Secretome from iPSC-derived MSCs exerts proangiogenic and immunosuppressive effects to alleviate radiation-induced vascular endothelial cell damage
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1131086 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29686805_1.fastq.gz | Fastqsanger.gz | |||
| SRR29686805_2.fastq.gz | Fastqsanger.gz | |||
| SRR29686806_1.fastq.gz | Fastqsanger.gz | |||
| SRR29686806_2.fastq.gz | Fastqsanger.gz | |||
| SRR29686807_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Radiation therapy is the standard of care for central nervous system tumours. Despite the success of radiation therapy in reducing tumour mass, irradiation (IR)-induced vasculopathies and neuroinflammation contribute to late-delayed complications, neurodegeneration, andpremature ageing in long-term cancer survivors. Mesenchymal stromal cells (MSCs) are adult stem cells that facilitate tissue integrity, homeostasis, and repair. Here, we investigated the potential of the iPSC-derived MSC(iMSC) secretome in immunomodulation and vasculature repair in response to radiation injury utilizing human cell lines. Methods: We generated iPSC-derived iMSC lines and evaluated the potential of their conditioned media (iMSC CM) to treat IR-induced injuries in human monocytes (THP1) and brain vascular endothelial cells (hCMEC/D3). We further assessed factors in the iMSC secretome, their modulation, and the molecular pathways they elicit. Results: Increasing doses of IR disturbed endothelial tube and spheroid formation in hCMEC/D3. When IR-injured hCMEC/D3 (IR ≤ 5 Gy) were treated with iMSC CM, endothelial cell viability, adherence, spheroid compactness, and proangiogenic sprout formation were significantly ameliorated, and IR-induced ROS levels were reduced. iMSC CM augmented tube formation in cocultures of hCMEC/D3 and iMSCs. Consistently, iMSC CM facilitated angiogenesis in a zebrafish model in vivo. Furthermore, iMSC CM suppressed IR-induced NFκB activation, TNF-α release, and ROS production in THP1 cells. Additionally, iMSC CM diminished NF-kB activation in THP1 cells cocultured with irradiated hCMEC/D3, iMSCs, or HMC3 microglial lines. The cytokine array revealed that iMSC CM contains the proangiogenic and immunosuppressive factors MCP1/CCL2, IL6, IL8/CXCL8, ANG (Angiogenin), GROα/CXCL1, and RANTES/CCL5. Common promoter regulatory elements were enriched in TF-binding motifs such as androgen receptor (ANDR) and GATA2. hCMEC/D3 phosphokinome profiling revealed increased expression of pro-survival factors, the PI3K/AKT/mTOR modulator PRAS40 and β-catenin in response to CM. The transcriptome analysis revealed increased expression of GATA2 in iMSCs and the enrichment of pathways involved in RNA metabolism, translation, mitochondrial respiration, DNA damage repair, and neurodevelopment. Conclusions: The iMSC secretome is a comodulated composite of proangiogenic and immunosuppressive factors that has the potential to alleviate radiation-induced vascular endothelial cell damage and immune activation.
2024-08-26 | GSE271374 | GEO
Project description:Early senescence-induced immunosuppressive β-cell secretome prevents type 1 diabetes
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Project description:Cyclic regeneration of the endometrium, and its repair after parturition or injury, are crucial for successful reproduction. Mesenchymal stem cells (MSCs) derived from bone marrow (BM-MSC) facilitate tissue repair via their secretome, which contains growth factors and cytokines that promote wound healing. Despite the implication of MSCs in endometrial regeneration and repair, the mechanisms remain unclear. This study tested the hypothesis that the secretome of MSCs from human BM upregulates human endometrial stromal cell (HESC) proliferation, migration and invasion, and activates pathways to increase HESC motility. MSCs were purchased from ATCC (BM-MSC-1) and cultured from the BM aspirate of a healthy female donor (BM-MSC-2). Indirect co-culture of MSCs and hTERT-immortalized HESCs via a transwell system studied the effect of the BM-MSC secretome on HESC proliferation, migration, and invasion. To study the effect of the MSC secretome on HESC gene expression, HESCs were exposed to the BM-MSC secretome via indirect co-culture for 24 h. Total RNA was extracted from HESCs for RNA sequencing (RNA-Seq). Differentially expressed genes (DEG) and significantly altered pathways were identified. Indirect co-culture of HESCs with BM- MSCs resulted in significant increase in HESC migration and invasion regardless of the source of MSCs. Effects on cellular proliferation varied among the BM-MSC source. Exposure of HESCs to the secretome of BM-MSCs changed the expression of 10,141 genes with FDR < 0.05. There was overlap among 4351 genes between HESCs exposed to BM-MSC-1 and BM-MSC-2, including upregulated expression of cell motility genes common to both BM-MSC exposures. Increased HESC motility by the secretome of BM-MSC appears to be mediated by paracrine and autocrine mechanisms, in part by modifying HESC gene expression. These data support the potential for leveraging the MSC secretome as a novel cell-free therapy in the treatment of disorders of endometrial regeneration.
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Project description:Background: Advanced Renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs’ migration to RCC remain unknown. Here, we comprehensively analyzed RCC secretome to identify MSCs attractants. Methods: Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T, KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. Results: When compared with normal cells, CM from advanced RCC cell lines (Caki-1, KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1, and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs’ transcriptional reprogramming, stimulating the expression of CD44, PTX3, and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs’ homing to the kidney. AREG emerged as an upregulator of MSCs’ transcription. Conclusions: advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs’ transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets. We used microarrays to determine the effect of the conditioned media (CM) collected from two RCC-derived cell lines (Caki-1, KIJ265T) and non-tumorous control cell line (RPTEC/TERT1) on the transcriptome change in mesenchymal stem/stromal cells (MSCs).
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Project description:Using an unbiased RNA sequencing approach of primary CD4+ T cells infected with three wild type primary HIV-1 isolates and selective mutants thereof, Langer et al. show that the HIV-1 accessory protein Vpu exerts broad immunosuppressive effects, inhibiting the induction of innate and adaptive immune responses. Transcription factor network analyses reveal that Vpu suppresses the expression of NF‑κB rather than IRF3 target genes. As a result, Vpu impairs the production of pro-inflammatory cytokines such as IFNβ, CXCL10 and IL-6.
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Project description:Umbilical cord mesenchymal stromal cells (UC-MSCs) were treated with different concentration with hIL10 and the influences on the secretome analyzed
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Project description:Canine adipose-derived mesenchymal stem cells (cAD-MSCs) show therapeutic promise for their regenerative potential, particularly in their secretome. However, concerns arise regarding the impact of in vitro cultivation need for storing therapeutic doses, prompting this study to comprehensively explore the impact of in vitro aging on gene expression and secretome composition. The study involved collecting abdominal adipose tissue samples from nine healthy female dogs, from which cAD-MSCs were extracted and cultured. Stem cells were validated through trilineage differentiation assays and flow cytometry immunophenotyping. Gene expression profiling, using RT-qPCR array and cAD-MSCs secretome LC-MS/MS analysis, were conducted at passages 3 and 6 to reveal gene expression and protein composition alterations during in vitro culture. Gene expression profiling of in vitro aged cAD-MSCs revealed expression alterations, while significant downregulation was observed in two MSC-associated genes. Proteomic analysis revealed 10% distinctively expressed proteins, and several up- and downregulations. Grouping these proteins with biologically significant ones, Gene Ontology Panther Pathway analysis revealed that P3 proteins were significantly associated with cytoskeletal regulation, nicotinic acetylcholine receptor signaling, inflammation mediated by chemokine and cytokine signaling, Wnt signaling, and CCKR signaling map. In contrast, P6 proteins were linked to the xanthine and guanine salvage pathway, adenine and hypoxanthine salvage pathway, and blood coagulation pathway. To the best of our knowledge, this study presents the first original perspective on the changes in secretome composition that occur when cAD-MSCs age in vitro. Our findings highlight significant changes that, in conclusion, indicate the regenerative potential of cAD-MSCs and that their secretome may be compromised due to in vitro aging. Consequently, our study suggests a preference for earlier passages when considering these cells for therapeutic applications.
2024-02-15 | GSE255585 | GEO
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2015-01-20 | E-MTAB-2396 | biostudies-arrayexpress
Project description:Parkinson’s disease (PD) is characterized by a selective loss of dopamine (DA) neurons in the human midbrain causing motor dysfunctions. The exact mechanism behind dopaminergic cell death is still not completely understood and, so far, no cure or neuroprotective treatment for PD is available. Recent studies have brought attention to the wide array of bioactive molecules produced by mesenchymal stem cells (MSCs), generally referred to as the secretome. Herein, we evaluated whether human MSCs-bone marrow derived (hBMSCs) secretome would be beneficial in a PD pre-clinical model, when compared directly with cell transplantation of hBMSCs alone. We used a 6-hydroxydpomanie (6-OHDA) rat PD model, and motor behavior was evaluated at different time points after treatments (1, 4 and 7 weeks). The impact of the treatments in the recovery of DA neurons was estimated by determining TH-positive neuronal densities in the substantia nigra and fibers in the striatum, respectively, at the end of the behavioral characterization. Furthermore, we determined the effect of the hBMSCs secretome on the neuronal survival of human neural progenitors in vitro, and characterized the secretome through proteomic-based approaches. This work demonstrates that the injection of hBMSCs secretome potentiated the histological recovery of DA neurons, when compared to transplantation of hBMSCs themselves, a fact that probably explains the improved behavioral performance of secretome-injected animals in the staircase test. Moreover, we observed that hBMSCs secretome induces higher levels of in vitro neuronal differentiation. Finally, the proteomic analysis revealed that hBMSCs secrete a variety of important exosome-related molecules such as those related with the ubiquitin-proteasome and histone systems. Overall, this work provided important insights on the potential use of hBMSCs secretome as a therapeutic tool for PD, and further confirms the importance of the secreted molecules rather than the transplantation of hBMSCs for the observed positive effects. These could be likely through normalization of defective processes in PD, namely proteostasis or altered gene transcription, which lately can lead to neuroprotective effects.
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