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Effects of human adipose tissue-derived and umbilical cord tissue-derived mesenchymal stem cells in a dextran sulfate sodium-induced mouse model

ABSTRACT: Background: Mesenchymal stem cells (MSCs) can be acquired from medical waste. MSCs are easily expanded and have multiple functions, including anti-inflammatory effects. We evaluated the effects of human adipose tissue-derived MSCs (AD-MSCs) and umbilical cord tissue-derived MSCs (UC-MSC) in a dextran sulfate sodium (DSS)-induced mouse model. Methods: Human AD-MSCs and UC-MSCs (1 × 106 cells) were injected intravenously into a 7-day DSS-induced colitis model. The therapeutic effects of cell origin, injection timing, and supernatants obtained from MSC cultures were evaluated. We also analyzed mRNA expression in MSCs, tissues, and intestinal flora. Results: AD-MSCs and UC-MSCs had strong anti-inflammatory effects when injected on day 3 in a mouse model. On day 11, mRNA levels of inflammatory factors in colon tissues were significantly decreased after injection of MSCs on day 3. Supernatants from MSCs culture decreased mRNA levels of tumor necrosis factor (Tnf)-α, but had reduced therapeutic effects compared with MSC cell injection. RNA sequencing using colon tissues obtained the day after cell injection revealed changes in the TNF-α/nuclear factor-κB and T-cell receptor signaling pathways. Additional analyses showed that several factors, including chromosome 10 open reading frame 54, stanniocalcin-1, and TNF receptor superfamily member 11b were increased in MSCs after adding serum from DSS colitis mice. Furthermore, both AD-MSCs and UC-MSCs maintained the balance of intestinal flora. Conclusion: AD-MSCs and UC-MSCs showed therapeutic effects against inflammation after early cell injection while maintaining the intestinal flora. Although supernatants showed therapeutic effects, cell injection was more effective against inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE136397 | GEO | 2019/11/19

REPOSITORIES: GEO

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Project description:Background: Preclinical studies showed thatmesenchymal stem cells (MSCs) ameliorate tau phosphorylation, amyloid-betaaccumulation, and inflammation in Alzheimer’s disease (AD) mouse models viasecretion of neurotrophic factors and cytokines. We aimed to identify CSFbiomarkers that can be used to predict or monitor the response to MSCs inpatients with AD. Methods: AD patients were injected withhuman umbilical cord blood-MSCs (n=22) or placebo (n=12). The cerebrospinalfluid (CSF) samples were collected at baseline, one day after the firstinjection, and one day after the third injection. The patients injected withMSCs were classified into good responder (GR) or poor responder (PR) groupsbased on the rate of changes in the ratio of total-tau and phosphorylated-tauin the CSF. We selected three typical participants in each group, and their CSFprotein levels were analyzed using liquid chromatography-tandem massspectrometry (LC-MS/MS). Results: In the LC-MS/MS analysis 1,667proteins were identified. 11 proteins showed significant differences betweenthe typical GR and PR at baseline. Based on their significance level and knownfunctions two proteins, reticulocalbin-3 (RCN3) and follistatin-related protein3 (FSTL3), were selected as potential biomarkers to predict MSC response. 173proteins showed significant change one day after the third injection comparedto the baseline in typical GR. We excluded 45 proteins that showed significantchange after the third injection compared to the baseline in the typical PR.Based on their significance level and known function, four proteins,scrapie-responsive protein 1 (SCRG1), neural proliferation and differentiationcontrol protein (NPDC1), apolipoprotein E (ApoE), and cystatin C (CysC), wereselected as potential biomarker to monitor MSC response. Additionally,functional analysis revealed that the increased CSF proteins after the thirdinjection compared to the baseline in the typical GR were associated withsynaptogenesis. Conclusions: This study identified twoproteins (RCN3 and FSTL3) that may be potential biomarkers for predicting MSCresponse and four proteins (SCRG1, NPDC1, ApoE, CysC) that may be potentialbiomarkers for monitoring MSC response in patients with AD. Further studies areneeded to validate our results.

Project description:Purpose: Most studies conducted towards understanding the differences among the adult sources of MSCs (BM-MSC and AD-MSC) and UC-MSCs have focused on their phenotypic properties which cannot provide an idea of the functional characteristics changing at the molecular level. Even NGS studies done before, each each study focuses on a different profiling methodology, which makes it difficult to establish a molecular equivalency among the various datasets. We undertake an integrative omics comparison between UC-MSC and two other popular sources of adult MSC (BM-MSC and AD-MSC), with the reasoning that a joint modeling of the changes occurring at the various functional levels will provide greater in-depth insight into the molecular heterogeneity related to different sources of MSCs. Methods: human Mesenchymal Stem Cell (MSC) mRNA cultured under basal conditions in Xeno-free media were subjected to deep sequencing. Three different MSC sourcers : adipose (AD-MSC), bone-marrow (BM-MSC) and Wharton-jelly umbilical cord (UC-MSC) were used and three donors from each tissues source along with three biological replicates for each donor were sequenced using the Illumina PE 150 platform. The sequence reads that passed quality filters Q30≥ 80% were analyzed using DESeq2. Results: Using an optimized data analysis workflow, we identified 24,804 transcripts among the three different sources of MSCs. Among these 2127 transcripts (~10%) were found to be differentially expressed among the three sources of MSC, with a\Log2FC| ≥2 and FDR <0.05. Hierarchical clustering of differentially expressed genes uncovered significant differences among the neonatal source (UC-MSC) and adult-MSCs (AD-MSC and BM-MSC). Altered gene expression profiles among the sources was also confirmed using a proteomics study of the same three sources of MSC with the same donors. Further, secretory immune-regulatory molecules which were confirmed to be differentially expressed among the MSC sources using the integrated transcriptomics-proteomics approach was validated using a Luminex cytokine profiling study. Conclusions: Our study represents the first detailed integrated analysis of differential gene expression profiling among source-specific human Mesenchymal Stem Cells using a multi-omics approach to validate the observed transcriptomic changes at both the translational as well as secretory levels. Our results offer a comhrehensive evaluation of the differences in immune signaling that exists among the different sourcrs of MSC based on their tissue of origina nd which subsequently plays a decisive role in determining the "regenrative siganture" of these MSCs based on the match between "immune-signature" and "disease type".

Project description:Nonresolving inflammation is correlated to carcinogenesis. Ulcerative colitis-associated colorectal cancer (UC-CRC), one of the typical carcinoma generated by inflammation that cannot be resolved properly, has been widely believed to involve a multistep process contains M-bM-^@M-^\inflammation-dysplasia-cancerM-bM-^@M-^] sequence. The exact molecular mechanisms underlying the step-wise development of UC-CRC is still not fully understood. Detecting the changes in gene expression profiles may help to reveal why and how does the prolonged inflammatory response lead to carcinogenesis, and to characterize potential diagnostic/prognostic markers or additional therapeutic targets for UC-CRC. There for, we performed temporal genome expression profiling analysis using the Affymetrix genome wide microarray system to identify broad scale changes in gene expression associated with the development of colitis-associated cancer, based on an AOM/DSS induced mouse model of UC-CRC. 6-week-old male ICR mice were given a single intraperitoneal injection of AOM (10mg/kg) at Day 1, followed by three cycles of DSS administration (cycle 1: 2%, Day 8~14; cycle 2: 1.5%, Day 29~33; cycle 3: 1.5%, Day 50~54) in the drinking water. Instead, control group of mice were given a single intraperitoneal injection of saline (10mg/kg) at Day 1 and distilled water drinking from the beginning to the end without DSS. Colorectal tissues were collected at days 14, 28, 42, 56 and 140 (at the end of the 2nd, 4th, 6th, 8th and 20th week) from the AOM/DSS group and at day 14 from the control group. Pathological changes of each sample were identified under microscope. Samples collected at the end of the 2nd week were inflamed mucosae, the 4th week were low grade dysplasias, the 6th week were high grade dysplasias, the 8th week were high grade dysplasias with active inflammation, the 20th week were carcinomas, and the control sample were normal mucosae. Total RNA were extracted and detected by Affymerix GeneChip Mouse Genome 430 2.0 Array.

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Effects of human adipose tissue-derived and umbilical cord tissue-derived mesenchymal stem cells in a dextran sulfate sodium-induced mouse model

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