Dataset Information

Altered Adhesion and Migration of Human Mesenchymal Stromal Cells under Febrile Temperature Stress Involves NF-?? Pathway.

ABSTRACT: Mesenchymal stromal cells (MSCs) are clinically beneficial for regenerative treatment of chronic inflammation and autoimmune disorders. However, to attain maximum efficacy from the transplanted MSCs, evaluation of its interaction with the microenvironment, becomes critical. Fever being an important hallmark of inflammation, we investigated the effect of febrile temperature stress on adhesion and migration of umbilical cord-derived MSCs. 40?°C-exposure altered cellular morphology with significant cell flattening, delayed cell-matrix de-adhesion response and slower migration of MSCs, accompanied by suppressed directionality ratio and cell trajectory. Corresponding to the observed changes, mRNA expression of extracellular matrix genes like COLs and VTN were upregulated, while matrix metalloproteinase MMP-1, showed a significant downregulation. NF-?? pathway inhibition at 40?°C, led to reversal of gene expression pattern, cell spreading, de-adhesion dynamics and migration rate. Independent knockdown of p65 and p53 at 40?°C indicated inhibitory role of p65/p53/p21 axis in regulation of MMP-1 expression. P21 inhibits JNK activity, and JNK pathway inhibition at 40?°C resulted in further downregulation of MMP-1. Hence, our study provides the first evidence of cell migration getting adversely affected in MSCs under elevated temperature stress due to an inverse relationship between p65/p53/p21 and MMP1 with a possible involvement of the JNK pathway.

SUBMITTER: Sen A

PROVIDER: S-EPMC7066177 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Altered Adhesion and Migration of Human Mesenchymal Stromal Cells under Febrile Temperature Stress Involves NF-κβ Pathway.

Sen Ankita A Ta Malancha M

Scientific reports 20200311 1

Mesenchymal stromal cells (MSCs) are clinically beneficial for regenerative treatment of chronic inflammation and autoimmune disorders. However, to attain maximum efficacy from the transplanted MSCs, evaluation of its interaction with the microenvironment, becomes critical. Fever being an important hallmark of inflammation, we investigated the effect of febrile temperature stress on adhesion and migration of umbilical cord-derived MSCs. 40 °C-exposure altered cellular morphology with significant ...[more]

PMID: 32161303

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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: Syndecans are proteoglycans whose core proteins have a short cytoplasmic domain, a transmembrane domain and a large N-terminal extracellular domain possessing glycosaminoglycan chains. Syndecans are involved in many important cellular processes. Our recent publications have demonstrated that syndecan-1 translocates into the nucleus and hampers tumor cell proliferation. In the present study, we aimed to investigate the role of syndecan-1 in tumor cell adhesion and migration, with special focus on the importance of its distinct protein domains, to better understand the structure-function relationship of syndecan-1 in tumor progression. METHODOLOGY/PRINCIPAL FINDINGS: We utilized two mesenchymal tumor cell lines which were transfected to stably overexpress full-length syndecan-1 or truncated variants: the 78 which lacks the extracellular domain except the DRKE sequence proposed to be essential for oligomerization, the 77 which lacks the whole extracellular domain, and the RMKKK which serves as a nuclear localization signal. The deletion of the RMKKK motif from full-length syndecan-1 abolished the nuclear translocation of this proteoglycan. Various bioassays for cell adhesion, chemotaxis, random movement and wound healing were studied. Furthermore, we performed gene microarray to analyze the global gene expression pattern influenced by syndecan-1. Both full-length and truncated syndecan-1 constructs decrease tumor cell migration and motility, and affect cell adhesion. Distinct protein domains have differential effects, the extracellular domain is more important for promoting cell adhesion, while the transmembrane and cytoplasmic domains are sufficient for inhibition of cell migration. Cell behavior seems to depend also on the nuclear translocation of syndecan-1. Many genes are differentially regulated by syndecan-1 and a number of genes are actually involved in cell adhesion and migration. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that syndecan-1 regulates mesenchymal tumor cell adhesion and migration, and different domains have differential effects. Our study provides new insights into better understanding of the role of syndecans in tumor progression.

Dataset Information

Altered Adhesion and Migration of Human Mesenchymal Stromal Cells under Febrile Temperature Stress Involves NF-?? Pathway.

Publications

Altered Adhesion and Migration of Human Mesenchymal Stromal Cells under Febrile Temperature Stress Involves NF-κβ Pathway.

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