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Molecular insights in the anti-cancer potential of mesenchymal stem cells derived from the amniotic fluid and chorionic villi

ABSTRACT: The environment created during embryogenesis contributes to reducing aberrations that drive structural malformations and tumorigenesis. In this study, we investigate the anti-cancer potential of mesenchymal stem cells (MSCs) derived from two different gestational tissues, the amniotic fluid (AF) and the chorionic villi (CV), with particular emphasis on the role of the paracrine signals they release. Methods: Next generation sequencing was performed on patient-derived AF- and CV-MSCs to obtain molecular insights into the molecular mechanisms driving their anti-cancer features. Secretome enrichment analysis allowed the identification of soluble moieties involved in target cell regulation, tissue homeostasis and cancer cell inhibition. Data were experimentally confirmed through in vitro assays, by evaluating the cytotoxic effect of the media conditioned (CM) by AF- and CV-MSCs and their derived exosomes (EXO) on two human ovarian cancer cell lines (OVCAR and SKOV-3), in 2D and 3D conditions. Results: The presence of molecular moieties (i.e., mRNAs, lncRNAs) released by these cells to support tissue homeostasis by inhibiting biological processes involved in the etiology of aggressive cancers, as well as to regulate immune pathways at the basis of chronic disorders. Secretome enrichment analysis showed the presence, in both cell lines, of lncRNAs with the predicted function of inhibiting cancer cell proliferation. The exposure of OVCAR and SKOV-3 cells to CM and EXOs revealed a detrimental effect in 2D (by reducing cell viability and inducing apoptosis), and to negatively interfere with spheroid formation in 3D conditions. Conclusion: Data presented here provides molecular insight on the role AF- and CV-MSCs as source of anti-tumor factors, paving the way for the development of therapeutics with the potential to create a pro-regenerative environment for tissue restoration following injury, disease, and cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240855 | GEO | 2024/07/30

REPOSITORIES: GEO

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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).

Project description:BACKGROUND: Ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal Stromal Cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy, however, their full potential in treating AKI remains unknown.METHODS: In this study, we employed an in vitro model of chemically-induced ischemia using antimycin A combined with 2-deoxy-D-glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards, we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential) and overall cell metabolism by metabolomics.RESULTS: Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40-50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites.CONCLUSION: Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.

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Molecular insights in the anti-cancer potential of mesenchymal stem cells derived from the amniotic fluid and chorionic villi

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