Intercellular nanotube-mediated mitochondrial transfer enhances T-cell metabolic fitness and antitumor efficacy
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PROVIDER: EGAS00001007356 | EGA |
REPOSITORIES: EGA
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Project description:Mitochondrial loss and dysfunction drive T cell exhaustion and represent major barriers to successful T cell immunotherapies. We found that mesenchymal stromal cells (MSC) establish nanotubular connections with T cells in a TLN2-dependent manner and leveraged these intercellular highways to supply new mitochondria to CD8+ T cells. Acquisition of MSC mitochondria increased T cell basal mitochondrial respiration and spare respiratory capacity. When transferred into tumor-bearing hosts, tumor-specific CD8+ T cells with donated mitochondria expanded more robustly, infiltrated the tumor more efficiently, and exhibited fewer signs of exhaustion compared to CD8+ T cells that did not take up mitochondria. As a result, mitochondria-boosted CD8+ T cells mediated superior antitumor responses, prolonging animal survival. To unravel the mechanisms behind mitochondrial transfer we performed RNA sequencing on CD8+ T cells that acquired donor mitochondria (MitoPositive), or did not acquire donor mitochondira (MitoNegative) directly after after co-culture (0hr timepoint).
2024-09-13 | GSE229487 | GEO
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Cellular interactions within the bone marrow microenvironment modulate the properties of subsets of leukemic cells leading to the development of drug-resistant phenotypes. The intercellular transfer of proteins and organelles contributes to this process but the set of transferred proteins and their effects in the receiving cells remain unclear. This study aimed to detect the intercellular protein transfer from mouse bone marrow stromal cells (OP9 cell line) to human T-lymphoblasts (CCRF-CEM cell line) using nanoLC-MS/MS-based shotgun proteomics in a 3D co-culture system. After 24 hours of co-culture, 1513 and 67 proteins from human and mouse origin respectively, were identified in human CCRF-CEM cells. The presence of mouse proteins in the human cell line, detected by analyzing the differences in amino acid sequences of orthologous peptides, was interpreted as the result of intercellular transfer. Although further validation is necessary, our results suggest that shotgun proteomic analyses of co-cultured cells from different species could be a simple option to get a preliminary survey of the proteins exchanged among interacting cells.
2022-12-15 | MSV000090911 | MassIVE
Project description:Mesenchymal stem cells (MSCs) have fueled ample translation for the treatment of immune mediated diseases. They exert immunoregulatory and tissue restoring effects. MSCmediated transfer of mitochondria (MitoT) had been demonstrated to rescue target organs from tissue damage. While the mechanism remains to be fully resolved, we explored the effect of MitoT on lymphoid cells. Here, we describe dose dependent MitoT from mitochondria-labelled MSCs mainly to T CD4+ rather than to T CD8+ or CD19+ B-cells. Artificial transfer of isolated MSC-derived mitochondria increased the expression of mRNA transcripts involved in T cell activation and T-regulatory cell differentiation including FOXP3, IL2RA, CTLA4 and TGFβ1, leading to an increase of a highly suppressive CD25+FoxP3+ population. In a GVHD mouse model, transplantation of MitoT-induced human T cells led to significant improvement in survival and reduction in tissue damage and organ T CD4+, CD8+ and IFNγ+ expressing cell infiltration. These findings point to a unique CD4+ T cell reprogramming mechanism with pre-clinical proof of concept data that pave the way for the exploration of organelle-based therapies in immune diseases.
2019-11-16 | GSE140483 | GEO
Project description:This dataset represent the RNA-seq, which was done on untreated small intestinal organoids; small intestinal organoids treated with chemotherapeutic, busulfan; untreated small intestinal organoids co-cultured wth mesenchymak stromal/stem cells (MSCs; busulfan treated small intestinal organoids co-cultured with MSCs. The same set of samples was done for 3 different primary bone marrow MSC donors.
| EGAD00001011176 | EGA
Project description:Mitochondria are the powerhouse of eukaryotic cells, which regulate cell metabolism and differentiation. Recently, mitochondrial transfer between cells has been shown to direct recipient cell fate. However, it is unclear whether mitochondria can translocate to stem cells and whether this transfer alters stem cell fate. Here, we examined mesenchymal stem cell (MSC) regulation by macrophages in the bone marrow environment. We found that macrophages promote osteogenic differentiation of MSCs by delivering mitochondria to MSCs. However, under osteoporotic conditions, macrophages with altered phenotypes and metabolic statuses release oxidatively damaged mitochondria. The transfer of dysfunctional mitochondria to MSCs triggers a reactive oxygen species burst, which leads to metabolic remodeling. We showed that abnormal metabolism in MSCs is caused by the abnormal succinate accumulation, which is a key factor in abnormal osteogenic differentiation. These results reveal that mitochondrial transfer from macrophages to MSCs allows metabolic crosstalk to regulate bone homeostasis. This mechanism identifies a potential target for the treatment of osteoporosis.
2022-09-11 | GSE198806 | GEO
Project description:Retinitis pigmentosa (RP) is a rod-cone degenerative disease that induces irreversible vision loss. Stem cell-derived extracellular vehicles (EVs) have been reported to prevent retinal neurons from apoptosis and inflammation, but the molecular mechanisms remained unclear. Here we probed the ability of mesenchymal stem cell-derived EVs (MSC-EVs) to protect the retinas of RP model mice rd10 and explored the underlying mechanisms. Treatment with MSC-EVs increased the survival of photoreceptors and preserved their structure and visual function. Mechanistically, MSC-EVs suppressed the activation of microglial, Müller glial, macrophages and the NF-κB pathway. MSC-EVs upregulated anti-inflammatory cytokines and downregulated pro-inflammatory cytokines. MSC-EVs application in vitro decreased the number of TUNEL-positive photoreceptor cell line 661W co-cultured with LPS-stimulated glial cell BV2, with similar impact on the cytokine expression as in vivo study. MiR-146a, one of the major miRNAs in MSC-EVs was upregulated in co-cultured cells after MSC-EVs treatment. Upregulation of miR-146a decreased the expression of the transcription factor Nr4a3, and its inhibition promoted Nr4a3 expression in both cells. Nr4a3 was further identified as the target gene of miR-146a. Therefore, MSC-EVs delays retinal degeneration in rd10 mice mainly by its anti-inflammatory effect via the miR-146a-Nr4a3 axis, indicating a strong potential of applying MSC-EVs to treat neurodegenerative diseases.
2022-04-16 | GSE200621 | GEO
Project description:This depository contains data from two bulk RNA sequencing experiments:
1) Bulk RNA sequencing data of peripheral blood neutrophils from healthy donors cultured with a) human adipose-derived stromal cells (ADSC) as a model for mesenchymal stromal cells (MSC), and b) IL-1β stimulated ADSC as a model for inflammatory MSC as found in multiple myeloma (MM).
2) Bulk RNA sequencing data from ADSCs cultured a) without stimuli, b) with recombinant human IL-1β, c) with supernatant from iMSC-like cells, d) with neutrophils previously cultured with MSC, e) with neutrophils previously cultured with iMSC, f) with neutrophils previously cultured with iMSC in the presence of anti-human IL-1β or g) with neutrophils previously cultured with iMSC in the presence of an isotype control.
| EGAD00001010080 | EGA
Project description:To analyze the changes induced in MSC transcriptome by activated T cells, MSC were co-cultured in transwell with anti CD3/CD28 activated T cells for 48 hrs before RNA extraction IFNγ-induced plasticity of mesenchymal stem cells is regulated by STATs through inhibition of mTOR and TGFβ pathways. Vigo T, Procaccini C, Ferrara G, Baranzini S, Oksenberg J, Diaspro A, Kerlero de Rosbo N, Uccella A. The expression of MSC co-cultured with activated T cells ( two replicates) were compared to that of naive MSC (3 replicates)
2015-12-08 | E-GEOD-75749 | biostudies-arrayexpress
Project description:It has been reported that human mesenchymal stem cells (MSCs) can transfer mitochondria to the cells with severely compromised mitochondrial function. We tested whether MSCs transfer mitochondria to the cells under several different conditions of mitochondrial dysfunction, including human pathogenic mitochondrial DNA (mtDNA) mutations. Using biochemical selection methods, we found that exponentially growing cells in restrictive media (uridine and bromodeoxyuridine [BrdU]+) after coculture of MSCs (uridine-independent and BrdU-sensitive) and 143B-derived cells with severe mitochondrial dysfunction induced by either long-term ethidium bromide treatment or short-term rhodamine 6G (R6G) treatment (uridine-dependent but BrdU-resistant). The exponentially growing cells had nuclear DNA fingerprint patterns identical to 143B, and a sequence of mtDNA identical to the MSCs. Since R6G causes rapid and irreversible damage to mitochondria without the removal of mtDNA, the mitochondrial function appears to be restored through a direct transfer of mitochondria rather than mtDNA alone. Conditioned media, which were prepared by treating mtDNA-less 143B 0 cells under uridine-free condition, induced increased chemotaxis in MSC, which was also supported by transcriptome analysis. A chemotaxis inhibitory agent blocked mitochondrial transfer phenomenon in the above condition. However, we could not find any evidence of mitochondrial transfer to the cells harboring human pathogenic mtDNA mutations (A3243G mutation or 4,977 bp deletion). Thus, the mitochondrial transfer is limited to the condition of a near total absence of mitochondrial function. Elucidation of the mechanism of mitochondrial transfer will help us create a potential “cell therapy-based mitochondrial restoration or mitochondrial gene therapy” for human diseases caused by mitochondrial dysfunction. time series
2011-11-22 | E-GEOD-33831 | biostudies-arrayexpress
Project description:Mesenchymal stem cells (MSCs) are cells with high regenerative and immunosuppressive capacity that are known to be very potent donors of functional mitochondria to all surrounding cells, including immune cells. As metabolism shapes immune cell response and phenotype, mitochondrial transfer might be one of the main immunosuppressive mechanisms used by stem cells. However, the precise mechanism underlying horizontal mitochondrial transfer and its effect on some cell populations has yet to be discovered. In our project, we have shown that MSCs transfer mitochondria to B lymphocytes less efficiently in comparison to other immune populations. To describe the effect of mitochondrial transfer on activated B lymphocytes, MSCs were co-cultivated with B lymphocytes which were activated prior to co-cultivation. Then B cell acceptors and non-acceptors of mitochondria were sorted for further RNA isolation and the performance of bulk RNA-seq.
2024-03-02 | E-MTAB-13438 | biostudies-arrayexpress