Therapeutic effects of in vivo-differentiated stem cell and Matricaria chamomilla L. Oil in diabetic rabbit

Adipose tissue derived mesenchymal stem cell (ADSC)-based therapy is attractive for liver diseases, but the long-term therapeutic outcome is still far from satisfaction due to low hepatic engraftment efficiency of...

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Mesenchymal Stromal (stem) Cell (MSC) therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury

European Respiratory Journal ◽

10.1183/13993003.04216-2020 ◽

2021 ◽

pp. 2004216

Author(s):

Claudia C. dos Santos ◽

Hajera Amatullah ◽

Chirag M. Vaswani ◽

Tatiana Maron-Gutierrez ◽

Michael Kim ◽

...

Keyword(s):

Stem Cell ◽

Lung Injury ◽

Conditioned Media ◽

Therapeutic Effects ◽

Host Immune System ◽

Gene And Protein Expression ◽

Stromal Stem Cell ◽

Mesenchymal Stromal Stem Cell ◽

Deficient Mice

Although mesenchymal stromal (stem) cell (MSC) administration attenuates sepsis-induced lung injury in pre-clinical models, the mechanism(s) of action and host immune system contributions to its therapeutic effects, remain elusive. We show that treatment with MSCs decreased expression of host-derived microRNA (miR)-193b-5p and increased expression of its target gene, the tight junctional protein occludin (Ocln), in lungs from septic mice. Mutating the Ocln 3′ UTR miR-193b-5p binding sequence impaired binding to Ocln mRNA. Inhibition of miR-193b-5p in human primary pulmonary microvascular endothelial cells (HPMECs) prevents tumor necrosis factor (TNF)-induced decrease in Ocln gene and protein expression and loss of barrier function. MSC conditioned media mitigated TNF-induced miR-193b-5p upregulation and Ocln downregulation in vitro. When administered in vivo, MSC conditioned media recapitulated the effects of MSC administration on pulmonary miR-193b-5p and Ocln expression. MiR-193b deficient mice were resistant to pulmonary inflammation and injury induced by LPS instillation. Silencing of Ocln in miR-193b deficient mice partially recovered the susceptibility to LPS-induced lung injury. In vivo inhibition of miR-193b-5p protected mice from endotoxin-induced lung injury. Finally, the clinical significance of these results was supported by the finding of increased miR-193b-5p expression levels in lung autopsy samples from Acute Respiratory Distress Syndrome patients who died with diffuse alveolar damage.

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Regulation of JAM2 Expression in the Lungs of Streptozotocin-Induced Diabetic Mice and Human Pluripotent Stem Cell-Derived Alveolar Organoids

Biomedicines ◽

10.3390/biomedicines8090346 ◽

2020 ◽

Vol 8 (9) ◽

pp. 346 ◽

Cited By ~ 2

Author(s):

Roya Rasaei ◽

Eunbi Kim ◽

Ji-Young Kim ◽

Sunghun Na ◽

Jung-Hyun Kim ◽

...

Keyword(s):

Stem Cell ◽

Pluripotent Stem Cell ◽

Causative Factor ◽

Human Mesenchymal Stem Cell ◽

Therapeutic Effects ◽

Diabetic Mice ◽

Human Pluripotent Stem Cell ◽

Potential Indicator

Hyperglycemia is a causative factor in the pathogenesis of respiratory diseases, known to induce fibrosis and inflammation in the lung. However, little attention has been paid to genes related to hyperglycemic-induced lung alterations and stem cell applications for therapeutic use. In this study, our microarray data revealed significantly increased levels of junctional adhesion molecule 2 (JAM2) in the high glucose (HG)-induced transcriptional profile in human perivascular cells (hPVCs). The elevated level of JAM2 in HG-treated hPVCs was transcriptionally and epigenetically reversible when HG treatment was removed. We further investigated the expression of JAM2 using in vivo and in vitro hyperglycemic models. Our results showed significant upregulation of JAM2 in the lungs of streptozotocin (STZ)-induced diabetic mice, which was greatly suppressed by the administration of conditioned medium obtained from human mesenchymal stem cell cultures. Furthermore, JAM2 was found to be significantly upregulated in human pluripotent stem cell-derived multicellular alveolar organoids by exposure to HG. Our results suggest that JAM2 may play an important role in STZ-induced lung alterations and could be a potential indicator for predicting the therapeutic effects of stem cells and drugs in diabetic lung complications.

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Chronic AMPK inactivation slows SHH medulloblastoma progression by inhibiting mTORC1 signaling and depleting tumor stem cell populations

10.1101/2021.12.09.471978 ◽

2021 ◽

Author(s):

Taylor Dismuke ◽

Daniel S Malawsky ◽

Hedi Liu ◽

Jay Brenman ◽

Andrey Tikunov ◽

...

Keyword(s):

Stem Cell ◽

Genetic Model ◽

Cellular Heterogeneity ◽

Tumor Stem Cell ◽

Cell Populations ◽

Therapeutic Effects ◽

Conditional Expression ◽

Mtorc1 Signaling ◽

Stem Cell Populations

We show that inactivating AMPK in vivo in a genetic model of medulloblastoma depletes tumor stem cell populations and slows tumor progression. Medulloblastoma, the most common malignant pediatric brain tumor, grows as heterogenous communities comprising diverse types of tumor and stromal cells. We have previously shown that different types of cells in medulloblastomas show different sensitivities to specific targeted therapies. To determine if specific populations depend on AMPK, we analyzed mice with AMPK-inactivated medulloblastomas. We engineered mice with brain-wide, conditional deletion of the AMPK catalytic subunits Prkaa1 and Prkaa2 and conditional expression SmoM2, an oncogenic Smo allele that hyperactivates Sonic Hedgehog (SHH) signaling. We compared the medulloblastomas that formed in these mice to tumors that form in AMPK-intact mice with conditional SmoM2 expression. AMPK-inactivated tumors progressed more slowly, allowing longer event-free survival. AMPK inactivation altered the cellular heterogeneity, determined by scRNA-seq, increasing differentiation, decreasing tumor stem cell populations and reducing glio-neuronal multipotency. Mechanistically, AMPK inactivation altered glycolytic gene expression and decreased mTORC1 pathway activation. Hk2-deletion reproduced key aspects of the AMPK-inactivation phenotype, implicating altered glycolysis in the tumor suppressive effect of AMPK inactivation. Our results show that AMPK inactivation impairs tumor growth through mechanisms that disproportionately affect tumor stem cell populations. As stem cells are intrinsically resistant to current cytotoxic therapy that drives recurrence, finding ways to target these populations may prevent treatment failure. Our data suggest that targeted AMPK inactivation may produce therapeutic effects in tumor stem cell populations refractory to other therapeutic approaches.

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A novel peptide with a potential to enhance sorafenib’s therapeutic effects in hepatocellular carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13505 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13505-e13505

Author(s):

Joline Sijing Lim ◽

Todor Dimitrov ◽

Kol Jia Yong ◽

Chong Gao ◽

Daniel G Tenen ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Stem Cell ◽

Tumor Growth ◽

Mechanism Of Action ◽

Stem Cell Factor ◽

Tumor Burden ◽

Therapeutic Effects ◽

Novel Approach

e13505 Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide, with chemotherapy or targeted therapy such as sorafenib achieving limited success. Recently stem cell factor SALL4 has emerged as a novel oncogene associated with leukemogenesis and is also implicated in many solid tumors. We have observed that SALL4 is not expressed in adult human liver tissues, but expressed in 30-40% of liver cancer, and this is associated with poorer prognosis and overall survival. We further tested whether inhibition of SALL4 function could be used for HCC treatment. Methods: A novel peptide blocking SALL4 function was designed and used to treat HCC lines with or without SALL4 expression. This is followed by evaluation for binding affinity, tumor growth inhibitory activity and mechanism of action. Treated cells were then transplanted in vivo into NOD/SCID mice and monitored for tumor growth. Comparison and/or combination of peptide with sorafenib were also carried out. Further modification of the peptide was done to allow for in vivo administration. Results: The peptide can effectively block SALL4 function. When used to treat HCC cell lines, it showed inhibitory effects in SNU398 cells (SALL4 expression), but not SNU387 cells (non-SALL4 expression). Post-xenotransplant, mice which received cells treated with peptide had slower rate of tumor growth (p=0.028) and lower tumor burden at dissection 26 days post transplant (p=0.048). Searching for its mechanism of action, we discovered that the peptide could affect the PTEN/AKT pathway, which was validated by western blot. When the peptide was combined with sorafenib, decreased cell viability was observed (p=0.03), suggestive of at least an additive effect between the peptide and sorafenib. Modification of peptide with TAT-protein showed similar inhibition of growth in vitro and was tested for further in-vivo usage through intraperitoneal injection. Conclusions: Our proof-of-principle studies have showed that a peptide blocking the function of stem cell factor SALL4 can be used as a novel approach for treating HCC. Combined with sorafenib, it may be able to enhance cell death and potentially lead to better outcomes in HCC patients.

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Photoreceptor protection by mesenchymal stem cell transplantation identifies exosomal MiR-21 as a therapeutic for retinal degeneration

Cell Death and Differentiation ◽

10.1038/s41418-020-00636-4 ◽

2020 ◽

Author(s):

Chun-Lei Deng ◽

Cheng-Biao Hu ◽

Sheng-Tao Ling ◽

Na Zhao ◽

Li-Hui Bao ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Stem Cell Transplantation ◽

Retinal Degeneration ◽

Cell Transplantation ◽

Therapeutic Effects ◽

Mesenchymal Stem Cell Transplantation ◽

Programmed Cell Death 4 ◽

Functional Regulation

Abstract Photoreceptor apoptosis is recognized as one key pathogenesis of retinal degeneration, the counteraction of which represents a promising approach to safeguard visual function. Recently, mesenchymal stem cell transplantation (MSCT) has demonstrated immense potential to treat ocular disorders, in which extracellular vesicles (EVs), particularly exosomes, have emerged as effective ophthalmological therapeutics. However, whether and how MSCT protects photoreceptors against apoptotic injuries remains largely unknown. Here, we discovered that intravitreal MSCT counteracted photoreceptor apoptosis and alleviated retinal morphological and functional degeneration in a mouse model of photoreceptor loss induced by N-methyl-N-nitrosourea (MNU). Interestingly, effects of MSCT were inhibited after blockade of exosomal generation by GW4869 preconditioning. Furthermore, MSC-derived exosomal transplantation (EXOT) effectively suppressed MNU-provoked photoreceptor injury. Notably, therapeutic efficacy of MSCT and EXOT on MNU-induced retinal degeneration was long-lasting as photoreceptor preservance and retinal maintenance were detected even after 1–2 months post to injection for only once. More importantly, using a natural occurring retinal degeneration model caused by a nonsense mutation of Phosphodiesterase 6b gene (Pde6bmut), we confirmed that MSCT and EXOT prevented photoreceptor loss and protected long-term retinal function. In deciphering therapeutic mechanisms regarding potential exosome-mediated communications, we identified that miR-21 critically maintained photoreceptor viability against MNU injury by targeting programmed cell death 4 (Pdcd4) and was transferred from MSC-derived exosomes in vivo for functional regulation. Moreover, miR-21 deficiency aggravated MNU-driven retinal injury and was restrained by EXOT. Further experiments revealed that miR-21 mediated therapeutic effects of EXOT on MNU-induced photoreceptor apoptosis and retinal dysfunction. These findings uncovered the efficacy and mechanism of MSCT-based photoreceptor protection, indicating exosomal miR-21 as a therapeutic for retinal degeneration.

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Experimental Strategies of Mesenchymal Stem Cell Propagation: Adverse Events and Potential Risk of Functional Changes

Stem Cells International ◽

10.1155/2019/7012692 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 22

Author(s):

Katarzyna Drela ◽

Luiza Stanaszek ◽

Adam Nowakowski ◽

Zuzanna Kuczynska ◽

Barbara Lukomska

Keyword(s):

Stem Cell ◽

Negative Impact ◽

Ex Vivo ◽

Biological Properties ◽

Therapeutic Effects ◽

Functional Changes ◽

Cell Propagation ◽

Ex Vivo Culture

Mesenchymal stem cells (MSCs) are attractive candidates for cell-based tissue repair approaches. Hundreds of clinical trials using MSCs have been completed and many others are still being investigated. For most therapeutic applications, MSC propagation in vitro is often required. However, ex vivo culture condition is not fully physiological and may affect biological properties of MSCs including their regenerative potential. Moreover, both cell cryopreservation and labelling procedure prior to infusion may have the negative impact on their expected effect in vivo. The incidence of MSC transformation during in vitro culture should be also taken into consideration before using cells in stem cell therapy. In our review, we focused on different aspects of MSC propagation that might influence their regenerative properties of MSC. We also discussed the influence of different factors that might abolish MSC proliferation and differentiation as well as potential impact of stem cell senescence and aging. Despite of many positive therapeutic effects of MSC therapy, one has to be conscious about potential cell changes that could appear during manufacturing of MSCs.

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Spontaneous apoptosis of cells in therapeutic stem cell preparation exert immunomodulatory effects through release of phosphatidylserine

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00688-z ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Xuemei He ◽

Weiqi Hong ◽

Jingyun Yang ◽

Hong Lei ◽

Tianqi Lu ◽

...

Keyword(s):

Stem Cell ◽

Chemokine Receptor ◽

Apoptotic Cell ◽

Underlying Mechanism ◽

Therapeutic Effects ◽

Apoptotic Cells ◽

Protective Effects ◽

Cell Preparation ◽

Cord Injury

AbstractMesenchymal stem cell (MSC)-mediated immunomodulation has been harnessed for the treatment of human diseases, but its underlying mechanism has not been fully understood. Dead cells, including apoptotic cells have immunomodulatory properties. It has been repeatedly reported that the proportion of nonviable MSCs in a MSC therapeutic preparation varied from 5~50% in the ongoing clinical trials. It is conceivable that the nonviable cells in a MSC therapeutic preparation may play a role in the therapeutic effects of MSCs. We found that the MSC therapeutic preparation in the present study had about 5% dead MSCs (DMSCs), characterized by apoptotic cells. Namely, 1 × 106 MSCs in the preparation contained about 5 × 104 DMSCs. We found that the treatment with even 5 × 104 DMSCs alone had the equal therapeutic effects as with 1 × 106 MSCs. This protective effect of the dead MSCs alone was confirmed in four mouse models, including concanavalin A (ConA)- and carbon tetrachloride (CCl4)-induced acute liver injury, LPS-induced lung injury and spinal cord injury. We also found that the infused MSCs died by apoptosis in vivo. Furthermore, the therapeutic effect was attributed to the elevated level of phosphatidylserine (PS) upon the injection of MSCs or DMSCs. The direct administration of PS liposomes (PSLs) mimic apoptotic cell fragments also exerted the protective effects as MSCs and DMSCs. The Mer tyrosine kinase (MerTK) deficiency or the knockout of chemokine receptor C–C motif chemokine receptor 2 (CCR2) reversed these protective effects of MSCs or DMSCs. These results revealed that DMSCs alone in the therapeutic stem cell preparation or the apoptotic cells induced in vivo may exert the same immunomodulatory property as the “living MSCs preparation” through releasing PS, which was further recognized by MerTK and participated in modulating immune cells.

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Challenges and Controversies in Human Mesenchymal Stem Cell Therapy

Stem Cells International ◽

10.1155/2019/9628536 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 75

Author(s):

Barbara Lukomska ◽

Luiza Stanaszek ◽

Ewa Zuba-Surma ◽

Pawel Legosz ◽

Sylwia Sarzynska ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Cell Therapy ◽

Stem Cell Therapy ◽

Human Mesenchymal Stem Cell ◽

Complex Nature ◽

Specific Cell ◽

Therapeutic Effects ◽

Mesenchymal Stem Cell Therapy

Stem cell therapy is being intensely investigated within the last years. Expectations are high regarding mesenchymal stem cell (MSC) treatment in translational medicine. However, many aspects concerning MSC therapy should be profoundly defined. Due to a variety of approaches that are investigated, potential effects of stem cell therapy are not transparent. On the other hand, most results of MSC administration in vivo have confirmed their safety and showed promising beneficial outcomes. However, the therapeutic effects of MSC-based treatment are still not spectacular and there is a potential risk related to MSC applications into specific cell niche that should be considered in long-term observations and follow-up outcomes. In this review, we intend to address some problems and critically discuss the complex nature of MSCs in the context of their effective and safe applications in regenerative medicine in different diseases including graft versus host disease (GvHD) and cardiac, neurological, and orthopedic disorders.

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Emerging Antioxidant Paradigm of Mesenchymal Stem Cell-Derived Exosome Therapy

Frontiers in Endocrinology ◽

10.3389/fendo.2021.727272 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chen Xia ◽

Zhanqiu Dai ◽

Yongming Jin ◽

Pengfei Chen

Keyword(s):

Oxidative Stress ◽

Stem Cell ◽

Mesenchymal Stem Cell ◽

Direct Reduction ◽

Antioxidant Properties ◽

Therapeutic Effects ◽

Diverse Range ◽

Anti Inflammatory

Mesenchymal stem cell-derived exosomes have been under investigation as potential treatments for a diverse range of diseases, and many animal and clinical trials have achieved encouraging results. However, it is well known that the biological activity of the exosomes is key to their therapeutic properties; however, till date, it has not been completely understood. Previous studies have provided different explanations of therapeutic mechanisms of the exosomes, including anti-inflammatory, immunomodulatory, and anti-aging mechanisms. The pathological effects of oxidative stress often include organ damage, inflammation, and disorders of material and energy metabolism. The evidence gathered from research involving animal models indicates that exosomes have antioxidant properties, which can also explain their anti-inflammatory and cytoprotective effects. In this study, we have summarized the antioxidant effects of exosomes in in vivo and in vitro models, and have evaluated the anti-oxidant mechanisms of exosomes by demonstrating a direct reduction in excessive reactive oxygen species (ROS), promotion of intracellular defence of anti-oxidative stress, immunomodulation by inhibiting excess ROS, and alteration of mitochondrial performance. Exosomes exert their cytoprotective and anti-inflammatory properties by regulating the redox environment and oxidative stress, which explains the therapeutic effects of exosomes in a variety of diseases, mechanisms that can be well preserved among different species.

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