scholarly journals Safety of Intraovarian Injection of Human Mesenchymal Stem Cells in a Premature Ovarian Insufficiency Mouse Model

2021 ◽  
Vol 30 ◽  
pp. 096368972098850
Author(s):  
Hang-Soo Park ◽  
Rishi Man Chugh ◽  
Amro Elsharoud ◽  
Mara Ulin ◽  
Sahar Esfandyari ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Mouse Model ◽  
Ovarian Function ◽  
Imaging System ◽  
Whole Body ◽  
Ovarian Insufficiency ◽  
Cell Based Therapy ◽  
Human Dna

Primary ovarian insufficiency (POI), a condition in which there is a loss of ovarian function before the age of 40 years, leads to amenorrhea and infertility. In our previously published studies, we demonstrated recovery of POI, correction of serum sex hormone levels, increase in the granulosa cell population, and restoration of fertility in a chemotherapy-induced POI mouse model after intraovarian transplantation of human bone marrow-derived mesenchymal stem cells (hBM-MSCs). While hBM-MSC may be a promising cell source for treatment of POI, there are few reports on the safety of stem cell-based therapy for POI. For future clinical applications, the safety of allogenic hBM-MSCs for the treatment of POI through intraovarian engraftment needs to be addressed and verified in appropriate preclinical models. In this study, we induced POI in C57/BL6 mice using chemotherapy, then treated the mice with hBM-MSCs (500,000 cells/ovary) by intraovarian injection. After hBM-MSC treatment, we analyzed the migration of engrafted cells by genomic DNA polymerase chain reaction (PCR) using a human-specific ALU repeat and by whole-body sectioning on a cryo-imaging system. We examined the possibility of transfer of human DNA from the hBM-MSCs to the resulting offspring, and compared the growth rate of offspring to that of normal mice and hBM-MSC-treated mice. We found that engrafted hBM-MSCs were detected only in mouse ovaries and did not migrate into any other major organs including the heart, lungs, and liver. Further, we found that no human DNA was transferred into the fetus. Interestingly, the engrafted cells gradually decreased in number and had mostly disappeared after 4 weeks. Our study demonstrates that intraovarian transplantation of hBM-MSCs could be a safe stem cell-based therapy to restore fertility in POI patients.

scholarly journals Fetal liver mesenchymal stem cells restore ovarian function in premature ovarian insufficiency by targeting MT1

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Boxian Huang ◽  
Chunfeng Qian ◽  
Chenyue Ding ◽  
Qingxia Meng ◽  
Qinyan Zou ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Cell Therapy ◽  
Stem Cell Therapy ◽  
Ovarian Function ◽  
Ovarian Insufficiency ◽  
Apoptotic Genes

Abstract Background With the development of regenerative medicine and tissue engineering technology, almost all stem cell therapy is efficacious for the treatment of premature ovarian failure (POF) or premature ovarian insufficiency (POI) animal models, whereas little stem cell therapy has been practiced in clinical settings. The underlying molecular mechanism and safety of stem cell treatment in POI are not fully understood. In this study, we explored whether fetal mesenchymal stem cells (fMSCs) from the liver restore ovarian function and whether melatonin membrane receptor 1 (MT1) acts as a regulator for treating POI disease. Methods We designed an in vivo model (chemotherapy-induced ovary damage) and an in vitro model (human ovarian granulosa cells (hGCs)) to understand the efficacy and molecular cues of fMSC treatment of POI. Follicle development was observed by H&E staining. The concentration of sex hormones in serum (E2, AMH, and FSH) and the concentration of oxidative and antioxidative metabolites and the enzymes MDA, SOD, CAT, LDH, GR, and GPx were measured by ELISA. Flow cytometry (FACS) was employed to detect the percentages of ROS and proliferation rates. mRNA and protein expression of antiapoptotic genes (SURVIVIN and BCL2), apoptotic genes (CASPASE-3 and CASPASE-9), and MT1 and its downstream genes (JNK1, PCNA, AMPK) were tested by qPCR and western blotting. MT1 siRNA and related antagonists were used to assess the mechanism. Results fMSC treatment prevented cyclophosphamide (CTX)-induced follicle loss and recovered sex hormone levels. Additionally, fMSCs significantly decreased oxidative damage, increased oxidative protection, improved antiapoptotic effects, and inhibited apoptotic genes in vivo and in vitro. Furthermore, fMSCs also upregulated MT1, JNK1, PCNA, and AMPK at the mRNA and protein levels. With MT1 knockdown or antagonist treatment in normal hGCs, the protein expression of JNK1, PCNA, and AMPK and the percentage of proliferation were impaired. Conclusions fMSCs might play a crucial role in mediating follicular development in the POI mouse model and stimulating the activity of POI hGCs by targeting MT1.

scholarly journals Human umbilical cord mesenchymal stem cells restore the ovarian metabolome and rescue premature ovarian insufficiency in mice

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yan Zhao ◽  
Jiao Ma ◽  
Peiye Yi ◽  
Jun Wu ◽  
Feiyan Zhao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Umbilical Cord ◽  
Ovarian Function ◽  
Premature Ovarian Insufficiency ◽  
Reproductive Capacity ◽  
Human Umbilical Cord ◽  
Ovarian Insufficiency

Abstract Background Premature ovarian insufficiency (POI) is an ovarian dysfunction that seriously affects a woman’s physiological health and reproduction. Mesenchymal stem cell (MSC) transplantation offers a promising treatment option for ovarian restoration in rodent POI models. However, the efficacy and mechanism of it remain unclear. Methods POI mice model was generated by cyclophosphamide and busulfan, followed with the treatment of tail-vein injection of the human umbilical cord mesenchymal stem cells (hUCMSCs). Maternal physiological changes and offspring behavior were detected. To reveal the pathogenesis and therapeutic mechanisms of POI, we first compared the metabolite profiles of healthy and POI ovarian tissues using untargeted metabolomics analyses. After stem cell therapy, we then collected the ovaries from control, POI, and hUCMSC-treated POI groups for lipid metabolomics and pseudotargeted metabolomics analysis. Results Our results revealed remarkable changes of multiple metabolites, especially lipids, in ovarian tissues after POI generation. Following the transplantation of clinical-grade hUCMSCs, POI mice exhibited significant improvements in body weight, sex hormone levels, estrous cycles, and reproductive capacity. Lipid metabolomics and pseudotargeted metabolomics analyses for the ovaries showed that the metabolite levels in the POI group, mainly lipids, glycerophospholipids, steroids, and amino acids changed significantly compared with the controls’, and most of them returned to near-healthy levels after receiving hUCMSC treatment. Meanwhile, we also observed an increase of monosaccharide levels in the ovaries from POI mice and a decrease after stem cell treatment. Conclusions hUCMSCs restore ovarian function through activating the PI3K pathway by promoting the level of free amino acids, consequently improving lipid metabolism and reducing the concentration of monosaccharides. These findings provide potential targets for the clinical diagnosis and treatment of POI.

scholarly journals Label-Free Rapid Separation and Enrichment of Bone Marrow-Derived Mesenchymal Stem Cells from a Heterogeneous Cell Mixture Using a Dielectrophoresis Device

Sensors ◽  
2018 ◽  
Vol 18 (9) ◽  
pp. 3007 ◽  
Author(s):  
Junya Yoshioka ◽  
Yu Ohsugi ◽  
Toru Yoshitomi ◽  
Tomoyuki Yasukawa ◽  
Naoki Sasaki ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Gradient Method ◽  
Label Free ◽  
Rapid Separation ◽  
Isolation System ◽  
Tissue Samples ◽  
Cell Based Therapy

Bone marrow-derived mesenchymal stem cells (BMSCs) are an important cell resource for stem cell-based therapy, which are generally isolated and enriched by the density-gradient method based on cell size and density after collection of tissue samples. Since this method has limitations with regards to purity and repeatability, development of alternative label-free methods for BMSC separation is desired. In the present study, rapid label-free separation and enrichment of BMSCs from a heterogeneous cell mixture with bone marrow-derived promyelocytes was successfully achieved using a dielectrophoresis (DEP) device comprising saw-shaped electrodes. Upon application of an electric field, HL-60 cells as models of promyelocytes aggregated and floated between the saw-shaped electrodes, while UE7T-13 cells as models of BMSCs were effectively captured on the tips of the saw-shaped electrodes. After washing out the HL-60 cells from the device selectively, the purity of the UE7T-13 cells was increased from 33% to 83.5% within 5 min. Although further experiments and optimization are required, these results show the potential of the DEP device as a label-free rapid cell isolation system yielding high purity for rare and precious cells such as BMSCs.

Stem cell-based therapy for Parkinson’s disease with a focus on human endometrium-derived mesenchymal stem cells

2018 ◽  
Vol 234 (2) ◽  
pp. 1326-1335 ◽  
Author(s):  
Saeid Bagheri-Mohammadi ◽  
Mohammad Karimian ◽  
Behrang Alani ◽  
Javad Verdi ◽  
Rana Moradian Tehrani ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Stem Cells ◽  
Parkinson's Disease ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Human Endometrium ◽  
Cell Based Therapy

scholarly journals Glutathione–Allylsulfur Conjugates as Mesenchymal Stem Cells Stimulating Agents for Potential Applications in Tissue Repair

2020 ◽  
Vol 21 (5) ◽  
pp. 1638 ◽  
Author(s):  
Emilia Di Giovanni ◽  
Silvia Buonvino ◽  
Ivano Amelio ◽  
Sonia Melino
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Tissue Repair ◽  
Dermal Fibroblasts ◽  
Water Soluble ◽  
Dependent Manner ◽  
Tissue Repair And Regeneration ◽  
Stem Cell Delivery ◽  
Cell Based Therapy

The endogenous gasotransmitter H2S plays an important role in the central nervous, respiratory and cardiovascular systems. Accordingly, slow-releasing H2S donors are powerful tools for basic studies and innovative pharmaco-therapeutic agents for cardiovascular and neurodegenerative diseases. Nonetheless, the effects of H2S-releasing agents on the growth of stem cells have not been fully investigated. H2S preconditioning can enhance mesenchymal stem cell survival after post-ischaemic myocardial implantation; therefore, stem cell therapy combined with H2S may be relevant in cell-based therapy for regenerative medicine. Here, we studied the effects of slow-releasing H2S agents on the cell growth and differentiation of cardiac Lin− Sca1+ human mesenchymal stem cells (cMSC) and on normal human dermal fibroblasts (NHDF). In particular, we investigated the effects of water-soluble GSH–garlic conjugates (GSGa) on cMSC compared to other H2S-releasing agents, such as Na2S and GYY4137. GSGa treatment of cMSC and NHDF increased their cell proliferation and migration in a concentration dependent manner with respect to the control. GSGa treatment promoted an upregulation of the expression of proteins involved in oxidative stress protection, cell–cell adhesion and commitment to differentiation. These results highlight the effects of H2S-natural donors as biochemical factors that promote MSC homing, increasing their safety profile and efficacy after transplantation, and the value of these donors in developing functional 3D-stem cell delivery systems for cardiac muscle tissue repair and regeneration.

scholarly journals Chronic Toxicity Test in Cynomolgus Monkeys For 98 Days with Repeated Intravenous Infusion of Cynomolgus Umbilical Cord Mesenchymal Stem Cells

2017 ◽  
Vol 43 (3) ◽  
pp. 891-904 ◽  
Author(s):  
Jie He ◽  
Guang-ping Ruan ◽  
Xiang Yao ◽  
Ju-fen Liu ◽  
Xiang-qing Zhu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Umbilical Cord ◽  
Intravenous Infusion ◽  
Dose Group ◽  
High Dose ◽  
Human Umbilical Cord ◽  
Cynomolgus Monkeys ◽  
Cell Based Therapy

Background/Aims: Stem cell-based therapy is attractive in many clinical studies, but current data on the safety of stem cell applications remains inadequate. This study observed the safety, immunological effect of cynomolgus monkey umbilical cord mesenchymal stem cells (mUC-MSCs) injected into cynomolgus monkeys, in order to evaluate the safety of human umbilical cord mesenchymal stem cells (hUC-MSCs) prepared for human clinical application. Methods: Eighteen cynomolgus monkeys were divided into three groups. Group 1 is control group, Group 2 is low-dose group, Group 3 is high-dose group. After repeated administrations of mUC-MSCs, cynomolgus monkeys were observed for possible toxic reactions. Results: During the experiment, no animal died. There were no toxicological abnormalities in body weight, body temperature, electrocardiogram, coagulation and pathology. In the groups 2 and 3, AST and CK transiently increased, and serum inorganic P slightly decreased. All animals were able to recover at 28 days after the infusion was stopped. In the groups 2 and 3, CD3+ and IL-6 levels significantly increased, and recovery was after 28 days of infusion. There were no obvious pathological changes associated with the infusion of cells in the general and microscopic examinations. Conclusions: The safe dosage of repeated intravenous infusion of mUC-MSCs in cynomolgus monkeys is 1.0 × 107/kg, which is 10 times of that in clinical human use.

scholarly journals Mesenchymal Stem Cells and COVID-19: Cure, Prevention, and Vaccination

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Mehrdad Afarid ◽  
Fatemeh Sanie-Jahromi
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Viral Disease ◽  
Host Immune System ◽  
Immune Disorder ◽  
Efficient Treatment ◽  
Cell Based Therapy ◽  
Rapid Spread ◽  
Global Health Problem

COVID-19 disease has been a global health problem since late 2019. There are many concerns about the rapid spread of this disease, and yet, there is no approved treatment for COVID-19. Several biological interventions have been under study recently to investigate efficient treatment for this viral disease. Besides, many efforts have been made to find a safe way to prevent and vaccinate people against COVID-19 disease. In severe cases, patients suffer from acute respiratory distress syndrome usually associated with an increased level of inflammatory cytokines, called a cytokine storm. It seems that reequilibrating the hyperinflammatory response of the host immune system and regeneration of damaged cells could be the main way to manage the disease. Mesenchymal stem cells (MSCs) have been recently under investigation in this regard, and the achieved clinical outcomes show promising evidence for stem cell-based therapy of COVID-19. MSCs are known for their potential for immunomodulation, defense against virus infection, and tissue regeneration. MSCs are a newly emerged platform for designing vaccines and show promising evidence in this area. In the present study, we provided a thorough research study on the most recent clinical studies based on stem cells in the treatment of COVID-19 while introducing stem cell exclusivities for use as an immune disorder or lung cell therapy and its potential application for protection and vaccination against COVID-19.

scholarly journals Effect of CoCl2 or H2O2 pre-conditioned mesenchymal stem cells in a mouse model of pulmonary fibrosis

2018 ◽  
Vol 5 (4) ◽  
pp. 2208-2222
Author(s):  
Alpana Dave ◽  
Srabani Kar ◽  
Ena Ray Banerjee
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Pulmonary Fibrosis ◽  
Mouse Model ◽  
Structural Changes ◽  
Airway Remodeling ◽  
Proliferative Potential ◽  
Matrix Deposition ◽  
Cell Based Therapy

Introduction: Pulmonary Fibrosis is characterized by excessive matrix deposition which leads to airway remodeling and disruption of the typical architecture of the lung parenchyma. The disease progression is associated with a high mortality rate. The current treatment for pulmonary fibrosis includes drugs which either reduce progression of the disease or provide symptomatic relief. Multiple studies have examined the effect of cell-based therapy in pulmonary fibrosis. We investigated the effect of administration of pre-conditioned bone marrow-derived mesenchymal stem cells (BMMSC) in a mouse model of pulmonary fibrosis. Methods: Firstly, we examined the effect of pre-conditioning on the cells using cell-based assays. We found that pre-conditioning did not significantly alter cell proliferation or led to cellular inflammation. The cells continued to express MSC marker, CD105, and pluripotency marker Oct3/4. Next, we evaluated the proliferative and anti-inflammatory potential of BMMSC administration using a series of assays in a mouse model of pulmonary fibrosis. Bleomycin was administered to induce pulmonary fibrosis in mice on Day 0. MSCs were administered on day 1 and day 3; the mice were sacrificed on day 22, and their tissues were collected for analysis. Results: We found that similar to untreated cells, administration of pre-conditioned cells resulted in an increase in the proliferative potential and reduction in inflammation in the lung tissue, bronchoalveolar lavage, bone marrow, and blood. We observed reduction in the number of granulocytes in peripheral blood upon MSC administration. However, we did not observe any structural changes in the lung upon MSC administration. We found a small reduction in collagen content in the lung which was also seen upon staining with Masson's trichrome. Conclusion: These results demonstrate that pre-conditioned BM-MSC lead to improvement in the disease state through paracrine effects but pre-conditioning of cells for 24 hours does not significantly improve the beneficial effect of MSC administration.

scholarly journals Cell-Based Therapy for Stroke

Stroke ◽  
2020 ◽  
Vol 51 (9) ◽  
pp. 2854-2862 ◽  
Author(s):  
You Jeong Park ◽  
Kuniyasu Niizuma ◽  
Maxim Mokin ◽  
Mari Dezawa ◽  
Cesar V. Borlongan
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Stem Cell ◽  
Ischemic Stroke ◽  
Cell Therapy ◽  
Therapeutic Potential ◽  
Host Tissue ◽  
In Vivo Models ◽  
Cell Based Therapy ◽  
Muse Cells

Stem cell-based regenerative therapies may rescue the central nervous system following ischemic stroke. Mesenchymal stem cells exhibit promising regenerative capacity in in vitro studies but display little to no incorporation in host tissue after transplantation in in vivo models of stroke. Despite these limitations, clinical trials using mesenchymal stem cells have produced some functional benefits ascribed to their ability to modulate the host’s inflammatory response coupled with their robust safety profile. Regeneration of ischemic brain tissue using stem cells, however, remains elusive in humans. Multilineage-differentiating stress-enduring (Muse) cells are a distinct subset of mesenchymal stem cells found sporadically in connective tissue of nearly every organ. Since their discovery in 2010, these endogenous reparative stem cells have been investigated for their therapeutic potential against a variety of diseases, including acute myocardial infarction, stroke, chronic kidney disease, and liver disease. Preclinical studies have exemplified Muse cells’ unique ability mobilize, differentiate, and engraft into damaged host tissue. Intravenously transplanted Muse cells in mouse lacunar stroke models afforded functional recovery and long-term engraftment into the host neural network. This mini-review article highlights these biological properties that make Muse cells an exceptional candidate donor source for cell therapy in ischemic stroke. Elucidating the mechanism behind the therapeutic potential of Muse cells will undoubtedly help optimize stem cell therapy for stroke and advance the field of regenerative medicine.

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