Inhibition of T Lymphocyte (TL) Proliferation by Mesenchymal Stem Cells (MSCs): Role of Cell Contact between MSCs and TL, Role of MSCs Dose Effect, and Role of Soluble Factors and Adhesion Molecules Expressed by MSCs.

Abstract Mesenchymal stem cells (MSCs) can inhibit T lymphocyte (TL) proliferation in mixed lymphocyte reaction (MLR) and are candidate to induce tolerance of allogeneic haematopoietic stem cell graft. Results of previous studies evaluating the role of cell contact between MSCs and TL are contradictory. Some soluble factors produced by MSCs have been shown to be involved in TL inhibition such as Transforming Growth Factor-b (TGF-b), Hepatocyte Growth Factor (HGF), and Indoleamine 2,3 dioxygenase (IDO). In this study inhibition of TL proliferation in MLR was evaluated in cultures with MSCs-TL contact and in cultures without MSCs-TL contact (transwell), at different concentration of MSCs (ratio MSCs/TL: 0.3, 0.1, 0.03, 0.01). Expression of mRNA encoding cytokines and adhesion molecules produced by MSCs were analysed by semi-quantitative RT-PCR. Inhibitory cytokines studied were IDO, HLA-G, LIF, IL-10, TGF-b and HGF; adhesion molecules studied were VCAM and LFA3. Results of MSCs dose effect. In MLR with MSCs-TL contact, inhibition of proliferative index was related to the dose of MSCs. The percentage of inhibition was 74%, 60%, 48%, and 28% at ratio 0.3, 0.1, 0.03 and 0.01 respectively (p<0.05). In MLR without MSCs-TL contact, no dose effect was observed: the percentage of inhibition was 48%, 46% and 46% at ratio 0.3, 0.1 and 0.03 respectively; no inhibition was observed at ratio 0.01. Results of comparison between inhibition with cell contact and without cell contact. At ratio 0.3 the percentage of inhibition was 74% with cell contact and 48% without cell contact (p<0.05), at ration 0.1 the percentage of inhibition was 60% and 46% respectively (p<0.05). These results confirmed that TL inhibition is mediated by soluble factors but is increased when MSCs and TL are in contact. Results of mRNA RT-PCR in MSCs showed an overexpression of IDO, HLA-G and LIF in cultures with cell contact and without cell contact. In cultures with cell contact an overexpression of IL10 and TGF-b was observed, but not in cultures without cell contact. Adhesion molecules VCAM and LFA3 were overexpressed in both types of cultures with and without cell contact. In conclusion although cell contact is not mandatory to inhibit T cell proliferation, inhibition is higher when TL and MSCs are in contact, concomitantly an overexpression of additional inhibitory molecules is observed.

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Mesenchymal stem cells induce mature dendritic cells into a novel Jagged-2–dependent regulatory dendritic cell population

Blood ◽

10.1182/blood-2008-04-154138 ◽

2009 ◽

Vol 113 (1) ◽

pp. 46-57 ◽

Cited By ~ 199

Author(s):

Bin Zhang ◽

Rui Liu ◽

Dan Shi ◽

Xingxia Liu ◽

Yuan Chen ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Dendritic Cells ◽

Immune Cells ◽

Cell Contact ◽

Multilineage Differentiation ◽

Immunomodulatory Effects ◽

Cd11b Expression ◽

Dendritic Cell Population

Abstract Mesenchymal stem cells (MSCs), in addition to their multilineage differentiation, exert immunomodulatory effects on immune cells, even dendritic cells (DCs). However, whether they influence the destiny of full mature DCs (maDCs) remains controversial. Here we report that MSCs vigorously promote proliferation of maDCs, significantly reduce their expression of Ia, CD11c, CD80, CD86, and CD40 while increasing CD11b expression. Interestingly, though these phenotypes clearly suggest their skew to immature status, bacterial lipopolysaccharide (LPS) stimulation could not reverse this trend. Moreover, high endocytosic capacity, low immunogenicity, and strong immunoregulatory function of MSC-treated maDCs (MSC-DCs) were also observed. Furthermore we found that MSCs, partly via cell-cell contact, drive maDCs to differentiate into a novel Jagged-2–dependent regulatory DC population and escape their apoptotic fate. These results further support the role of MSCs in preventing rejection in organ transplantation and treatment of autoimmune disease.

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Insulin-Like Growth Factor Binding Protein-6 Promotes the Differentiation of Placental Mesenchymal Stem Cells into Skeletal Muscle Independent of Insulin-Like Growth Factor Receptor-1 and Insulin Receptor

Stem Cells International ◽

10.1155/2019/9245938 ◽

2019 ◽

Vol 2019 ◽

pp. 1-18 ◽

Cited By ~ 2

Author(s):

Doaa Aboalola ◽

Victor K. M. Han

Keyword(s):

Skeletal Muscle ◽

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Muscle Differentiation ◽

Insulin Like Growth Factor ◽

Differentiation Process ◽

Placental Mesenchymal Stem Cells

As mesenchymal stem cells (MSCs) are being investigated for regenerative therapies to be used in the clinic, delineating the roles of the IGF system in MSC growth and differentiation, in vitro, is vital in developing these cellular therapies to treat degenerative diseases. Muscle differentiation is a multistep process, starting with commitment to the muscle lineage and ending with the formation of multinucleated fibers. Insulin-like growth factor binding protein-6 (IGFBP-6), relative to other IGFBPs, has high affinity for IGF-2. However, the role of IGFBP-6 in muscle development has not been clearly defined. Our previous studies showed that in vitro extracellular IGFBP-6 increased myogenesis in early stages and could enhance the muscle differentiation process in the absence of IGF-2. In this study, we identified the signal transduction mechanisms of IGFBP-6 on muscle differentiation by placental mesenchymal stem cells (PMSCs). We showed that muscle differentiation required activation of both AKT and MAPK pathways. Interestingly, we demonstrated that IGFBP-6 could compensate for IGF-2 loss and help enhance the muscle differentiation process by triggering predominantly the MAPK pathway independent of activating either IGF-1R or the insulin receptor (IR). These findings indicate the complex interactions between IGFBP-6 and IGFs in PMSC differentiation into the skeletal muscle and that the IGF signaling axis, specifically involving IGFBP-6, is important in muscle differentiation. Moreover, although the major role of IGFBP-6 is IGF-2 inhibition, it is not necessarily the case that IGFBP-6 is the main modulator of IGF-2.

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Notch Signaling Pathway in Hematopoietic Stem Cells Is Activated through Interactive Communication with Mesenchymal Stem Cells.

Blood ◽

10.1182/blood.v110.11.1408.1408 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1408-1408

Author(s):

Yuji Kikuchi ◽

Akihiro Kume ◽

Masashi Urabe ◽

Hiroaki Mizukami ◽

Takahiro Suzuki ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Notch Signaling ◽

Notch Signaling Pathway ◽

Cell Contact ◽

Rt Pcr ◽

Interactive Communication ◽

Hematopoietic Stem ◽

Notch Ligands

Abstract Mesenchymal stem cells (MSCs), which are key elements of hematopoietic microenvironment in bone marrow, are known to play a critical role in supporting hematopoiesis. A variety of hematopoietic growth factors are produced from MSCs, and cell-to-cell contact is also believed to be crucial in the interaction between hematopoietic stem cells (HSCs) and MSCs. However, the molecular mechanisms of hematopoiesis-supporting ability of MSCs are still unclear. In particular, there is little information regarding the effects of HSCs on MSC function. In the present study, we investigated the cellular and molecular events in the interactive communication between HSCs and MSCs using a differentiation-inducible MSC model; i.e. parent C3H10T1/2 cells and 10T1/2-derived cell lines, A54 preadipocytes and M1601 myoblasts. These cells were co-cultured with murine HSCs (Lin-Sca1+) isolated from bone marrow. There was 9-fold increase in the number of hematopoietic progenitors after co-culture with A54 preadipocytes, whereas there was no increase when co-cultured with parent 10T1/2 or M1601 cells. More intriguingly, cobblestone areas were observed only when HSCs were co-cultured with A54 cells. Quantitative RT-PCR showed that A54 cells express significantly higher levels of SCF, SDF-1, and angiopoietin-1 (Ang-1) compared with parent 10T1/2 cells and M1601 cells, although these cytokines were not up-regulated when co-cultured with HSCs. To search for the genes involved in the interaction between HSCs and MSCs, we compared gene expression profiles before and after the co-culture by using a microarray analysis. Among the candidate genes with up-regulation after the co-culture, we paid attention to the Notch system, because Notch ligands are considered to play an important role in nurturing HSCs within the hematopoietic microenvironment. As a result, the expression of Notch ligands, Jagged1 and Dll3, increased in A54 cells after the coculture with HSCs. On the other hand, the expression of Notch1 and Hes-1 also increased in HSCs upon co-culture with A54 cells. These data were confirmed by quantitative RT-PCR. Moreover, when HSCs were co-cultured with A54 cells without cell-to-cell contact using Transwell permeable supports, there was neither increase in the number of progenitors in the upper wells, nor the up-regulation of Notch ligands in A54 cells in the lower wells. These findings support the idea that HSCs act on MSCs to induce the expression of Notch ligands via direct cell-to-cell contact and that the Notch ligands derived from MSCs act on HSCs in turn to activate Notch signaling pathway, possibly leading to the cobblestone formation with the maintenance of immature state of HSCs. The Notch system may be one of the critical elements in the interactive communication between HSCs and MSCs.

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Differentiation of Mesenchymal Stem Cells from Rat Bone Marrow into Dopaminergic Neuron-Like Cells In Vitro.

Blood ◽

10.1182/blood.v110.11.4067.4067 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4067-4067

Author(s):

Li Chen ◽

Dongmei He ◽

Yuan Zhang

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Growth Factor ◽

Dopaminergic Neuron ◽

Bone Marrow Mscs ◽

Rt Pcr ◽

Promising Source ◽

Rat Bone

Abstract Mesenchymal stem cells (MSC) from bone marrow cavity are multipotent cells. Their primary function is to support the growth and differentiation of hematologic progenitors. MSCs have been shown to differentiate into a variety of cell types including: bone, adipocytes, cartilage, neuron-like, and muscle-like cells. This project aimed to induce MSCs from rat bone marrow into mature dopamine secreting cells. MSCs were isolated from rat bone marrow, cultured and passaged. After propagating for three generations in vitro culture, MSCs were induced by epidermal growth factor, basic fibroblast growth factor and retinoic acid. After induction, morphologic change was examined by light microscope. NSE,MAP-2a, b and tyrosine hydroxylase (TH) was examined by immunocytochemistry. The related genes of the differentiated neurons, such as Nurr-1, nestin, mash-1,DR2-L,AADC and TH were detected by RT-PCR. After MSCs were inducted for 7 days,14 days and 21 days, dopamine production and release in the extract and medium of dopaminergic-induced cultured cells was assayed by dopamine ELISA. After 14 days of induction, MSC showed neuron-like morphologic changes and expressed NSE, MAP-2a, b and TH. RT-PCR. showed that these induced cells expressed nerves stem cells gene Nestin,Nurr-1 and dopamine nerves gene mash-1,DR2-L,AADC,TH. Most importantly, dopamine ELISA analysis showed the evidence of dopamine release in the extract and medium of dopaminergic-induced clonal MSCs. The results suggest that bone marrow MSCs from rat can be induced to differentiate into dopaminergic neuron-like cells in vitro. Bone marrow MSCs will provide a promising source of neural progenitor cells and may be a favorable candidate for cellular therapy of Parkinson’s disease.

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Paracrine interactions between mesenchymal stem cells and macrophages are regulated by 1,25-dihydroxyvitamin D3

Scientific Reports ◽

10.1038/s41598-017-15217-8 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 8

Author(s):

Laura Saldaña ◽

Gema Vallés ◽

Fátima Bensiamar ◽

Francisco José Mancebo ◽

Eduardo García-Rey ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Three Dimensional ◽

Soluble Factors ◽

Dihydroxyvitamin D3 ◽

Inflammatory Cytokine Production ◽

1,25 Dihydroxyvitamin D3 ◽

Important Regulator ◽

Matrix Maturation

Abstract Mesenchymal stem cells (MSC) modulate the macrophage-mediated inflammatory response through the secretion of soluble factors. In addition to its classical effects on calcium homeostasis, 1,25-dihydroxyvitamin D3 (1,25D3) has emerged as an important regulator of the immune system. The present study investigates whether 1,25D3 modulates the paracrine interactions between MSC and macrophages. 1,25D3 stimulated MSC to produce PGE2 and VEGF and regulated the interplay between macrophages and MSC toward reduced pro-inflammatory cytokine production. Conditioned media (CM) from co-cultures of macrophages and MSC impaired MSC osteogenesis. However, MSC cultured in CM from 1,25D3-treated co-cultures showed increased matrix maturation and mineralization. Co-culturing MSC with macrophages prevented the 1,25D3-induced increase in RANKL levels, which correlated with up-regulation of OPG secretion. MSC seeding in three-dimensional (3D) substrates potentiated their immunomodulatory effects on macrophages. Exposure of 3D co-cultures to 1,25D3 further reduced the levels of soluble factors related to inflammation and chemotaxis. As a consequence of 1,25D3 treatment, the recruitment of monocytes toward CM of 3D co-cultures decreased, while the osteogenic maturation of MSC increased. These data add new insights into the pleiotropic effects of 1,25D3 on the crosstalk between MSC and macrophages and highlight the role of the hormone in bone regeneration.

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Elucidating the Pivotal Role of Immune Players in the Management of COVID-19: Focus on Mesenchymal Stem Cells and Inflammation

Current Stem Cell Research & Therapy ◽

10.2174/1574888x15666200705213751 ◽

2020 ◽

Vol 15 ◽

Author(s):

Seidu A. Richard ◽

Sylvanus Kampo ◽

Marian Sackey ◽

Maite Esquijarosa Hechavarria ◽

Alexis D. B. Buunaaim ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Disease Burden ◽

Viral Disease ◽

Inflammatory Factors ◽

Rt Pcr ◽

Chain Reaction ◽

Paracrine Secretion ◽

Polymerase Chain

: The world is currently engulfed with a viral disease with no cure. So, far, millions of people are infected with the virus across the length and breadth of world with thousand losing their lives each passing day. The WHO is February 2020 classified the virus as a coronavirus and the name Coronavirus-19 (CoV-19) was offered to the virus. The disease caused by the virus was termed coronavirus disease-19 (COVID-19). The pathogenesis of COVID-19 is associated with elevation of several immune plays as well as inflammatory factors which contributes to cytokine storms. Currently, the detection of CoV-19 RNA is through reverse transcriptase polymerase chain reaction (RT-PCR). Mesenchymal stem cells (MSCs) are capable of suppressing several kinds of cytokines via the paracrine secretion system. Therefore, MSCs therapy could be game charges in the treatment of the current COVID-19 pandemic. Also, intravenous IG may be capable of suppressing the high expression of IL-6 by the CoV-19 resulting in lessen disease burden. Anti-inflammatory medications like, corticosteroids, tocilizumab, glycyrrhetinic acid, as well as etoposide may be very advantageous in decreasing the COVID-19 burden because, their mode of action targets the cytokine storms initiated by the CoV-19. It is important to indicate that, these medication does not target the virus itself. Therefore, potent CoV-19 anti-viral medications are needed to completely cure patients with COVID-19. Also, a vaccine is urgently needed to stop the spread of the virus. This review therefore elucidates the immune players in the management of COVID-19; focusing principally on MSCs and inflammatory mediators.

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