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Transcriptome Analysis and Functional Identification of Adipose-Derived Mesenchymal Stem Cells in Secondary Lymphedema

ABSTRACT: We isolated adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with malignancy-related extremity lymphedema, and we used adipose tissue from the normal upper abdomen of the same patients as control tissue. We compared the proliferation and adipogenic differentiation capacity between the two kinds of ASCs, and we explored the transcriptomic differences between them. We found that lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 inhibitors could return the abnormal biological characteristics of these cells to normal phenotype, suggesting that CDK1 is a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema, indicating the CDK1 may be a potential target for lymphedema therapy. On the other hand, our finding showed that ASCs from lymphedema adipose tissues have higher immunosuppressive effect, and the inhibition of up-regulated cytokine CHI3L1 may be clinically beneficial. In summary, explore the underlying mechanisms of fat deposition in lymphedema may provide powerful strategies for the treatment of lymphedema.

ORGANISM(S): Homo sapiens

PROVIDER: GSE132936 | GEO | 2019/06/19

REPOSITORIES: GEO

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Project description:The treatment of bone defects caused by infection, trauma or neoplasms remains a clinical challenge. Autologous bone transplantation is limited by availability, donor site morbidity and surgical risk factors. This has given rise to stromal/stem-cell based therapy. Bone marrow derived stromal cells (BMSCs) have been studied to a large extent and show high regenerative potential but their use is limited by availability, donor site morbidity and the relatively low cell yield as they represent only <0.1% of cell harvested from bone marrow aspirate. At the same time, they are the closest mesenchymal stromal cells for bone tissue engineering given their tissue origin and, unlike other mesenchymal stromal cells, can support the formation of hematopoietic marrow. Adipose tissue derived stromal cells (ASCs) as part of the stromal vascular fraction of adipose tissue can as well undergo osteogenic differentiation but can be additionally isolated in a sufficient quantity from lipoaspirate after liposuction of abundant subcutaneous fat tissue. Here, it has been shown that there are no major differences in regard to proliferation or differentiation capacity of ASCs derived from subcutaneous fat of different anatomical regions. It has been shown that BMSCs are more prone to senescence during expansion and passage than ASCs and that ageing impacts proliferative capabilities of BMSCs more than that of ASCs while it has also been reported that osteogenic differentiation capacity is least impacted by age. Multiple studies have compared the characteristics of these two mesenchymal stromal cells in regard to bone tissue engineering in vitro. Most studies point to inferior extracellular matrix mineralization and lower expression of key osteogenic transcription markers like Runx2 in osteogenic differentiated ASCs compared to BMSCs. On the other hand, a study by Rath et al. found contrary results using particular culturing conditions like 3D bioglass scaffolds. An intraindividual comparison of human MSCs of three donors cultured on decellularized porcine bone confirmed superior osteogenic capacity of BMSCs compared to ASCs. In contrast to BMSCs, ASCs were not able to induce heterogenic ossification in a mouse model. In a sheep tibia defect model application of BMSCs resulted in a significantly higher amount of newly formed bone tissue. Importantly, Osteogenic differentiated ASCs do not support the formation of a hematopoietic marrow. Proteomics enables large-scale analysis of proteins present in a cell type and can be used to identify differentially regulated key proteins in a comparative approach. A comparative proteomic analysis of BMSCs and ASCs by Roche et al. in 2009 identified 556 proteins with 78% of these not being differentially regulated between these two cell populations, regarded as high similarity. Another comparative proteomic study of 2016 by Jeon et al. found 90 differentially regulated proteins out of 3000 total identified proteins. Both studies do not specify a number of different tissue donors and in part using cell lines. Looking for differences upon osteogenic differentiation, transcriptomic comparison of osteogenic differentiated porcine ASCs and BMSCs has been performed, resulting in 21 differentially expressed genes after 21 days of osteogenic culture conditions. Still, it remains unanswered, which are the key distinctive features of osteogenic differentiated ASCs and BMSCs at protein level that might help address the abovementioned weaknesses of ASCs in bone tissue engineering/regeneration for translational research. To overcome this need, an intraindividual comparative DIA based proteomic analysis of osteogenic differentiated human BMSC and ASCs was performed in this study.

Project description:To better understand the scale of gene expression changes that occur during the formation of mature adipocytes from preadipocytes, we compared and characterised the transcriptome profile of mesenchymal stromal cells derived from human adipose tissue, otherwise known as adipose-derived stromal cells (ASCs), undergoing adipocyte differentiation on day 1, 7, 14 and 21 (representing the early to late stage process of adipogenesis). Microarray technique was systematically employed to study gene expression in adipose-derived stromal cells during adipogenic differentiation over a 21 day period to identify genes that are important in driving adipogenesis in humans. We have undertaken an in-depth transcriptome analysis of adipogenesis in human adipose-derived stromal cells (ASCs) induced to differentiate into adipocytes in vitro. Genes were differentially expressed on days 1, 7, 14 and 21 post-induction and numbered 128, 218, 253 and 240 respectively. Up-regulated genes were associated with neural and blood vessel development, leukocyte migration, and tumor growth, invasion and metastasis. They also shared common pathways with certain obesity-related pathophysiological conditions. Down-regulated genes were associated with osteogenesis and the immune response. KLF15, LMO3, FOXO1 and ZBTB16 transcription factors were up-regulated throughout the differentiation process. CEBPA, PPARG, ZNF117, MLXIPL, MMP3 and RORB were up-regulated only on days 14 - 21, which coincides with the maturation of adipocytes and could possibly serve as candidates for controlling fat accumulation and the size of mature adipocytes. We identified genes that were up-regulated only on day 1 - 7 and day 14 - 21 that could serve as potential early and late-stage differentiation markers. This study reveals potential markers for the different stages in ASC adipogenic differentiation which could serve as good candidates to combat obesity and further link the biology of fat cell formation to the co-morbidities of obesity.

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Transcriptome Analysis and Functional Identification of Adipose-Derived Mesenchymal Stem Cells in Secondary Lymphedema

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