CD317-Positive Immune Stromal Cells in Human "Mesenchymal Stem Cell" Populations
Ontology highlight
ABSTRACT:
INSTRUMENT(S): maXis
ORGANISM(S): Homo Sapiens (ncbitaxon:9606)
SUBMITTER: 
Professor Paul Genever
PROVIDER: MSV000089336 | MassIVE | Fri Apr 29 09:42:00 BST 2022
SECONDARY ACCESSION(S): PXD033565
REPOSITORIES: MassIVE
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Project description:Heterogeneity of bone marrow mesenchymal stromal cells (MSCs, frequently referred to as “mesenchymal stem cells”) clouds biological understanding and hampers their clinical development. In MSC cultures most commonly used in research and therapy, we have identified an MSC subtype characterized by CD317 expression (CD317pos (29.77 ± 3.00% of the total MSC population), comprising CD317dim (28.10 ± 4.60%) and CD317bright (1.67 ± 0.58%) MSCs) and a constitutive interferon signature linked to human disease. We demonstrate that CD317pos MSCs induced cutaneous tissue damage when applied a skin explant model of inflammation, whereas CD317neg MSCs had no effect. Only CD317neg MSCs were able to suppress proliferative cycles of activated human T cells in vitro, whilst CD317pos MSCs increased polarization towards pro-inflammatory Th1 cells and CD317neg cell lines did not. Using an in vivo peritonitis model, we found that CD317neg and CD317pos MSCs suppressed leukocyte recruitment but only CD317neg MSCs suppressed macrophage numbers. Using MSC-loaded scaffolds implanted subcutaneously in immunocompromised mice we were able to observe tissue generation and blood vessel formation with CD317neg MSC lines, but not CD317pos MSC lines. Our evidence is consistent with the identification of an immune stromal cell, which is likely to contribute to specific physiological and pathological functions and influence clinical outcome of therapeutic MSCs.
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Project description:The heterogeneity of mesenchymal stem cells (MSCs) remains incompletely inventoried, which often hampers reproducibility in clinical applications and basic research. Advanced single-cell RNA sequencing (scRNAseq) is a robust tool for dissecting cellular heterogeneity, while the comprehensive single-cell atlas still has not been achieved for human MSCs.Using massively parallel multiplexing scRNAseq, we constructed this atlas of >130,000 single-MSC transcriptomes across multiple tissues and donors to decipher their heterogeneity. The most widely clinical-utilized tissue-resources for MSCs were collected, including normal bone marrow (n=3), adipose (n=3), umbilical cord (n=2), and dermis (n=3).Based on this high-quality data, we identified the 7 tissue-specific and 5 conserved MSC subpopulations with distinct gene-expression signatures from multiple tissue origins, which has not been achieved previously. We noticed that extracellular matrix hugely contributes to MSC heterogeneity. Notably, tissue-specific MSC subpopulations exhibited hugely heterogeneous on ECM-associated immune regulation, antigen processing/presentation, and senescence, which also contributed to inter-donor and intra-tissue heterogeneity. The variable dynamics of ECM-associated genes depicted the discrete trajectory patterns across multiple tissues. Additionally, the conserved and tissue-specific transcriptomic-regulons and protein-protein interactions were identified, representing common or tissue-specific MSC potentially functional roles. Furthermore, we also discovered that the umbilical-cord-specific subpopulation possessed advantages in immunosuppressive properties.In summary, our work provides timely and exciting insights into MSC heterogeneity on multiple levels. In addition to resource value, this MSC atlas taxonomy provides a comprehensive understanding of cellular heterogeneity, revealing the potential improvements in MSC-based therapeutic efficacy.
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Project description:Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought to regulate the innate and adaptive immune systems. I will discuss some of the reasons why clinical applications are still lacking. Much more work will have to be done to find the sources, doses, and culture conditions needed to exploit MSCs optimally and learn their healing potential. They are worth the effort.
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Project description:Multiple myeloma (MM) is a B-cell neoplasm characterized by clonal expansion of malignant plasma cells (MM cells) in the bone marrow (BM) compartment, where they acquire resistance to chemotherapy-mediated apoptosis. Natural history of patients include a premalignant stage, the MM diagnosis, the treatment, the remission, and for most of them the relapse. BM mesenchymal stromal cells (MSC) from newly diagnosed MM patients are functionally different from healthy donors (HD) MSC and display a distinct transcriptome. They have been largely involved in MM pathogenesis and chemoresistance acquisition. In order to determine if MM-MSC also participate to relapse, we focused on the characterization of MSC from patients with MM at different stages of the disease. We obtained patient MSC’s samples at diagnosis, at 2 years after intensive treatment without relapse and at the relapse from an intensive treatment. We used MCS from HD as control. All MSC were able to support MM cells growth through released factors, and still multipotent since able to differentiate into osteoblast and adipocyte. A transcriptomic analysis between these groups reveals differences in gene expression between HD and MM MSC whatever stage of the disease, suggesting that the difference in gene expression in MM-MSC persist with time. These data demonstrate an imprinting of MSC as soon as they were in contact with MM cells, which persist even after the disappearance of MM cells. This imprinting is in favour of an easier differentiation towards adipogenesis.
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Project description:Background: Extracellular vesicles (EVs) isolated from mesenchymal stem/stromal cells (MSCs) contribute to recovery of damaged tissue in animals models of human disease. We have previously shown that EVs isolated from porcine MSCs transport mRNA and miRNA capable of modulating several cellular pathways in recipient cells, yet their proteome remained to be profiled. Using a quantitative proteomic strategy, we sought to study the protein cargo of porcine MSC-derived EVs to identify candidate molecules for mediating their therapeutic effect.
Methods: Autologous MSCs were collected from abdominal fat of 3 female domestic pigs, and MSC-derived EVs were subsequently isolated, cultured, and characterized by the expression of typical MSC and EV markers. LC-MS/MS proteomic analysis was performed and proteins classified using the Panther Classification System. Functional pathway analysis was performed with DAVID 6.7. Three candidate proteins were selected for validation and their expression in EVs and MSCs confirmed by Western blot. Results: Proteomics analysis identified 5,469 protein groups in MSCs and 4,937 in EVs. Average protein intensity was higher in MSCs compared to EVs (p<0.0001). Differential expression analysis revealed 128 proteins upregulated in EVs vs. MSCs (log2 fold change>10, p<0.05), whereas 563 proteins were excluded from EVs (log2 fold change<-10, p<0.05). Biological functional analysis of proteins enriched in EVs indicated a broad distribution, with the most frequently represented categories being proteins involved in angiogenesis, blood coagulation, apoptosis, extracellular matrix remodeling, and regulation of inflammatory responses. Proteins excluded from EVs were mostly nuclear proteins and proteins involved in nucleotide binding and RNA splicing.
Conclusions: The present study provides novel proteomic characterization of the biological signatures of porcine adipose MSC-derived EVs. The selective cargo that EVs shuttle may define the spectrum of their roles in mediating MSC intercellular communication.
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2019-02-12 | PXD011643 | Pride