Comparison between the therapeutic effects of differentiated and undifferentiated Wharton's jelly mesenchymal stem cells in rats with streptozotocin-induced diabetes

Extracellular matrix (ECM) components play an important role in maintaining skeletal muscle function, but excessive accumulation of ECM components interferes with skeletal muscle regeneration after injury, eventually inducing fibrosis. Increased oxidative stress level caused by dystrophin deficiency is a key factor in fibrosis in Duchenne muscular dystrophy (DMD) patients. Mesenchymal stem cells (MSCs) are considered a promising therapeutic agent for various diseases involving fibrosis. In particular, the paracrine factors secreted by MSCs play an important role in the therapeutic effects of MSCs. In this study, we investigated the effects of MSCs on skeletal muscle fibrosis. In 2–5-month-old mdx mice intravenously injected with 1 × 105 Wharton’s jelly (WJ)-derived MSCs (WJ-MSCs), fibrosis intensity and accumulation of calcium/necrotic fibers were significantly decreased. To elucidate the mechanism of this effect, we verified the effect of WJ-MSCs in a hydrogen peroxide-induced fibrosis myotubes model. In addition, we demonstrated that matrix metalloproteinase-1 (MMP-1), a paracrine factor, is critical for this anti-fibrotic effect of WJ-MSCs. These findings demonstrate that WJ-MSCs exert anti-fibrotic effects against skeletal muscle fibrosis, primarily via MMP-1, indicating a novel target for the treatment of muscle diseases, such as DMD.

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Evaluating the Differential Effects of Valproic Acid on Wharton’s Jelly Mesenchymal Stem Cells

Advanced Pharmaceutical Bulletin ◽

10.15171/apb.2019.059 ◽

2019 ◽

Vol 9 (3) ◽

pp. 497-504 ◽

Cited By ~ 1

Author(s):

Homa Salami ◽

Seyed Javad Mowal ◽

Rasoul Moukhah ◽

Zahra Hajebrahimi ◽

Seyed Abdolhakim Hosseini ◽

...

Keyword(s):

Stem Cells ◽

Valproic Acid ◽

Mesenchymal Stem Cells ◽

Neural Differentiation ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Differential Effects ◽

Wharton's Jelly ◽

Differentiation Medium ◽

Pluripotency Markers

Purpose: The histone deacetylases (HDAC) inhibitor, valproic acid (VPA), is a common antiepileptic drug and is attractive for its broad range of therapeutic effects on many diseases. It has been employed as an inducer of pluripotency in some cultured cells. Conversely, VPA has also been employed as an inducer of in vitro differentiation in many other cells. Therefore, we employed WJMSCs as a cellular target to evaluate the differential effects of of VPA on potency state and differentiation level of Wharton’s Jelly mesenchymal stem cells (WJMSCs) in various concentrations and different culture mediums. Methods: The isolated WJMSCs were cultured in DMEM (MSC medium). According to previous protocols, WJMSCs were treated with 0, 0.5 and 1 mM VPA in MSC or embryonic stem cell (ESC) medium and 2 mM VPA in neural differentiation medium. Real-time polymerase chain reaction (PCR) and western blot analysis were performed for evaluating the expression of pluripotency markers. MTT and caspase assays were also performed on VPA-treated cells. Results: The expression of pluripotency markers and the viability of the WJMSCs – determined by MTT assay – were significantly increased after 0.5 mM VPA treatment in ESC medium. A 2 mM VPA treatment in neural differentiation medium significantly diminished the expression of pluripotency markers and the viability of WJMSCs. Conclusion: According to our results, both VPA concentration and the medium context can influence VPA effects on WJMSCs. The differential effects of VPA on WJMSCs can reflect its wide range of effects in the treatment of various diseases.

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Wharton’s Jelly Derived Mesenchymal Stem Cells: Future of Regenerative Medicine? Recent Findings and Clinical Significance

BioMed Research International ◽

10.1155/2015/430847 ◽

2015 ◽

Vol 2015 ◽

pp. 1-11 ◽

Cited By ~ 82

Author(s):

Ilona Kalaszczynska ◽

Katarzyna Ferdyn

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Adult Stem Cells ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Ethical Concerns ◽

Wharton's Jelly ◽

Privileged Status ◽

Therapeutic Properties

Around 5 million annual births in EU and 131 million worldwide give a unique opportunity to collect lifesaving Wharton’s jelly derived mesenchymal stem cells (WJ-MSC). Evidences that these cells possess therapeutic properties are constantly accumulating. Collection of WJ-MSC is done at the time of delivery and it is easy and devoid of side effects associated with collection of adult stem cells from bone marrow or adipose tissue. Likewise, their rate of proliferation, immune privileged status, lack of ethical concerns, nontumorigenic properties make them ideal for both autologous and allogeneic use in regenerative medicine applications. This review provides an outline of the recent findings related to WJ-MSC therapeutic effects and possible advantage they possess over MSC from other sources. Results of first clinical trials conducted to treat immune disorders are highlighted.

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CHIP Reverses Hyperglycemia-associated PTEN Stability in Wharton's Jelly Derived Mesenchymal Stem Cells and Promotes Its Therapeutic Potential Against Diabetes-induced Cardiac Injury

10.21203/rs.3.rs-165217/v1 ◽

2021 ◽

Author(s):

Ayaz Ali ◽

Wei-Wen Kuo ◽

Chia-Hua Kuo ◽

Jeng-Feng Lo ◽

Ray-Jade Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Cardiac Injury ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Downstream Signaling ◽

Wharton's Jelly ◽

Induced Apoptosis ◽

And Oxidative Stress

Abstract BackgroundRecent studies indicate that umbilical cord stem cells are cytoprotective against several disorders. One critical limitation in using stem cells is reduction in their viability under stressful conditions, such as diabetes. However, the molecular intricacies responsible for diabetic conditions are not fully elucidated.MethodsEffects of HG on Wharton's jelly derived mesenchymal stem cells (WJMSCs) viability was evaluated by MTT assay and flow cytometry. The mechanism responsible for HG-induced PTEN degradation was assessed using loss and gain of function, immunofluorescence, co-immunoprecipitation, and western blot analysis. Co-culturing of CHIP-overexpressed WJMSCs with embryo derived cardiomyoblasts was performed to analyze their ameliorative effects. The therapeutic effects of CHIP expressing WJMSCs were further validated in Sprague Dawley male (eight weeks old) STZ-induced diabetic animals by echocardiography, immunohistochemistry, hematoxylin eosin, and masson’s trichrome and TUNEL staining. Multiple comparisons were accessed through one‐way ANOVA and p-Value of <0.05 was considered statistically signiﬁcant. ResultsIn this study, we found that high glucose (HG) conditions induced loss of chaperone homeostasis, stabilized PTEN, triggered the downstream signaling cascade, and induced apoptosis and oxidative stress in Wharton's jelly derived mesenchymal stem cells (WJMSCs). Increased CHIP expression promoted PTEN degradation via the ubiquitin-proteasome system and shortened its half-life during HG stress. Docking studies confirmed the interaction of CHIP with PTEN and FOXO3a with the Bim promoter region. Further, it was found that the chaperone system is involved in CHIP-mediated PTEN proteasomal degradation. CHIP depletion stabilizes PTEN whereas PTEN inhibition showed an inverse effect. CHIP overactivation suppressed the binding of FOXO3a with bim. Co-culturing CHIP overexpressed WJMSCs suppressed HG-induced apoptosis and oxidative stress in cardiac cells. Finally, CHIP overexpression and PTEN inhibition minimized blood glucose levels, improved body and heart weight, and rescued hyperglycemia-induced cardiac injury in diabetic rats. ConclusionThe current study suggests that CHIP confers resistance to apoptosis and oxidative stress and modulates PTEN and the downstream signaling cascade by promoting PTEN proteasomal degradation, thereby potentially exerting therapeutic effects against diabetes-induced cardiomyopathies.

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Comparative Proteomic Analysis of the Mesenchymal Stem Cells Secretome from Adipose, Bone Marrow, Placenta and Wharton’s Jelly

International Journal of Molecular Sciences ◽

10.3390/ijms22020845 ◽

2021 ◽

Vol 22 (2) ◽

pp. 845

Author(s):

Sungho Shin ◽

Jeongmin Lee ◽

Yumi Kwon ◽

Kang-Sik Park ◽

Jae-Hoon Jeong ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Therapeutic Potential ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Human Mscs ◽

Paracrine Effects ◽

Wharton's Jelly ◽

Different Sources

Mesenchymal stem cells (MSCs) have the potential to be a viable therapy against various diseases due to their paracrine effects, such as secretion of immunomodulatory, trophic and protective factors. These cells are known to be distributed within various organs and tissues. Although they possess the same characteristics, MSCs from different sources are believed to have different secretion potentials and patterns, which may influence their therapeutic effects in disease environments. We characterized the protein secretome of adipose (AD), bone marrow (BM), placenta (PL), and Wharton’s jelly (WJ)-derived human MSCs by using conditioned media and analyzing the secretome by mass spectrometry and follow-up bioinformatics. Each MSC secretome profile had distinct characteristics depending on the source. However, the functional analyses of the secretome from different sources showed that they share similar characteristics, such as cell migration and negative regulation of programmed cell death, even though differences in the composition of the secretome exist. This study shows that the secretome of fetal-derived MSCs, such as PL and WJ, had a more diverse composition than that of AD and BM-derived MSCs, and it was assumed that their therapeutic potential was greater because of these properties.

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Therapeutic Effects of Genetically Modified Wharton’s Jelly Mesenchymal Stem Cells Expressing Erythropoietin on Breast Cancer-related Anemia in Mice Model

10.21203/rs.3.rs-84099/v2 ◽

2021 ◽

Author(s):

Mohammad Estiri ◽

Bahareh Estiri ◽

Asghar Fallah ◽

Marzyeh Aghazadeh ◽

Amir Sedaqati ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Lentiviral Vector ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Mice Model ◽

Wharton's Jelly ◽

Therapy Strategy ◽

Cancer Related Anemia

Abstract Cancer-related anemia (CRA) negatively influences cancer patients’ survival, disease progression, treatment efficacy, and quality of life. Therefore, development of long-lasting and curative therapies is highly required. In this study, we developed cell and gene therapy strategy for in-vivo delivery of EPO cDNA via genetic engineering human Wharton’s jelly mesenchymal stem cells (hWJMSCs) to long-term produce human EPO protein after transplantation into the mice model of CRA. To evaluate CRA's treatment in cancer-free and cancerous conditions, we designed recombinant breast cancer cell line 4T1 expressing herpes simplex virus type 1 thymidine kinase (HSV1-TK) by a lentiviral vector encoding HSV1-TK and injected into mice. After confirming CRA in mice by blood analysis, half of them received ganciclovir for 10 days to clear cancer cells. Meanwhile, we designed another lentiviral vector encoding EPO to transduce hWJMSCs. Following implantation of rhWJMSCs-EPO, the whole peripheral blood samples were collected once per week for 10 weeks. The blood analyzing showed that plasma EPO, hemoglobin (Hb), and hematocrit (Hct) concentration significantly increased and remained at a therapeutic level for >10 weeks in the both treatment groups which indicate that the rhWJMSCs-EPO could improve CRA in both cancer-free and cancerous mice model.

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Wharton’s Jelly-Derived Mesenchymal Stem Cells Reduce Fibrosis in a Mouse Model of Duchenne Muscular Dystrophy by Upregulating microRNA 499

Biomedicines ◽

10.3390/biomedicines9091089 ◽

2021 ◽

Vol 9 (9) ◽

pp. 1089

Author(s):

Sang Eon Park ◽

Jang Bin Jeong ◽

Shin Ji Oh ◽

Sun Jeong Kim ◽

Hyeongseop Kim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Wharton’S Jelly ◽

Mdx Mice ◽

Therapeutic Effects ◽

Western Blots ◽

Muscle Disorders ◽

Wharton's Jelly

The aim of this study was to evaluate the therapeutic effects and mechanisms of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) in an animal model of Duchenne muscular dystrophy (DMD). Mdx mice (3–5 months old) were administered five different doses of WJ-MSCs through their tail veins. A week after injection, grip strength measurements, creatine kinase (CK) assays, immunohistochemistry, and western blots were performed for comparison between healthy mice, mdx control mice, and WJ-MSC-injected mdx mice. WJ-MSCs exerted dose-dependent multisystem therapeutic effects in mdx mice, by decreasing CK, recovering normal behavior, regenerating muscle, and reducing apoptosis and fibrosis in skeletal muscle. We also confirmed that miR-499-5p is significantly downregulated in mdx mice, and that intravenous injection of WJ-MSCs enhanced its expression, leading to anti-fibrotic effects via targeting TGFβR 1 and 3. Thus, WJ-MSCs may represent novel allogeneic “off-the-shelf” cellular products for the treatment of DMD and possibly other muscle disorders.

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Mitochondrial Transfer of Wharton’s Jelly Mesenchymal Stem Cells Eliminates Mutation Burden and Rescues Mitochondrial Bioenergetics in Rotenone-Stressed MELAS Fibroblasts

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/9537504 ◽

2019 ◽

Vol 2019 ◽

pp. 1-17 ◽

Cited By ~ 3

Author(s):

Tsu-Kung Lin ◽

Shang-Der Chen ◽

Yao-Chung Chuang ◽

Min-Yu Lan ◽

Jiin-Haur Chuang ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mitochondrial Diseases ◽

Wharton’S Jelly ◽

Mitochondrial Morphology ◽

Therapeutic Effects ◽

Wharton's Jelly ◽

Mutation Burden ◽

Mitochondrial Transfer ◽

Mitochondrial Functions

Wharton’s jelly mesenchymal stem cells (WJMSCs) transfer healthy mitochondria to cells harboring a mitochondrial DNA (mtDNA) defect. Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the major subgroups of mitochondrial diseases, caused by the mt.3243A>G point mutation in the mitochondrial tRNALeu(UUR) gene. The specific aim of the study is to investigate whether WJMSCs exert therapeutic effect for mitochondrial dysfunction in cells of MELAS patient through donating healthy mitochondria. We herein demonstrate that WJMSCs transfer healthy mitochondria into rotenone-stressed fibroblasts of a MELAS patient, thereby eliminating mutation burden and rescuing mitochondrial functions. In the coculture system in vitro study, WJMSCs transferred healthy mitochondria to rotenone-stressed MELAS fibroblasts. By inhibiting actin polymerization to block tunneling nanotubes (TNTs), the WJMSC-conducted mitochondrial transfer was abrogated. After mitochondrial transfer, the mt.3243A>G mutation burden of MELAS fibroblasts was reduced to an undetectable level, with long-term retention. Sequencing results confirmed that the transferred mitochondria were donated from WJMSCs. Furthermore, mitochondrial transfer of WJMSCs to MELAS fibroblasts improves mitochondrial functions and cellular performance, including protein translation of respiratory complexes, ROS overexpression, mitochondrial membrane potential, mitochondrial morphology and bioenergetics, cell proliferation, mitochondrion-dependent viability, and apoptotic resistance. This study demonstrates that WJMSCs exert bioenergetic therapeutic effects through mitochondrial transfer. This finding paves the way for the development of innovative treatments for MELAS and other mitochondrial diseases.

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Regenerative Potential of the Product “CardioCell” Derived from the Wharton’s Jelly Mesenchymal Stem Cells for Treating Hindlimb Ischemia

International Journal of Molecular Sciences ◽

10.3390/ijms20184632 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4632 ◽

Cited By ~ 3

Author(s):

Musiał-Wysocka ◽

Kot ◽

Sułkowski ◽

Majka

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Regenerative Medicine ◽

Wharton’S Jelly ◽

Great Promise ◽

Therapeutic Effects ◽

Hindlimb Ischemia ◽

Wharton's Jelly ◽

Cell Based Therapy ◽

Therapeutic Benefits

In recent years, mesenchymal stem cells (MSCs) have emerged as a promising therapeutic modality in regenerative medicine. They hold great promise for treating civilization-wide diseases, including cardiovascular diseases, such as acute myocardial infarction and critical limb ischemia. MSCs isolated from Wharton’s jelly (WJ-MSCs) may be utilized in both cell-based therapy and vascular graft engineering to restore vascular function, thereby providing therapeutic benefits for patients. The efficacy of WJ-MSCs lies in their multipotent differentiation ability toward vascular smooth muscle cells, endothelial cells and other cell types, as well as their capacity to secrete various trophic factors, which are potent in promoting angiogenesis, inhibiting apoptosis and modulating immunoreaction. Ischemic limb disease is caused by insufficient nutrient and oxygen supplies resulting from damaged peripheral arteries. The lack of nutrients and oxygen causes severe tissue damage in the limb, thereby resulting in severe morbidities and mortality. The therapeutic effects of the conventional treatments are still not sufficient. Cell transplantations in small animal model (mice) are vital for deciphering the mechanisms of MSCs’ action in muscle regeneration. The stimulation of angiogenesis is a promising strategy for the treatment of ischemic limbs, restoring blood supply for the ischemic region. In the present study, we focus on the therapeutic properties of the human WJ-MSCs derived product, Cardio. We investigated the role of CardioCell in promoting angiogenesis and relieving hindlimb ischemia. Our results confirm the healing effect of CardioCell and strongly support the use of the WJ-MSCs in regenerative medicine.

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Ethionamide Preconditioning Enhances the Proliferation and Migration of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21197013 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7013

Author(s):

Na-Hee Lee ◽

Su Hyeon Myeong ◽

Hyo Jin Son ◽

Jung Won Hwang ◽

Na Kyung Lee ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Protein Kinase ◽

Wharton’S Jelly ◽

Therapeutic Effects ◽

Migration Ability ◽

Wharton's Jelly ◽

Extracellular Signal ◽

And Migration ◽

Proliferation And Migration

Mesenchymal stem cells (MSCs) are a useful source for cell-based therapy of a variety of immune-mediated diseases, including neurodegenerative disorders. However, poor migration ability and survival rate of MSCs after brain transplantation hinder the therapeutic effects in the disease microenvironment. Therefore, we attempted to use a preconditioning strategy with pharmacological agents to improve the cell proliferation and migration of MSCs. In this study, we identified ethionamide via the screening of a drug library, which enhanced the proliferation of MSCs. Preconditioning with ethionamide promoted the proliferation of Wharton’s jelly-derived MSCs (WJ-MSCs) by activating phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase/extracellular signal-regulated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK)1/2 signaling. Preconditioning with ethionamide also enhanced the migration ability of MSCs by upregulating expression of genes associated with migration, such as C-X-C motif chemokine receptor 4 (CXCR4) and C-X-C motif chemokine ligand 12 (CXCL12). Furthermore, preconditioning with ethionamide stimulated the secretion of paracrine factors, including neurotrophic and growth factors in MSCs. Compared to naïve MSCs, ethionamide-preconditioned MSCs (ETH-MSCs) were found to survive longer in the brain after transplantation. These results suggested that enhancing the biological process of MSCs induced by ethionamide preconditioning presents itself as a promising strategy for enhancing the effectiveness of MSCs-based therapies.

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