivo milieu, hUCMSCs were able to inhibit the differentiation of Th0 into Th2 cells. Further evidence demonstrated that repression of Th2 cell differentiation by hUCMSCs is mediated by CRISPLD2 through downregulation of STAT6 phosphorylation. Additionally, hUMCSCs were able to promote the differentiation of Th0 cells into regulatory T cells in CLNs of EAC mice.ConclusionsSubconjunctival injection of hUCMSCs suppressed the Th2-allergic response and alleviated clinical symptoms. This study provides not only a potential therapeutic target for the treatment of AC but also other T cell-mediated diseases.

Comparative Regenerative Effects of Allogeneic Bone Marrow and Patellar Ligament Fat Pad Mesenchymal Stem Cells on Experimental Superficial Digital Flexor Tendonitis in New Zealand Rabbits

Background: Cell therapy is applied in tendonitis to speed the healing process of tendon tissue and restore its functional properties. Almost all types of stem cells can differentiate from the recipient cells after transplantation. Objectives: The main goal of this study is to compare the effects of two sources of mesenchymal stem cells on tendon regeneration. Methods: This study randomly divided 32 New Zealand rabbits into 4 groups. The bacterial collagenase was induced at the superficial digital flexor tendon (SDFT) of all rabbits, and the treatment was performed 48 hours after collagenase induction. Group 1 was treated with allogeneic bone marrow mesenchymal stem cells (BMMSCs). Group 2 was treated with adipose-derived stem cells (ADSCs) from the patellar ligament fat pad. Group 3 (sham group) was treated with 0.9% normal saline, and group 4 (control group) was left with no treatment. All rabbits were euthanized 2 and 4 weeks after surgery, and tendon samples were harvested. The histopathology was assessed by hematoxylin-eosin, Masson’s trichrome, and Vangieson’s dye, and tendon structure, fiber arrangement, cell nuclei, tissue inflammation, vascularity (angiogenesis), and density were surveyed. Results: The tendon healing process in the BMMSC and ADSC groups revealed better regeneration than the control and sham groups (P≤0.05). Significant changes (P≤0.05) in some microscopic parameters were seen by comparing the BMMSC and ADSC groups. Conclusion: According to the present study, the injection of mesenchymal stem cells (BMMSCs or ADSCs) showed beneficial results in tendon tissue healing. Furthermore, ADSCs showed better regeneration of the injured tendon tissue than BMMSCs.

OC16.02: The study of ultrasound guidance injection of bone marrow mesenchymal stem cells to treat fetal rabbit bronchopulmonary dysplasia

OC16.02: The study of ultrasound guidance injection of bone marrow mesenchymal stem cells to treat fetal rabbit bronchopulmonary dysplasia

Serum biochemical indicators in rats of different ages after replacing femoral metaphysis defects with allogeneic bone implants saturated with mesenchymal stem cells

The aim of the study: to evaluate the course of metabolic processes after replacing femoral metaphysis defects with allogeneic bone implants saturated with allogeneic mesenchymal stem cells (MSCs) based on the analysis of serum biochemical indicators of connective tissue metabolism in laboratory rats. Material and methods. A critical-sized transcortical femoral defect model in the femur metaphysis of white rats was used. Blood serum concentrations of glycoproteins, total chondroitin sulfates, total protein and calcium, alkaline and acid phosphatase activity were measured. Results. On the 28th day, in 3-month-old animals with MSC, in comparison with the data of rats without MSC, clear signs of connective tissue formation and bone resorption activity were observed, as evidenced by an increase in serum chondroitin sulfates and acid phosphatase activity. On the 90th day, this group of rats under the influence of MSCs showed signs of decreased bone tissue formation with lower serum activity of alkaline phosphatase. In 3-month-old rats with MSC, signs of the inflammatory process chronization with higher serum concentrations of glycoproteins were detected on the 90th day of the experiment in comparison with data from animals without MSC. In 12-month-old rats with MSCs, signs of bone resorption were documented on the 14th day, which were manifested by a higher serum activity of acid phosphatase with less formation of connective tissue and lower concentrations of chondroitin sulfates. On the 28th day, the effect of MSCs in 12-month-old animals was manifested in the form of a slowdown in bone formation with a decrease in alkaline phosphatase activity. On the 90th day, the connective tissue formation was activated with higher concentrations of chondroitin sulfates in these animals. Conclusions. The studied biochemical indicators in 3-month-old animals showed greater lability. The regeneration phases were faster in 3-month-old animals as well as in animals with alloimplants without MSCs. Injections of allogeneic MSCs together with an allograft immediately after a bone damage, regardless of age, caused signs of bone formation slowing and excessive formation of connective tissue, therefore, the combination of allogeneic MSCs with an allogeneic bone implant is not advisable to use in fresh fractures.

Intravitreal allogeneic mesenchymal stem cells: a non-randomized phase II clinical trial for acute non-arteritic optic neuropathy

BackgroundAn effective treatment for acute non-arteritic ischemic optic neuropathy (NA-AION) has not been known or proven yet. Previous studies have suggested a neuroprotective effect of allogeneic bone marrow-derived mesenchymal stem cells. This study aims to report the results of a clinical trial on patients with acute non-arteritic optic neuropathy (NA-AION) treated with an intravitreal injection of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) (MSV®).MethodsWe conducted a prospective, non-randomized, clinical phase-II study (Eudra CT number 2016-003029-40; ClinicalTrials.gov Registry NCT03173638) that included 5 patients with acute unilateral NA-AION diagnosed within 2 weeks after symptom onset and who received an intravitreal injection of allogeneic BM-MSCs (0.05 ml; cell concentration: 1.5 × 106cells/mL). The patients underwent regular ophthalmological examinations and were followed for one year.ResultsIn this trial, allogeneic BM-MSCs appeared to be safe as no patients developed signs of acute nor chronic intraocular inflammation or a significant change in intraocular pressure, although an epiretinal membrane was developed in one patient. A retrolental aggregate formed shortly after the injection spontaneously disappeared within a few weeks in another phakic patient, leaving a subcapsular cataract. Visual improvement was noted in 4 patients, and amplitudes of P100 on the visually evoked potentials recordings increased in three patients. The retinal nerve fiber layer and macular ganglion cell layer thicknesses significantly decreased during the follow-up.ConclusionsBesides the development of an epiretinal membrane in one patient, the intravitreal application of allogeneic BM-MSCs appeared to be intraocularly well tolerated. Consequently, not only NA-AION but also BM-MSCs deserve more clinical investigational resources and a larger randomized multicenter trial that would provide stronger evidence both about safety and the potential therapeutic efficacy of intravitreally injected allogeneic BM-MSCs in acute NA-AION.Trial registration: Safety Assessment of Intravitreal Mesenchymal Stem Cells for Acute Non-Arteritic Anterior Ischemic Optic Neuropathy (NEUROSTEM). NCT03173638. Registered June 02, 2017 https://clinicaltrials.gov/ct2/show/NCT03173638.

Morphostructural changes in the brain of experimental animals after using mesenchymal stem cells in the temporomandibular joint inflammation model

The article presents the results of structural and functional transformations in cerebellum, trigeminal nuclei, and hippocampus of male Wistar rats against the background of injection of mesenchymal stem cells (MSCs) into Meckel’s space in the temporomandibular joint (TMJ) inflammation model.The aim of the study was to clarify the effect of MSCs injections into Meckel’s space on the morphostructural features of cerebellum, trigeminal nuclei, and hippocampus in the TMJ inflammation model.Injecting the mesenchymal stem cells into Meckel’s space in an inflammatory model of the right lower temporomandibular joint promotes the structure restoration of the ganglionic layer of the cerebellum, the spinal nuclei of the trigeminal nerve, and the hippocampus of rats by the 28th day. This is manifested in increasing the neuronal density, decreasing the neurodegeneration index, and in activating glia elements.

Effectiveness and safety of mesenchymal stem/stromal cell for radiation-induced hyposalivation and xerostomia in previous head and neck cancer patients (MESRIX-III): a study protocol for a single-centre, double-blinded, randomised, placebo-controlled, phase II study

BackgroundA predominant side effect of radiotherapy for head and neck cancer is salivary gland hypofunction and xerostomia leading to debilitating oral disorders and impaired quality of life (QoL). Intraglandular mesenchymal stem cell therapy has shown promising results as a treatment for xerostomia.MethodsThis is a randomised, double-blinded, placebo-controlled, parallel-group, prospective, single-centre trial investigating the safety, tolerability, and effectiveness of allogeneic stem cells as a treatment for radiation-induced hyposalivation and xerostomia for previous head and neck cancer patients.We will include a total of 120 patients who previously have been treated with radiotherapy for a head and neck cancer in Denmark. Participants will be randomly assigned using block randomisation to one of two parallel groups in a 1:1 ratio to receive ultrasound-guided injection of allogeneic adipose-derived mesenchymal stem cell (ASC) (n = 60) or placebo (n = 60) into the submandibular glands. Placebo will consist of CryoStor10 (BiolifeSolutions), the freeze media for ASCs containing 10% dimethyl sulfoxide (DMSO). The primary endpoint is change in unstimulated whole saliva flow rate. The secondary endpoints are change in stimulated whole saliva flow rate, QoL, and composition of saliva. Further secondary endpoints are safety and immune response (human leukocyte antigen (HLA) response) to the stem cells will be assessed. Patients are evaluated at baseline (before treatment), after 4 months, and after 12 months. All study personnel, except study personnel thawing and preparing the treatment for injection, and participants will be blinded to group assignment. Unblinded study personnel will not participate in the outcome assessment.DiscussionThe trials will investigate the efficacy and safety of ASC injection to the submandibular gland as a potential new treatment for post-radiation xerostomia. We hope the results will pave the way for a clinically relevant treatment to ameliorate patients with xerostomia, a severely hampering condition.Trial registrationThe study is approved by the Danish Data Protection Agency (protocol number P-2020-1164), the National Ethics Committee protocol number: (Protocol number: 1802872), and the Danish Medical Agency (2018-000348-24). The protocol was registered at the ClinicalTrials.gov database (NCT04776538).

Intra-operative Guidelines for the Prevention of Uterine Niche Formation in Cesarean Sections: A Review.

Formation of a uterine niche following a C-section can predispose the patient to future obstetric complications such as dehiscence, uterine rupture, ectopic pregnancy, and placenta accreta. The significant morbidity and mortality of these complications along with increasing C-section rates emphasizes the importance of prevention. However, there are no clear guidelines on intra-operative protocol to prevent postpartum niche formation. Besides surgical technique, the novel use of platelet-rich plasma (PRP) and mesenchymal stem cell (MSC) injections has demonstrated promising potential and may have applications in hysterotomy closures. The objective is to examine current research on optimal C-section procedures to prevent uterine niche formation and subsequent obstetric complications. A systematic review was conducted using PubMed and Google Scholar. Initial searches yielded 827 results. Inclusion criteria werehuman, animal, and in-vitro studies, peer-reviewed sources, and outcomes pertinent to the uterine niche. Exclusion criteria applied to articles with outcomes unrelated to myometriumand interventions outside of the intra-operative and immediate pre-/post-operative period. Based on the criteria, 41 articles were cited. Pathophysiology of uterine niche formation was associated with incisions through cervical tissue, adhesion formation, and poor approximation. Significant risk factors were low uterine incisions, advanced cervical dilatation, low station, non-closure of the peritoneum, and creation of a bladder flap. There was no consensus on uterine closure as it likely depends on surgical proficiency with the given technique, but a double-layered non-locking suture appears reliable to reduce niche severity. Recent trials indicate that intra-operative PRP/MSC injections may decrease niche incidence and severity, but more research is needed. If prevention or minimization of uterine niche is desired, the optimal C-section protocol shouldavoid low uterine incisions, choose uterine closure technique based on the surgeon's proficiency (double-layered non-locking is reliable), and close the peritoneum, and myometrial injection of PRP/MSC may be a useful adjunct intervention pending further clinical evidence.