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Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells.

ABSTRACT: Mesenchymal stem cells (MSCs) are a potential source of adult stem cells for cell-based therapeutics due to their substantial multilineage differentiation capacity and secretory functions. No information is presently available regarding the maintenance of immunosuppressive properties of this cell type with repeated passages. It was therefore the aim of the present study to analyze the biological properties, particularly the immunoregulatory effect, of MSCs from late passages. The differences between young and old MSCs in morphology, cell surface antigen phenotype, proliferation, gene expression and immunomodulatory ability were investigated. The results of the current study demonstrated that with the passage of cells, senescent MSCs displayed a characteristically enlarged and flattened morphology, different gene expression profiles and stronger immunosuppressive activities. Increased interleukin-6 production may be a possible underlying mechanism for this enhanced immunomodulatory ability of MSCs. These findings suggest that aged MSCs may provide a treatment option for patients with graft versus host disease and other diseases associated with dysregulation of the immune system.

SUBMITTER: Zhuang Y

PROVIDER: S-EPMC4237101 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells.

Zhuang Yong Y Li Dong D Fu Jinqiu J Shi Qing Q Lu Yuanyuan Y Ju Xiuli X

Molecular medicine reports 20141023 1

Mesenchymal stem cells (MSCs) are a potential source of adult stem cells for cell-based therapeutics due to their substantial multilineage differentiation capacity and secretory functions. No information is presently available regarding the maintenance of immunosuppressive properties of this cell type with repeated passages. It was therefore the aim of the present study to analyze the biological properties, particularly the immunoregulatory effect, of MSCs from late passages. The differences bet ...[more]

PMID: 25339265

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Project description:BackgroundMesenchymal stromal cells (MSCs) are heterogeneous populations. Heterogeneity exists within the same tissue and between different tissues. Some studies have found enormous heterogeneity in immunomodulatory function among MSCs derived from different tissues. Moreover, the underlying mechanism of heterogeneity in immunomodulatory abilities is still unclear.MethodsForeskin mesenchymal stromal cells (FSMSCs) and human umbilical cord mesenchymal stromal cells (HuMSCs) were isolated and cultured until the third passage. According to the International Association for Cell Therapy standard, we confirmed the cell type. Then, FSMSCs and HuMSCs were cocultured with human peripheral blood mononuclear cells (PBMCs) stimulated by lipopolysaccharide (LPS) in vitro. Furthermore, the supernatant was sampled for an enzyme-linked immunosorbent assay to investigate the secretion of IL-1β, IL-6, IL-10, TNF-α, and TGF-β1. Finally, we performed single-cell RNA sequencing (scRNA-seq) of FSMSCs and HuMSCs.ResultsWe successfully identified FSMSCs and HuMSCs as MSCs. When cocultured with LPS pretreated PBMCs, FSMSCs and HuMSCs could effectively reduced the secretion of IL-1β and TNF-α. However, FSMSCs stimulated the PBMCs to secrete more IL-10, TGF-β1, and IL-6. Furthermore, 4 cell subsets were identified from integrated scRNA-seq data, including proliferative MSCs (MKI67+, CD146low+, NG2+, PDGFRB-), pericytes (CD146high+, PDGFRB+, MKI67-, CD31-, CD45-, CD34-), immune MSCs (CXCL12high+, PTGIShigh+, PDGFRB+, CD146-, MKI67-) and progenitor proliferative MSCs (CXCL12low+, PTGISlow+, PDGFRB+, CD146-, MKI67-). Among them, we found that immune MSCs with strengthened transcriptional activity were similar to pericytes with regard to the degree of differentiated. Various of immune-related genes, gene sets, and regulons were also enriched in immune MSCs. Moreover, immune MSCs were determined to be close to other cell subsets in cell-cell communication analysis. Finally, we found that the proportion of immune MSCs in foreskin tissue was highest when comparing the subset compositions of MSCs derived from different tissues.ConclusionsFSMSCs show better immunomodulatory capacity than HuMSCs in vitro. Moreover, immune MSCs may play a vital role in the heterogeneity of immunoregulatory properties. This study provides new insights suggesting that immune MSCs can be isolated to exert stable immunoregulatory functions without being limited by the heterogeneity of MSCs derived from different tissues.

Project description:Despite the increasing demand of cellular therapies for dogs, little is known on the differences between adult and fetal adnexa canine mesenchymal stem cells (MSCs), and data on their metabolic features are lacking. The present study aimed at comparing the characteristics of canine adipose tissue (AT) and umbilical cord matrix (UC) MSCs. Moreover, for the first time in the dog, the cellular bioenergetics were investigated by evaluating the two main metabolic pathways (oxidative phosphorylation and glycolysis) of ATP production. Frozen-thawed samples were used for this study. No differences in mean cell proliferation were found (P>0.05). However, while AT-MSCs showed a progressive increase in doubling time over passages, UC-MSCs showed an initial post freezing-thawing latency. No differences in migration, spheroid formation ability, and differentiation potential were found (P>0.05). RT-PCR analysis confirmed the expression of CD90 and CD44, the lack of CD14 and weak expression of CD34, mostly by AT-MSCs. DLA-DRA1 and DLA-DQA1 were weakly expressed only at passage 0 by UC-MSCs, while they were expressed at different passages for AT-MSCs. There was no difference (P>0.05) in total ATP production between cell cultures, but the ratio between the "mitochondrial ATP Production Rate" and the "glycolytic ATP Production Rate" was higher (P<0.05) in AT- than in UC-MSCs. However, in both MSCs types the mitochondrial respiration was the main pathway of ATP production. Mitochondrial respiration and ATP turnover in UC-MSCs were higher (P<0.05) than in AT-MSCs, but both had a 100% coupling efficiency. These features and the possibility of increasing the oxygen consumption by a spare respiratory capacity of four (AT-MSCSs) and two (UC-MSCs) order of magnitude greater than basal respiration, can be taken as indicative of the cell propensity to differentiate. The findings may efficiently contribute to select the most appropriate MSCs, culture and experimental conditions for transplantation experiments in mesenchymal stem cell therapy for companion animals.

Project description:Osteoarthritis (OA) is a degenerative illness that greatly impacts the life quality of patients. Currently, the therapeutic approaches for OA are very limited in clinical. The extracellular vesicles (EVs) derived from different mesenchymal stem cells displayed a prominent therapeutic effect on OA. But most EVs have limited resources and the risks of host rejection, immunological response, and etc. Human umbilical cord mesenchymal stem cells (hUCMSCs) hold the advantages of easy availability, minimal immune rejection, and excellent immunomodulatory effects, although hUCMSCs-EVs have seldom been applied in OA. Herein, we investigated the potential immunomodulatory and anti-inflammatory effects of hUCMSCs-EVs on the treatment of OA. In our results, the treatment of hUCMSCs-EVs promoted the polarization of M2-type macrophages and the expression of anti-inflammation-related cytokines (IL-10). Notably, the supernate of M2 macrophages induced by hUCMSCs-EVs inhibited the level of inflammation-associated factors in OA chondrocytes caused by IL-1β. Further, injection of hUCMSCs-EVs in the articular lumen ameliorated progression of OA and exerted chondroprotective potential based on the OA joint model created by the surgical transection of the anterior cruciate ligament (ACLT). In addition, we found five highly enriched miRNAs in hUCMSCs-EVs, including has-miR-122-5p, has-miR-148a-3p, has-miR-486-5p, has-miR-let-7a-5p, and has-miR-100-5p by High-throughput sequencing of miRNAs, with targeted genes mainly enriched in the PI3K-Akt signaling pathway. Furthermore, we also detected the protein abundance of hUCMSCs-EVs using liquidation chromatography with tandem quadrupole mass spectrometry (LC-MS/MS) analysis. Thus, our study indicates that hUCMSCs-EVs can alleviate cartilage degradation during the OA progression, mechanically may through delivering key proteins and modulating the PI3K-Akt signaling pathway mediated by miRNAs to promote polarization of M2 macrophage, exhibiting potent immunomodulatory potential. The current findings suggest that hUCMSCs-EVs might serve as a new reagent for the therapy of OA.

Dataset Information

Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells.

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Comparison of biological properties of umbilical cord-derived mesenchymal stem cells from early and late passages: immunomodulatory ability is enhanced in aged cells.

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