Co-culture with cardiomyocytes enhanced the myogenic conversion of mesenchymal stromal cells in a dose-dependent manner

The use of human telomerase reverse transcriptase-immortalized bone marrow mesenchymal stromal cells (hTERT-BMSCs) as vehicles to deliver antinociceptive galanin (GAL) molecules into pain-processing centers represents a novel cell therapy strategy for pain management. Here, an hTERT-BMSCs/Tet-on/GAL cell line was constructed using a single Tet-on-inducible lentivirus system, and subsequent experiments demonstrated that the secretion of rat GAL from hTERT-BMSCs/Tet-on/GAL was switched on and off under the control of an inducer in a dose-dependent manner. The construction of this cell line is the first promising step in the regulation of GAL secretion from hTERT-immortalized BMSCs, and the potential application of this system may provide a stem cell-based research platform for pain.

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Bone marrow-derived mesenchymal stromal cells improve vascular regeneration and reduce leukocyte-endothelium activation in critical ischemic murine skin in a dose-dependent manner

Cytotherapy ◽

10.1016/j.jcyt.2014.05.008 ◽

2014 ◽

Vol 16 (10) ◽

pp. 1345-1360 ◽

Cited By ~ 16

Author(s):

Riccardo Schweizer ◽

Pranitha Kamat ◽

Dennis Schweizer ◽

Cyrill Dennler ◽

Shengye Zhang ◽

...

Keyword(s):

Bone Marrow ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Dependent Manner ◽

Vascular Regeneration ◽

Dose Dependent

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Mesenchymal stromal cells inhibit graft-versus-host disease of mice in a dose-dependent manner

Cytotherapy ◽

10.3109/14653240903502712 ◽

2010 ◽

Vol 12 (3) ◽

pp. 361-370 ◽

Cited By ~ 49

Author(s):

Sun-Young Joo ◽

Kyung-Ah Cho ◽

Yun-Jae Jung ◽

Han-Seong Kim ◽

Seong-Yeol Park ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Graft Versus Host Disease ◽

Stromal Cells ◽

Dependent Manner ◽

Host Disease ◽

Graft Versus Host ◽

Dose Dependent

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Role of leukemia inhibitor factor (LIF) in decidualisation of murine uterine stromal cells in vitro

Journal of Endocrinology ◽

10.1677/joe.0.1810477 ◽

2004 ◽

Vol 181 (3) ◽

pp. 477-492 ◽

Cited By ~ 19

Author(s):

AA Fouladi Nashta ◽

CV Andreu ◽

N Nijjar ◽

JK Heath ◽

SJ Kimber

Keyword(s):

In Vitro Culture ◽

Stromal Cells ◽

Control Level ◽

Calf Serum ◽

Prostaglandin E ◽

Dependent Manner ◽

Alp Activity ◽

Dose Dependent ◽

In Cells

Decidualisation of uterine stromal cells is a prerequisite for implantation of the embryo in mice. Here we have used an in vitro culture system in which stromal cells decidualise as indicated by a number of markers, including an increase in alkaline phosphatase (ALP) activity. The latter was used as a quantitative marker of decidualisation in the presence of low (2%) fetal calf serum. Prostaglandin E(2) (PGE(2)), which is known to induce decidualisation, increased ALP activity, and this effect was blocked in a dose-dependent manner by indomethacin. Leukemia inhibitory factor (LIF) was then examined, but it had no effect on PGE(2) secretion. However, LIF suppressed ALP activity in a dose-dependent manner in the presence of 2% serum, while an inhibitor of LIF that competes for binding to its receptor reversed the effect of LIF and increased ALP activity above the control level. In serum-free cultures, stromal cells differentiated rapidly, and no differences were observed between LIF-treated and untreated cultures. Stromal cells produce LIF during in vitro culture, and this peaked at 48 h. Freshly collected stromal cells from both day-2 and -4 pregnant mice expressed mRNA for the LIF receptor, and the transcript level was higher in cells isolated on day 4. However, no differences were observed in the relative levels of transcripts in cells from day 2 and day 4 after culture, nor were there differences between the LIF-treated cultures and controls. Therefore, in this study, we have shown that LIF suppresses decidualisation of murine uterine stromal cells in the presence of serum, this is not due to the regulation of PGE(2) secretion by stromal cells.

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The oncometabolite R-2-hydroxyglutarate dysregulates the differentiation of human mesenchymal stromal cells via inducing DNA hypermethylation

BMC Cancer ◽

10.1186/s12885-020-07744-x ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Lizhen Liu ◽

Kaimin Hu ◽

Jingjing Feng ◽

Huafang Wang ◽

Shan Fu ◽

...

Keyword(s):

Osteogenic Differentiation ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Chondrogenic Differentiation ◽

Cell Counting ◽

Human Mscs ◽

Mrna Levels ◽

Dependent Manner ◽

Dna Hypermethylation ◽

Cartilaginous Tumors

Abstract Background Isocitrate dehydrogenase (IDH1/2) gene mutations are the most frequently observed mutations in cartilaginous tumors. The mutant IDH causes elevation in the levels of R-enantiomer of 2-hydroxylglutarate (R-2HG). Mesenchymal stromal cells (MSCs) are reasonable precursor cell candidates of cartilaginous tumors. This study aimed to investigate the effect of oncometabolite R-2HG on MSCs. Methods Human bone marrow MSCs treated with or without R-2HG at concentrations 0.1 to 1.5 mM were used for experiments. Cell Counting Kit-8 was used to detect the proliferation of MSCs. To determine the effects of R-2HG on MSC differentiation, cells were cultured in osteogenic, chondrogenic and adipogenic medium. Specific staining approaches were performed and differentiation-related genes were quantified. Furthermore, DNA methylation status was explored by Illumina array-based arrays. Real-time PCR was applied to examine the signaling component mRNAs involved in. Results R-2HG showed no influence on the proliferation of human MSCs. R-2HG blocked osteogenic differentiation, whereas promoted adipogenic differentiation of MSCs in a dose-dependent manner. R-2HG inhibited chondrogenic differentiation of MSCs, but increased the expression of genes related to chondrocyte hypertrophy in a lower concentration (1.0 mM). Moreover, R-2HG induced a pronounced DNA hypermethylation state of MSC. R-2HG also improved promotor methylation of lineage-specific genes during osteogenic and chondrogenic differentiation. In addition, R-2HG induced hypermethylation and decreased the mRNA levels of SHH, GLI1and GLI2, indicating Sonic Hedgehog (Shh) signaling inhibition. Conclusions The oncometabolite R-2HG dysregulated the chondrogenic and osteogenic differentiation of MSCs possibly via induction of DNA hypermethylation, improving the role of R-2HG in cartilaginous tumor development.

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Strawberry-Derived Exosome-Like Nanoparticles Prevent Oxidative Stress in Human Mesenchymal Stromal Cells

Biomolecules ◽

10.3390/biom11010087 ◽

2021 ◽

Vol 11 (1) ◽

pp. 87

Author(s):

Francesca Perut ◽

Laura Roncuzzi ◽

Sofia Avnet ◽

Annamaria Massa ◽

Nicoletta Zini ◽

...

Keyword(s):

Oxidative Stress ◽

Vitamin C ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Mammalian Cells ◽

Dependent Manner ◽

Potential Health ◽

Human Mesenchymal Stromal Cells ◽

Health Promoting ◽

Size And Morphology

Plant-derived exosome-like nanovesicles (EPDENs) have recently been isolated and evaluated as potential bioactive nutraceutical biomolecules. It has been hypothesized that EPDENs may exert their activity on mammalian cells through their specific cargo. In this study, we isolated and purified EPDENs from the strawberry juice of Fragaria x ananassa (cv. Romina), a new cultivar characterized by a high content of anthocyanins, folic acid, flavonols, and vitamin C and an elevated antioxidant capacity. Fragaria-derived EPDENs were purified by a series of centrifugation and filtration steps. EPDENs showed size and morphology similar to mammalian extracellular nanovesicles. The internalization of Fragaria-derived EPDENs by human mesenchymal stromal cells (MSCs) did not negatively affect their viability, and the pretreatment of MSCs with Fragaria-derived EPDENs prevented oxidative stress in a dose-dependent manner. This is possibly due to the presence of vitamin C inside the nanovesicle membrane. The analysis of EPDEN cargo also revealed the presence of small RNAs and miRNAs. These findings suggest that Fragaria-derived EPDENs may be considered nanoshuttles contained in food, with potential health-promoting activity.

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Effect of nutritional supplement on bone marrow-derived mesenchymal stem cells from aplastic anaemia

British Journal Of Nutrition ◽

10.1017/s0007114518000399 ◽

2018 ◽

Vol 119 (7) ◽

pp. 748-758

Author(s):

Shihua Luo ◽

Yinghai Chen ◽

Lifen Zhao ◽

Xia Qi ◽

Xiaoyan Miao ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Aplastic Anaemia ◽

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Nutritional Supplement ◽

High Dose ◽

Intragastric Administration ◽

Dependent Manner ◽

Mineral Density

AbstractAplastic anaemia (AA) is characterised by pancytopenia resulting from a marked reduction in haemopoietic stem cells (HSC). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the bone marrow (BM) microenvironment, including BM-derived mesenchymal stromal cells (BMSC). The purpose of this study was to analyse the biological effect of nutritional supplement (NS), a dietary supplement consisting of thirty-six compounds: amino acids, nucleotides, vitamins and micronutrients on the BMSC of AA rats. The AA rat model was established by irradiating X-ray (2·5 Gy) and intraperitoneal injections of cyclophosphamide (35 mg/kg; Sigma) and chloramphenicol (35 mg/kg; Sigma). Then AA rats were fed with NS in a dose-dependent manner (2266·95, 1511·3, 1057·91 mg/kg d) by intragastric administration. The effect of NS on the BMSC of AA rats was analysed. As compared with AA rats, NS treatment significantly improved these peripheral blood parameters and stimulated the proliferation of total femoral nucleated cells. NS treatment affected proliferative behaviour of BMSC and suppressed BMSC differentiation to adipocytes. Furthermore, NS treatment of AA rats accelerated osteogenic differentiation of BMSC and enhanced bone mineral density. Co-incubation of HSC with mesenchymal stromal cells and serum from AA rats subjected to high-dose NS markedly improved the yield of CD34+cells. Protein microarray analysis revealed that there were eleven differentially expressed proteins in the NS group compared with the AA rat group. The identified specific NS might be implicated in rehabilitation of BMSC in AA rats, suggesting their potential of nutritional support in AA treatment.

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Copper Does Not Induce Tenogenic Differentiation but Promotes Migration and Increases Lysyl Oxidase Activity in Adipose-Derived Mesenchymal Stromal Cells

Stem Cells International ◽

10.1155/2020/9123281 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Marta Milewska ◽

Anna Burdzińska ◽

Katarzyna Zielniok ◽

Katarzyna Siennicka ◽

Sławomir Struzik ◽

...

Keyword(s):

Mesenchymal Stromal Cells ◽

Stromal Cells ◽

Lysyl Oxidase ◽

Tendon Healing ◽

Human Adipose Tissue ◽

Cellular Respiration ◽

Dependent Manner ◽

Cupric Sulfate ◽

Tenogenic Differentiation ◽

Secretion Profile

Background. Copper belongs to the essential trace metals that play a key role in the course of cellular processes maintaining the whole body’s homeostasis. As there is a growing interest in transplanting mesenchymal stromal cells (MSCs) into the site of injury to improve the regeneration of damaged tendons, the purpose of the study was to verify whether copper supplementation may have a positive effect on the properties of human adipose tissue-derived MSCs (hASCs) which potentially can contribute to improvement of tendon healing. Results. Cellular respiration of hASCs decreased with increasing cupric sulfate concentrations after 5 days of incubation. The treatment with CuSO4 did not positively affect the expression of genes associated with tenogenesis (COL1α1, COL3α1, MKX, and SCX). However, the level of COL1α1 protein, whose transcript was decreased in comparison to a control, was elevated after a 5-day exposition to 25 μM CuSO4. The content of the MKX and SCX protein in hASCs exposed to cupric sulfate was reduced compared to that of untreated control cells, and the level of the COL3α1 protein remained unchanged. The addition of cupric sulfate to hASCs’ medium increased the activity of lysyl oxidase which was positively correlated with concentration of CuSO4. Moreover, a high level of CuSO4 stimulated the action of intracellular superoxide dysmutase. The hASC secretion profile after a 5-day exposure to 50 μM cupric sulfate differed from that of untreated cells and was similar to the secretion profile of human tenocytes. Additionally, cupric sulfate increased secretion of CXCL12 in hASCs. Furthermore, the exposition to the CuSO4 significantly increased directed migration of human ASCs in a dose-dependent manner. Conclusion. Copper sulfate supplementation can have a beneficial effect on tendon regeneration not by inducing tenogenic differentiation, but by improving the recruitment of MSCs to the site of injury, where they can secrete growth factors, cytokines and chemokines, and prevent the effects of oxidative stress at the site of inflammation, as well as improve the stabilization of collagen fibers, thereby accelerating the process of tendon healing.

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Adoptive transfer of mesenchymal stromal cells accelerates intestinal epithelium recovery of irradiated mice in an interleukin-6-dependent manner

Cytotherapy ◽

10.3109/14653249.2012.684378 ◽

2012 ◽

Vol 14 (10) ◽

pp. 1164-1170 ◽

Cited By ~ 18

Author(s):

Moïra François ◽

Elena Birman ◽

Kathy-Ann Forner ◽

Louis Gaboury ◽

Jacques Galipeau

Keyword(s):

Mesenchymal Stromal Cells ◽

Intestinal Epithelium ◽

Adoptive Transfer ◽

Stromal Cells ◽

Interleukin 6 ◽

Dependent Manner

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CAL-101, a Potent Selective Inhibitor of the p110δ Isoform of Phosphatidylinositol 3-kinase, Attenuates Pathway Signaling, Induces Apoptosis, and Overcomes Signals From the Microenvironment In Cellular Models of Hodgkin Lymphoma

Blood ◽

10.1182/blood.v116.21.3926.3926 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3926-3926 ◽

Cited By ~ 1

Author(s):

Sarah A Meadows ◽

Adam Kashishian ◽

Dave Johnson ◽

Volker Diehl ◽

Brian Lannutti

Keyword(s):

Hodgkin Lymphoma ◽

Cell Lines ◽

Stromal Cells ◽

Specific Inhibitor ◽

Lymphocytic Leukemia ◽

Class I ◽

Clinical Activity ◽

Dependent Manner ◽

Cellular Models ◽

Dose Dependent

Abstract Abstract 3926 Phosphatidylinositide 3-kinases (PI3Ks) are a family of lipid kinases that are involved in signaling events which control a diverse number of cellular processes. The class I kinases contain 4 isoforms designated p110α, β, δ, γ, and are activated by cell surface receptors. Aberrant regulation of the PI3K signaling pathway is frequently observed in human malignancies including those of hematological origin. CAL-101 is an oral p110δ-specific inhibitor which has shown preclinical and clinical activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). This compound is a potent p110δ inhibitor (EC50 of 65 nM in a whole-blood assay) with >200-fold selectivity over the other class I PI3K isoforms and no activity against Class II and III PI3K family members or other PI3K-related proteins, including mTOR and DNA-PK. Prior in vitro NHL studies revealed that CAL-101 induces caspase-dependent apoptosis, and inhibits CD40L-, BAFF-, CXCL12- and CXCL13-derived survival signals in cellular models (Lannutti BJ, et al., Blood 2010). To investigate the potential role of p110δ in Hodgkin lymphoma (HL) we screened a number of HL cell lines for p110δ isoform expression and constitutive PI3K pathway activation. We report high levels of p110δ protein and activated Akt in 5 of 5 HL cell lines evaluated (L428, L540, L591, L1236, KM-H2). Inhibition of p110δ with CAL-101 treatment of cell lines resulted in a reduction of Akt phosphorylation and a decrease in cellular viability. Because previous studies have established the importance of signals from the microenvironment for the survival and proliferation of malignant cells as well as for their resistance to standard therapies, we investigated the effect of p110δ inhibition by CAL-101 in HL cell line-stroma cocultures. In this setting, CAL-101 overcame tumor cell growth induced by coculture of HL cells with bone marrow stromal cells. In addition, CAL-101 induced dose-dependent apoptosis of HL cells at 48 hours. Furthermore, stromal cell coculture resulted in increased CCL5, CCL17, and CCL22 levels; productions of these chemokines by HL cells cultured in the presence of stromal cells were reduced by CAL-101 in a dose-dependent manner. These results indicate that specific inhibition of p110δ may disrupt signals between HL cells and their microenvironment, thereby providing the preclinical rationale for clinical evaluation of CAL-101 as a novel therapeutic approach in patients with Hodgkin lymphoma. Disclosures: Meadows: Calistoga Pharmaceuticals: Employment. Kashishian:Calistoga Pharmaceuticals: Employment. Johnson:Calistoga Pharmaceuticals: Employment. Lannutti:Calistoga Pharmaceutical Inc.: Employment.

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