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Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema.

ABSTRACT: Background:Secondary lymphedema is a common condition that affects patients with malignant tumors. Conservative treatments fail to provide lasting relief because they do not address the underlying pathological accumulation of excessive fat. Our aim is to clarify the molecular mechanisms of abnormal adipogenic differentiation in lymphedema adipose tissue. Methods:We compared the proliferation and adipogenesis potential of adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with extremity lymphedema with that of ASCs from adipose tissue from the normal upper abdomen of the same patients. Transcriptome analysis were performed to identify the differences between the two kinds of ASCs. Cyclin-dependent kinase 1 (CDK1) inhibitors were used to treat the abnormal ASCs in lymphedema adipose tissue. Results:Our results demonstrate that significant functional and transcriptomic differences exist between the two kinds of ASCs. Up-regulated genes were mainly involved in cell proliferation and division while down-regulated genes were mainly associated with immune responses and inflammatory as well as osteogenic and myogenic differentiation. Furthermore, we find that the excessive proliferation and adipogenesis of ASCs from lymphedema adipose tissue returned to the normal phenotype by CDK1 inhibitors. ASCs from lymphedema adipose tissues have higher immunosuppressive effect and the cytokines related to immunosuppressive was significantly up-regulated. Conclusions:In conclusion, lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 may be a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema. ASCs from lymphedema adipose tissues showed immunomodulation dysfunction and immunomodulation may play an important role in the pathogenesis of lymphedema.

SUBMITTER: Xiang Q

PROVIDER: S-EPMC7225476 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema.

Xiang Qinqin Q Xu Fen F Li Yunzhu Y Liu Xuanyu X Chen Qianlong Q Huang Jiuzuo J Yu Nanze N Zeng Ziyi Z Yuan Meng M Zhang Qixu Q Long Xiao X Zhou Zhou Z

Gland surgery 20200401 2

<h4>Background</h4>Secondary lymphedema is a common condition that affects patients with malignant tumors. Conservative treatments fail to provide lasting relief because they do not address the underlying pathological accumulation of excessive fat. Our aim is to clarify the molecular mechanisms of abnormal adipogenic differentiation in lymphedema adipose tissue.<h4>Methods</h4>We compared the proliferation and adipogenesis potential of adipose-derived mesenchymal stem cells (ASCs) from the lymph ...[more]

PMID: 32420291

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Project description:BackgroundMany breast cancer patients are plagued by the disabling complication of upper limb lymphedema after axillary surgery. Conservative treatments using massage and compression therapy do not offer a lasting relief, as they fail to address the chronic transformation of edema into excess adipose tissue. Liposuction to address the adipose nature of the lymphedema has provided an opportunity for a detailed analysis of the stromal fraction of lymphedema-associated fat to clarify the molecular mechanisms for this adipogenic transformation.MethodsAdipose-derived stem cells were harvested from human lipoaspirate of the upper extremity from age-matched patients with lymphedema (n = 3) or subcutaneous adipose tissue from control patients undergoing cosmetic procedures (n = 3). Immediately after harvest, adipose-derived stem cells were analyzed using single-cell transcriptional profiling techniques. Osteogenic, adipogenic, and vasculogenic gene expression and differentiation were assessed by quantitative real-time polymerase chain reaction and standard in vitro differentiation assays.ResultsDifferential transcriptional clusters of adipose-derived stem cells were found between lymphedema and subcutaneous fat. Interestingly, lymphedema-associated stem cells had a much higher adipogenic gene expression and enhanced ability to undergo adipogenic differentiation. Conversely, they had lower vasculogenic gene expression and diminished capability to form tubules in vitro, whereas the osteogenic differentiation capacity was not significantly altered.ConclusionsAdipose-derived stem cells from extremities affected by lymphedema appear to exhibit transcriptional profiles similar to those of abdominal adipose-derived stem cells; however, their adipogenic differentiation potential is strongly increased and their vasculogenic capacity is compromised. These results suggest that the underlying pathophysiology of lymphedema drives adipose-derived stem cells toward adipogenic differentiation.

Project description:BackgroundAdipose-derived mesenchymal stem cells (ASCs) are a promising cell therapy to treat inflammatory and immune-mediated diseases. Development of appropriate pre-clinical animal models is critical to determine safety and attain early efficacy data for the most promising therapeutic candidates. Naturally occurring diseases in cats already serve as valuable models to inform human clinical trials in oncologic, cardiovascular, and genetic diseases. The objective of this study was to complete a comprehensive side-by-side comparison of human and feline ASCs, with an emphasis on their immunomodulatory capacity and transcriptome.MethodsHuman and feline ASCs were evaluated for phenotype, immunomodulatory profile, and transcriptome. Additionally, transwells were used to determine the role of cell-cell contact in ASC-mediated inhibition of lymphocyte proliferation in both humans and cats.ResultsSimilar to human ASCs, feline ASCs were highly proliferative at low passages and fit the minimal criteria of multipotent stem cells including a compatible surface protein phenotype, osteogenic capacity, and normal karyotype. Like ASCs from all species, feline ASCs inhibited mitogen-activated lymphocyte proliferation in vitro, with or without direct ASC-lymphocyte contact. Feline ASCs mimic human ASCs in their mediator secretion pattern, including prostaglandin E2, indoleamine 2,3 dioxygenase, transforming growth factor beta, and interleukin-6, all augmented by interferon gamma secretion by lymphocytes. The transcriptome of three unactivated feline ASC lines were highly similar. Functional analysis of the most highly expressed genes highlighted processes including: 1) the regulation of apoptosis; 2) cell adhesion; 3) response to oxidative stress; and 4) regulation of cell differentiation. Finally, feline ASCs had a similar gene expression profile to noninduced human ASCs.ConclusionsFindings suggest that feline ASCs modulate lymphocyte proliferation using soluble mediators that mirror the human ASC secretion pattern. Uninduced feline ASCs have similar gene expression profiles to uninduced human ASCs, as revealed by transcriptome analysis. These data will help inform clinical trials using cats with naturally occurring diseases as surrogate models for human clinical trials in the regenerative medicine arena.

Project description:Mesenchymal stem cells (MSCs) possess self-renewal and multipotential differentiation abilities, and they are thought to be one of the most reliable stem cell sources for a variety of cell therapies. Recently, cell therapy using MSCs has been studied as a novel therapeutic approach for cancers that show refractory progress and poor prognosis. MSCs from different tissues have different properties. However, the effect of different MSC properties on their application in anticancer therapies has not been thoroughly investigated. In this study, to characterize the anticancer therapeutic application of MSCs from different sources, we established two different kinds of human MSCs: umbilical cord blood-derived MSCs (UCB-MSCs) and adipose-tissue-derived MSCs (AT-MSCs). We used these MSCs in a coculture assay with primary glioblastoma multiforme (GBM) cells to analyze how MSCs from different sources can inhibit GBM growth. We found that UCB-MSCs inhibited GBM growth and caused apoptosis, but AT-MSCs promoted GBM growth. Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling assay clearly demonstrated that UCB-MSCs promoted apoptosis of GBM via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL was expressed more highly by UCB-MSCs than by AT-MSCs. Higher mRNA expression levels of angiogenic factors (vascular endothelial growth factor, angiopoietin 1, platelet-derived growth factor, and insulin-like growth factor) and stromal-derived factor-1 (SDF-1/CXCL12) were observed in AT-MSCs, and highly vascularized tumors were developed when AT-MSCs and GBM were cotransplanted. Importantly, CXCL12 inhibited TRAIL activation of the apoptotic pathway in GBM, suggesting that AT-MSCs may support GBM development in vivo by at least two distinct mechanisms-promoting angiogenesis and inhibiting apoptosis. The opposite effects of AT-MSCs and UCB-MSCs on GBM clearly demonstrate that differences must be considered when choosing a stem cell source for safety in clinical application.

Dataset Information

Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema.

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Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema.

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