Dose Of Mesenchymal Stem Cells Research Articles

Efficacy and safety of mesenchymal stem cell-derived microvesicles in mouse inflammatory arthritis

ObjectiveTo determine the effective and safe intravenous doses of mesenchymal stem cells (MSCs)-derived microvesicles (MVs) and to elucidate the possible causes of death in mice receiving high-dose MVs. MethodsMVs were isolated from human MSCs by gradient centrifugation. Mice with collagen-induced arthritis were treated with different doses of intravenous MVs or MSCs. Arthritis severity, white blood cell count, and serum C-reactive protein levels were measured. To assess the safety profile of MSCs and MVs, mice were treated with different doses of MSCs and MVs, and LD50 was calculated. Mouse lungs and heart were assessed by live fluorescence imaging, histopathological measurements, and immunohistochemistry to explore the possible causes of death. Serum concentrations of cTnT, cTnI, and CK-MB were determined by ELISA. With the H9C2 cardiomyocyte cell line, cellular uptake of MVs was observed using confocal microscopy and cell toxicity was assessed by CCK-8 and flow cytometry. ResultsIntravenous treatment with MSCs and MVs alleviated inflammatory arthritis, while high doses of MSCs and MVs were lethal. Mice receiving a maximum dose of MSCs (0.1 mL of MSCs at 109/mL) died immediately, while mice receiving a maximum dose of MVs (0.1 mL of MVs at 1012/mL) exhibited tears, drooling, tachycardia, shortness of breath, unbalanced rollover, bouncing, circular crawling, mania, and death. Some mice died after exhibiting convulsions and other symptoms. All mice died shortly after injecting the maximum dose of MSCs. Histologically, mice receiving high doses of MSCs frequently developed pulmonary embolism, while those receiving high doses of MVs died of myocardial infarction. Consistently, the serum levels of cTnT, cTnI, and CK-MB were significantly increased in the MVs-treated group (P < 0.05). The LD50 of intravenous MVs was 1.60 × 1012/kg. Further, MVs could enter the cell. High doses of MVs induced cell apoptosis, though low concentrations of MVs induced cell proliferation. ConclusionsAppropriate dosages of MVs and MSCs are effective treatments for inflammatory arthritis while MVs and MSCs overdose is unsafe by causing cardiopulmonary complications.

Mesenchymal stem cells from bone marrow of patients with drug-resistant tuberculosis for cellular therapy

In this study, we evaluated the proliferative capacity of mesenchymal stem cells (MSCs) from the bone marrow of patients with drug-resistant tuberculosis (DR-TB) and selected the optimal conditions for obtaining autologous MSCs transplant. The results of the expansion of MSCs from 42 patients with DR-TB in medium with 10% FBS demonstrated low proliferative potential for of these cells compared with MSCs from 47 donors. MSCs content in 1 ml of bone marrow of patients was also lower. A relationship was found between the amount of MSCs in the primary culture and in the finished product, and with a small number of cells in the primary culture, we used 5% platelet lysate instead of 10% FTS, which made it possible to obtain a high dose of MSCs in the transplant.

Anti-inflammatory and anti-oxidant activities of mesenchymal stem cells in chemically induced arthritic rats.

Mesenchymal stem cells (MSCs) have been extensively used as cell-based treatments for decades due to their anti-inflammatory, immunomodulatory, and healing abilities. The intent of our study was to determine the efficacy of MSCs in alleviating rheumatoid arthritis (RA) induced by Complete Freund's adjuvant (CFA) and to investigate the anti-inflammatory and antioxidant characteristics of MSCs. Intrapedally injecting 0.1 ml of CFA directly into the footpad of the right hind paw daily for 2days was used to induce RA. Arthritic rats received four doses of MSCs (1 × 106 cells/rat/dose) intravenously through the lateral tail vein. Our results showed that arthritic rats treated with MSCs exhibited reduced levels of paw edema. Furthermore, arthritic rats treated with MSCs exhibiteda significant decreasein the levels of RF, CRP,IL-1β,TNF-α,IL-17 andADAMTS-5, along witha significant increasein thelevels of IL-4 and TIMP-3. Additionally, MSCs significantly reduced the expression of TGF-β. Both the glutathione (GSH) content and antioxidant activity of GST were enhanced by MSCs, while LPO levels were suppressed. These findings provide further evidence that MSCs are valuable in treating RA, possibly due to their anti-inflammatory and anti-oxidative properties. Thus, MSCs have potential as a more effective therapeutic strategy for treatingRA.

The efficacy of mesenchymal stem cell treatment and colistin-fosfomycin combination on colistin-resistant Acinetobacter baumannii sepsis model.

This study examines the role of mesenchymal stem cells (MSCs) in an experimental sepsis model developed with colistin-resistant Acinetobacter baumannii (CRAB). BALB-c mice were divided into treatment groups (MSC, MSC + colistin (C)-fosfomycin (F), and C-F and control groups (positive and negative)). CRAB was administered to mice through intraperitoneal injection. Three hours later, C, F, and MSC were given intraperitoneally to the treatment groups. Colistin administration was repeated every 12 h, F administration was done every 4 h, and the second dose of MSC was administered after 48 h. Mice were sacrificed at 24 and 72 h. The bacterial load was determined as colony-forming units per gram (cfu/g). Histopathological examination was conducted on the left lung, liver, and both kidneys. IL-6 and C-reactive protein (CRP) levels in mouse sera were determined by enzyme-linked immunosorbent assay. Among the treatment groups, the C-F group had the lowest colony count in the lung (1.24 ± 1.66 cfu/g) and liver (1.03 ± 1.08 cfu/g). The highest bacterial clearance was observed at 72 h compared to 24 h in the MSC-treated groups (p = 0.008). The MSC + C-F group showed the lowest histopathological score in the liver and kidney (p = 0.009). In the negative control group, the IL-6 level at the 24th hour was the lowest (p < 0.001). Among the treatment groups, the CRP level was the lowest in the MSC + C-F group at 24 and 72 h. In a CRAB sepsis model, adding MSCs to a colistin-fosfomycin treatment may be beneficial in terms of reducing bacterial loads and preventing histopathological damage.

Low-dose xenogeneic mesenchymal stem cells target canine osteoarthritis through systemic immunomodulation and homing

BackgroundAs current therapies for canine osteoarthritis (OA) provide mainly symptomatic improvement and fail to address the complex pathology of the disease, mesenchymal stem cells (MSCs) offer a promising biological approach to address both aspects of OA through their immunomodulatory properties.MethodsThis study aimed to investigate the safety and efficacy of xenogeneic MSCs in dogs with OA at different dose levels after intravenous injection. OA was surgically induced in the right stifle joint. Thirty-two male and female dogs were divided into three treatment groups and a control group. Regular general physical examinations; lameness, joint, radiographic, and animal caretaker assessments; pressure plate analyses; and blood analyses were performed over 42 days. At study end, joint tissues were evaluated regarding gross pathology, histopathology, and immunohistochemistry. In a follow-up study, the biodistribution of intravenously injected 99mTc-labeled equine peripheral blood-derived MSCs was evaluated over 24h in three dogs after the cruciate ligament section.ResultsThe dose determination study showed the systemic administration of ePB-MSCs in a canine OA model resulted in an analgesic, anti-inflammatory, and joint tissue protective effect associated with improved clinical signs and improved cartilage structure, as well as a good safety profile. Furthermore, a clear dose effect was found with 0.3 × 106 ePB-MSCs as the most effective dose. In addition, this treatment was demonstrated to home specifically towards the injury zone in a biodistribution study.ConclusionThis model-based study is the first to confirm the efficacy and safety of systemically administered xenogeneic MSCs in dogs with OA. The systemic administration of a low dose of xenogeneic MSCs could offer a widely accessible, safe, and efficacious treatment to address the complex pathology of canine OA and potentially slow down the disease progression by its joint tissue protective effect.

Treatment of Radiation Lesions with Mesenchymal Stem Cells

Acute radiation syndrome (ARS) is an acute illness caused by exposure to a high dose of ionizing radiation. ARS is the deterministic effect of radiation exposure of the whole body or a significant body volume (partial body irradiation) above a threshold dose of about 1 Gy (gray). Radiation accidents, such as those in Chernobyl (1986) and Fukushima (2011), or the possible use of nuclear weapons during the hostilities or terrorist attacks, can lead to the massive development of ARS in humans. The aim of the work is to introduce a new method of post-radiation treatment – the use of allogeneic mesenchymal stem cells (MSCs). Materials and methods. The information contained in specialized scientific journals that are freely available and accessible through the global Internet was studied. Discussion of the results. In the scenario of mass exposure of the population, when from several tens (hundreds) to millions of people can be irradiated, the transfusion of hematopoietic stem cells traditionally used in such cases would be impossible. MSCs can possibly differentiate into specialized cells, that is, turn into cells of various organs and tissues or induce such kind of regeneration. For practical use, there are two main sources of their isolation and reproduction ex vivo – bone marrow and adipose tissue. To date, it has been shown that MSCs derived from adipose tissue can be effective in mitigating the effects of acute radiation illness. Intravenously applied MSCs are migrating mainly to the bone marrow and are partially restoring its function. Deep anatomical structures are also involved in local radiation injuries: bone, muscles, nerves, blood and lymphatic vessels and skin. There is a strong body of evidence suggesting the «repair effect» of MSCs when used to treat such lesions. This is because MSCs can induce the repair and regeneration of the anatomical structures which they are locally applied, possibly by the paracrine effect. The main advantage of allogeneic MSCs over autologous ones is their logistical accessibility. They can be produced in advance in quantities and stored frozen. After thawing, the cells must be cultured for at least 48 hours in humidified incubators with the addition of 5 % CO2. Findings. Treatment of MSCs should be started as soon as possible after radiation exposure. Rescue of damaged hematopoiesis in the bone marrow can be achieved by multiple intravenous administration of up to 1 million (106) freshly prepared allogeneic MSCs/kg body weight. Locally (around and in the irradiation area), the dose of MSCs may be lower – 20 million cells. Repeated topical application should be carried out at intervals of two to four weeks. Subsequent surgical reconstruction should be performed by an experienced surgeon and in a specialized center with concomitant topicalapplication of MSCs.

Repeated intravenous infusion of mesenchymal stem cells enhances recovery of motor function in a rat model with chronic spinal cord injury

Spinal cord injury (SCI) can cause paralysis with a high disease burden with limited treatment options. A single intravenous infusion of mesenchymal stem cells (MSCs) improves motor function in rat SCI models, possibly through the induction of axonal sprouting and remyelination. Repeated infusions (thrice at weekly intervals) of MSCs were administered to rats with chronic SCI to determine if multiple-dosing regimens enhance motor improvement. Chronic SCI rats were randomized and infused with vehicle (vehicle), single MSC injection at week 6 (MSC-1) or repeatedly injections of MSCs at 6, 7, and 8 weeks (MSC-3) after SCI induction. In addition, a single high dose of MSCs (HD-MSC) equivalent to thrice the single dose was infused at week 6. Locomotor function, light and electron microscopy, immunohistochemistry and ex vivo diffusion tensor imaging were performed. Repeated infusion of MSCs (MSC-3) provided the greatest functional recovery compared to single and single high-dose infusions. The density of remyelinated axons in the injured spinal cord was the greatest in the MSC-3 group, followed by the MSC-1, HD-MSC and vehicle groups. Increased sprouting of the corticospinal tract and serotonergic axon density was the greatest in the MSC-3 group, followed by MSC-1, HD-MSC, and vehicle groups. Repeated infusion of MSCs over three weeks resulted in greater functional improvement than single administration of MSCs, even when the number of infused cells was tripled. MSC-treated rats showed axonal sprouting and remyelination in the chronic phase of SCI.

Comparison of the therapeutic effects between stem cells and exosomes in primary ovarian insufficiency: as promising as cells but different persistency and dosage

BackgroundPrimary ovarian insufficiency (POI) refers to the loss of ovarian function under the age of 40 and results in amenorrhea and infertility. Our previous studies have shown that transplantation of mesenchymal stem cells (MSCs) and MSC-derived exosomes in chemotherapy-induced POI mouse ovaries can reverse the POI and eventually achieve pregnancy. Based on our recent studies, MSC-derived exosomes have almost equal therapeutic potentials as transplanted MSCs. However, it is still unclear whether exosomes can completely replace MSCs in POI treatment. For the reliable application of cell-free treatment for POI patients using exosomes, there is a need to understand whether there is any outcome and effectiveness difference between MSC and MSC-derived exosome treatment.MethodsComparing the therapeutic effect of intravenous injection using MSCs and equal amounts of exosomes in a POI mouse model will reveal the difference between the two therapeutic resources. In this study, we induced POI in C57/BL6 mice by chemotherapy (CXT) using a standard protocol. We then injected four different doses of MSCs or equal amounts of commercialized MSC-derived exosomes by retro-orbital injection post-CXT.ResultAfter MSC/exosome treatment, tissue and serum samples were harvested to analyze molecular changes after treatment, while other mice in parallel experiments underwent breeding experiments to compare the restoration of fertility. Both the MSC- and exosome-treated groups had a restored estrous cycle and serum hormone levels compared to untreated POI mice. The pregnancy rate in the MSC-treated group was 60–100% after treatment, while the pregnancy rate in the exosome-treated group was 30–50% after treatment. Interestingly, in terms of long-term effects, MSC-treated mice still showed a 60–80% pregnancy rate in the second round of breeding, while the exosome-treated group became infertile again in the second round of breeding.ConclusionsAlthough there were some differences in the efficacy between MSC treatment and exosome treatment, both treatments were able to achieve pregnancy in the POI mouse model. In conclusion, we report that MSC-derived exosomes are a promising therapeutic option to restore ovarian function in POI conditions similar to treatment with MSCs.

Mesenchymal Stem Cells (MSCs) Treatment Alleviates Smoke Inhalation and Burn-Induced Acute Respiratory Distress Syndrome (ARDS) by Inhibiting HMGB1-TLR4 Signal

Abstract ARDS is one of the leading causes of high morbidity and mortality in trauma patients. Previously our data demonstrated autologous MSCs treatment improved survival in a swine model of smoke inhalation and burn injury. However, the pathophysiological mechanisms are still largely unknown. Twenty anesthetized female swine underwent smoke inhalation injury and 40% TBSA burns, were then randomly assigned to either mock treatment (IC, n=10), or autologous MSCs treatment (MSCs, n=10), followed by ICU care up to 72 hours except in case of early death. Three doses of MSCs collected by bone marrow aspiration and concentrated using a bedside cell concentrator device were applied at 2, 24, and 48 hours of post-injury (PI). Blood and tissue samples were collected for ELISA and IHC analyses. In IC group, 10/10 injured pigs developed ARDS, but only 6/10 pigs in MSCs group developed ARDS. Serum analysis revealed that the HMGB1 level gradually increased after injury and reached a peak at 48h PI (5.7-fold increase vs. baseline). The SDC-1 and C3a levels also increased after injury but reached a peak at 24h (2.9-fold) and 72h PI (2.2-fold), respectively. The MSCs treatment significantly reduced the HMGB1 level in the serum, especially at 6h and 12h PI compared to the IC group but failed to inhibit the SDC-1 and C3a increases. IHC analyses showed that injury triggered a significantly higher expressions of HMGB1 and TLR4, as well as co-localization of HMGB1 and TLR4 in the lung; while MSCs treatment was able to disrupt the HMGB1-TLR4 interaction and significantly reduce their expressions. Our data indicate that the way MSCs treatment mitigates ARDS might be by reducing HMGB1 release and inhibiting the HMGB1-TLR4 signal pathway activation in pigs after smoke and burn injury. This work was supported by the US Army Medical Research and Development Command (USAMRDC) under Grant No. W81XWH-13-2-0005.

Multiple Dosing and Preactivation of Mesenchymal Stromal Cells Enhance Efficacy in Established Pneumonia Induced by Antimicrobial-Resistant Klebsiella pneumoniae in Rodents.

Antimicrobial-resistant (AMR) bacteria, such as Klebsiella species, are an increasingly common cause of hospital-acquired pneumonia, resulting in high mortality and morbidity. Harnessing the host immune response to AMR bacterial infection using mesenchymal stem cells (MSCs) is a promising approach to bypass bacterial AMR mechanisms. The administration of single doses of naïve MSCs to ARDS clinical trial patient cohorts has been shown to be safe, although efficacy is unclear. The study tested whether repeated MSC dosing and/or preactivation, would attenuate AMR Klebsiella pneumonia-induced established pneumonia. Rat models of established K. pneumoniae-induced pneumonia were randomised to receive intravenous naïve or cytomix-preactivated umbilical cord MSCs as a single dose at 24 h post pneumonia induction with or without a subsequent dose at 48 h. Physiological indices, bronchoalveolar lavage (BAL), and tissues were obtained at 72 h post pneumonia induction. A single dose of naïve MSCs was largely ineffective, whereas two doses of MSCs were effective in attenuating Klebsiella pneumosepsis, improving lung compliance and oxygenation, while reducing bacteria and injury in the lung. Cytomix-preactivated MSCs were superior to naïve MSCs. BAL neutrophil counts and activation were reduced, and apoptosis increased. MSC therapy reduced cytotoxic BAL T cells, and increased CD4+/CD8+ ratios. Systemically, granulocytes, classical monocytes, and the CD4+/CD8+ ratio were reduced, and nonclassical monocytes were increased. Repeated doses of MSCs-particularly preactivated MSCs-enhance their therapeutic potential in a clinically relevant model of established AMR K. pneumoniae-induced pneumosepsis.

Intra-Articular Mesenchymal Stem Cell Injection for Knee Osteoarthritis: Mechanisms and Clinical Evidence

Knee osteoarthritis presents higher incidences than other joints, with increased prevalence during aging. It is a progressive process and may eventually lead to disability. Mesenchymal stem cells (MSCs) are expected to repair damaged issues due to trilineage potential, trophic effects, and immunomodulatory properties of MSCs. Intra-articular MSC injection was reported to treat knee osteoarthritis in many studies. This review focuses on several issues of intra-articular MSC injection for knee osteoarthritis, including doses of MSCs applied for injection and the possibility of cartilage regeneration following MSC injection. Intra-articular MSC injection induced hyaline-like cartilage regeneration, which could be seen by arthroscopy in several studies. Additionally, anatomical, biomechanical, and biochemical changes during aging and other causes participate in the development of knee osteoarthritis. Conversely, appropriate intervention based on these anatomical, biomechanical, biochemical, and functional properties and their interactions may postpone the progress of knee OA and facilitate cartilage repair induced by MSC injection. Hence, post-injection rehabilitation programs and related mechanisms are discussed.

A comparative study of different doses of bone marrow-derived mesenchymal stem cells improve post-stroke neurological outcomes via intravenous transplantation

BackgroundIschemic stroke treatments are intriguing and somewhat controversial. Recent findings have shown that human mesenchymal stem cells (MSC) may have therapeutic potential in ischemic stroke. Our hypothesis was that MSC therapy would promote sensory and motor recovery. Therefore, we intended to explore the optimal transplantation dose of MSC. MethodsAdult Sprague-Dawley (SD) rats were induced to undergo transient focal cerebral ischemia by occluding the middle cerebral artery. A series of standard neurological/neurobehavioral experiments, including Neurological Severity Score (NSS) assessment, corner turning test, von Frey test, and rotarod were then performed on post stroke rats following treatment with vehicle or different doses of MSC (1 × 106, 2 × 106, and 5 × 106) through tail vein. To figure out the time course of neurological and functional recovery following ischemic stroke, tests were administered at regular intervals (days 1, 3, 7, 14, 21, and 28) after reperfusion. And the cerebral infarction volume was measured and analyzed by multi-slices H&E staining and micro-PET / CT in all of the groups at day 35 after ischemia stroke. Activation of microglia was explored by immunofluorescence at day 35 after ischemia stroke. ResultsThe sensory and motor function was significantly improved by MSC treatment in stroke rats, along with cerebral infarction volume reduction. Besides, different doses of MSC have more or less reflected the therapeutic effect on stroke. The prominent treatment outcome in neurobehavioral recovery and infarction reduction was shown in low dose group with an injection dose of 1 × 106 cells. Nevertheless, the medium and high dose MSC could inhibit the activation of microglia much stronger. ConclusionsTreatment with MSC restored the sensory and motor function of cerebral ischemia rats, indicating it may be an effective therapy for ischemic stroke.

Efficacy and Safety of Mesenchymal Stem Cell Therapy in Patients with Acute Myocardial Infarction: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

The adjuvant treatment of stem cell therapy for acute myocardial infarction (AMI) has been studied in multiple clinical trials, but many questions remain to be addressed, such as efficacy, safety, identification of the optimal cell type, tractable route of delivery, transplant dosage, and transplant timing. The current meta-analysis aimed to explore the issues of mesenchymal stem cells (MSCs) transplantation in patients with AMI based on published randomized controlled trials (RCTs) and guide the design of subsequent clinical trials of MSCs therapy for AMI. The Cochrane Library, PubMed, EMBASE databases were searched for relevant clinical trials from January 1, 2000, to January 23, 2021. Results from RCTs involving MSCs transplantation for the treatment of AMI were identified. According to the Cochrane systematic review method, the literature quality, including studies, was evaluated and valid data was extracted. Rev- Man 5.3 and Stata 15.1 software were used for Meta-analysis. After literature search and detailed evaluation, 9 randomized controlled trials enrolling 460 patients were included in the quantitative analysis. Pooled analyses indicated that MSCs therapy was associated with a significantly greater improvement in overall left ventricular ejection fraction (LVEF), and the effect was maintained for up to 24 months. No significant difference in favor of MSCs treatment in left ventricular (LV) volume and in the risk of rehospitalization as a result of heart failure (HF) was noted, compared with the controls. For transplantation dose, the LVEF of patients accepting a MSCs dose of 107-108 cells was significantly increased by 2.62% (95% CI 1.54 to 3.70; P < 0.00001; I2 =0%), but this increase was insignificant in the subgroup that accepted a MSCs dose of < 107 cells (1.65% in LVEF, 95% CI, 0.03 to 3.27; P =0.05; I2 =75%) or >108 cells (4.65% in LVEF, 95% CI, -4.55 to 13.48; P =0.32; I2 =95%), compared with the controls. For transplantation timing, a significant improvement of LVEF of 3.18% was achieved in the group of patients accepting a MSCs infusion within 2 to 14 days after percutaneous coronary intervention (PCI) (95% CI, 2.89 to 3.47; P <0.00001; I2 = 0). There was no association between MSCs therapy and major adverse events. Results from our systematic review suggest that MSCs therapy for patients with AMI appears to be safe and might induce a significant increase in LVEF with a limited impact on LV volume and rehospitalization caused by HF. The effect was maintained for up to 24 months. MSCs dose of 107-108 cells was more likely to achieve better clinical endpoints than <107 or >108 cells. The optimal time window for cell transplantation might be within 2-14 days after PCI. This meta-analysis was registered with PROSPERO, number CRD 42021241104.

Mesenchymal stem cells as an adjuvant for the treatment of poi, and as a support in expectant management of placental hematomas and premature rupture of membranes: case report

In Mexico, 17% of women of childbearing age have infertility problems, this alteration may be associated to Premature Ovarian Insufficiency (POI). On the other hand, Premature Rupture of Membranes (PROM) is defined as the rupture of ovular membranes before labor begins. The application of Mesenchymal Stem Cells (MSCs) has been proposed for the treatment of POI, placental abruption and PROM. Objective: Describe a case report of a patient that received MSCs by intravenous injection as an adjuvant for the treatment of POI, and as an aid to reduce placental hematomas that appeared during pregnancy, which resulted in PROM (preterm, and previable), and a preterm baby delivery (alive). Clinical case presentation: A 30-year-old woman with history of primary infertility of 2 years; Anti-Müllerian Hormone (AMH) of 0.2 ng/mL; laparoscopic Bilateral Tubal Obstruction (BTO), endometriosis, diagnostic and surgical laparoscopy for myomatosis, and Factor VII deficiency; as well as 3 IVF, 4 embryo transfers, and 1 IUI unsuccessful. With confirmed POI diagnosis, the application of several doses at different times of MSCS is decided, resulting in pregnancy. Sometime later during pregnancy, placental hematomas and PROM are observed and decided to apply MSCs at different stages of pregnancy, resulting in the live birth of a baby (29.3 Weeks of Gestation) Conclusion: The application of multiple doses of MSCs turns more efficient the placental tissue restoration, allowing hematomas to disappear, and delaying a possible PROM.

Down-Regulation of CXCR4 in Mesenchymal Stem Cells by Septic Serum.

Sepsis is one of the main concerns of health and one of the leading causes of death in hospitals. It is essential to manage sepsis in hospitalized patients. In recent years, cell therapy has been considered as a new approach to treat sepsis. This study evaluated the effect of CXCR4 as one of the main proteins involved in the homing of mesenchymal stem cells in the sepsis serum in mice model. Mouse sepsis model was induced by injection of E.coli and biochemical analyses was done to confirm the organ failure. Mesenchymal stem cells (MSCs) derived from bone marrow were separated into sepsis and control groups. In the sepsis serum group, MSCs were treated with sepsis serum at two time points: 24 and 48h. Quantitative RT-PCR and flow cytometry were performed to determine the mRNA expression of CXCR4 in sepsis serum group compared to control group. Also, a migration assay was done to assess the migration capacity of bone marrow MSCs during inflammation and treatment in sepsis. Our result showed that treatment with sepsis serum can control migration by decrease in CXCR4 level (P ≤ 0.05) compared to control group. Moreover it was also reported that sepsis serum decreased mRNA expression of CXCR4 in MScs. In our study, MSCs treated with septic serum were no longer able to migrate . Probably many variables such as source, dose, injection time, and injection route of MSCs after sepsis induction in the animal models are key factors for successful cell therapy.

Therapeutic Potential of Mesenchymal Stem Cells versus Omega n - 3 Polyunsaturated Fatty Acids on Gentamicin-Induced Cardiac Degeneration.

This study compared the cardioprotective action of mesenchymal stem cells (MSCs) and PUFAs in a rat model of gentamicin (GM)-induced cardiac degeneration. Male Wistar albino rats were randomized into four groups of eight rats each: group I (control group), group II (gentamicin-treated rats receiving gentamicin intraperitoneally (IP) at dose of 100 mg/kg/day for 10 consecutive days), group III (gentamicin and PUFA group receiving gentamicin IP at dose of 100 mg/kg/day for 10 consecutive days followed by PUFAs at a dose of 100 mg/kg/day for 4 weeks), and group IV (gentamicin and MSC group receiving gentamicin IP at dose of 100 mg/kg/day followed by a single dose of MSCs (1 × 106)/rat IP). Cardiac histopathology was evaluated via light and electron microscopy. Immunohistochemical detection of proliferating cell nuclear antigen (PCNA), caspase-3 (apoptosis), Bcl2, and Bax expression was performed. Moreover, cardiac malonaldehyde (MDA) content, catalase activity, and oxidative stress parameters were biochemically evaluated. Light and electron microscopy showed that both MSCs and PUFAs had ameliorative effects. Their actions were mediated by upregulating PCNA expression, downregulating caspase-3 expression, mitigating cardiac MDA content, catalase activity, and oxidative stress parameters. MSCs and PUFAs had ameliorative effects against gentamicin-induced cardiac degeneration, with MSCs showing higher efficacy compared to PUFAs.

Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial

BackgroundType-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, mesenchymal stem cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients.MethodsAfter receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and was followed for at least one-year post-transplantation.ResultsThe results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices.ConclusionsTaken together, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes.Trial registration: This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) (https://en.irct.ir/trial/23256) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). (https://clinicaltrials.gov/ct2/show/NCT04078308).

Mesenchymal stem cell treatment for enteric neuropathy in the Winnie mouse model of spontaneous chronic colitis.

Inflammatory bowel disease (IBD) is a chronic gut inflammation with periods of acute flares and remission. Beneficial effects of a single dose of mesenchymal stem cell (MSC)-based treatment have been demonstrated in acute models of colitis. No studies investigated therapeutic effects of MSCs for the attenuation of enteric neuropathy in a chronic model of colitis. The short and long-term effects of MSC treatment in modulating inflammation and damage to the enteric nervous system (ENS) were studied in the Winnie mouse model of spontaneous chronic colitis highly representative of human IBD. Winnie mice received a single dose of either 1 × 106 human bone marrow-derived MSCs or 100µL PBS by intracolonic enema. C57BL/6 mice received 100µL PBS. Colon tissues were collected at 3 and 60days post MSC administration to evaluate the short-term and long-term effects of MSCs on inflammation and enteric neuropathy by histological and immunohistochemical analyses. In a separate set of experiments, multiple treatments with 4 × 106 and 2 × 106 MSCs were performed and tissue collected at 3days post treatment. Chronic intestinal inflammation in Winnie mice was associated with persistent diarrhea, perianal bleeding, morphological changes, and immune cell infiltration in the colon. Significant changes to the ENS, including impairment of cholinergic, noradrenergic and sensory innervation, and myenteric neuronal loss were prominent in Winnie mice. Treatment with a single dose of bone marrow-derived MSCs was ineffective in attenuating chronic inflammation and enteric neuropathy in Winnie.

Therapeutic effects of mesenchymal stem cells and vitamin D on Bleomycin triggered lung damage in male adult albino rats

ABSTRACT Bleomycin is a cancer chemotherapeutic agent that induces pulmonary fibrosis. Vitamin D plays an immunomodulation role. Bone marrow-derived mesenchymal stem cells have a strong therapeutic effect in fatal pulmonary fibrosis. The objective of this study was to evaluate the significance of vitamin D and bone marrow mesenchymal stem cells as therapeutic agents on lung injuries caused by Bleomycin in adult male rats. Thirty-five adult male albino rats were allocated into five experimental groups. The control group was the group I. The group given a single intratracheal instillation of Bleomycin was group II. The group was given vitamin D3 for 2 days before Bleomycin administration was group III. Group IV was the group that was injected by a single dose of mesenchymal stem cells (MSCs) after 4 weeks of Bleomycin injection. Group V was the withdrawal group. Histological, immunohistochemical, and ultrastructural techniques were used to process and evaluate lung tissues. The lung of group 2 was demonstrated interalveolar septal thickening by RBCs, infiltration of mononuclear cells, deposition of collagen, and marked positive alpha-smooth muscle actin immunoreactivity. Mesenchymal stem cells derived from bone marrow can diminish Bleomycin-generated fibrosis of the lungs and inflammation in rats better than vitamin D treatment.

Preclinical studies and clinical trials on mesenchymal stem cell therapy for knee osteoarthritis: A systematic review on models and cell doses.

To provide a systematic analysis of the study design in knee osteoarthritis (OA) preclinical studies, focusing on the characteristics of animal models and cell doses, and to compare these to the characteristics of clinical trials using mesenchymal stem cells (MSCs) for the treatment of knee OA. A systematic and comprehensive search was conducted using the PubMed, Web of Science, Ovid, and Embase electronic databases for research papers published in 2009-2020 on testing MSC treatment in OA animal models. The PubMed database and ClinicalTrials.gov website were used to search for published studies reporting clinical trials of MSC therapy for knee OA. In total, 9234 articles and two additional records were retrieved, of which 120 studies comprising preclinical and clinical studies were included for analysis. Among the preclinical studies, rats were the most commonly used species for modeling knee OA, and anterior cruciate ligament transection was the most commonly used method for inducing OA. There was a correlation between the cell dose and body weight of the animal. In clinical trials, there was large variation in the dose of MSCs used to treat knee OA, ranging from 1×106 to 200×106 cells with an average of 37.91×106 cells. Mesenchymal stem cells have shown great potential in improving pain relief and tissue protection in both preclinical and clinical studies of knee OA. Further high-quality preclinical and clinical studies are needed to explore the dose effectiveness relationship of MSC therapy and to translate the findings from preclinical studies to humans.