miR-301b~miR-130b—PPARγ axis underlies the adipogenic capacity of mesenchymal stem cells with different tissue origins

Liu, Lulu; Liu, Haihui; Chen, Mingtai; Ren, Shengxiang; Cheng, Panpan; Zhang, Hao

doi:10.1038/s41598-017-01294-2

Cited by 28 publications

(23 citation statements)

References 45 publications

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“…Of the listed factors, a number of studies indicated that long-term in vitro culture and continuous passages were the prohibiting factor for phenotype and function of MSCs, yet the evidence was still lacking [21,22,31]. Currently, even though we and other investigators have compared the biological signatures of hUC-MSCs with hBM-MSCs or hAD-MSCs in some respects at the cellular level, few of the studies are further focusing on the distinctions at the molecular level [21,37]. Very recently, by utilizing single-cell transcriptomic analysis, Huang et al reported that the in vitro expanded hUC-MSCs showed heterogeneity in inflammatory cytokines and cell cycle stages [31], which was consistent with our data by whole-exome sequencing.…”

Section: Discussionmentioning

confidence: 99%

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

et al. 2019

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Background: Mesenchymal stem cells are heterogenous populations with hematopoietic supporting and immunomodulating capacities. Enormous studies have focused on their preclinical or clinical therapeutic effects, yet the systematic study of continuous in vitro passages on signatures and functions of UC-MSCs at both the cellular and molecular levels is still lacking. Methods: In this study, to systematically evaluate the biological properties of MSCs at various passages, we analyzed biomarker expression, cell proliferation and apoptosis, chromosome karyotype, and tri-lineage differentiation potential. Subsequently, we took advantage of whole-exome sequencing to compare the somatic hypermutation of hUC-MSCs at P3, P6, and P15 including SNV and INDEL mutations. In addition, to explore the safety of the abovementioned hUC-MSCs, we performed metabolic pathway enrichment analysis and in vivo transplantation analysis. Furthermore, we cocultured the abovementioned hUC-MSCs with UCB-CD34 + HSCs to evaluate their hematopoietic supporting capacity in vitro. Finally, we transplanted the cells into acute graft-versushost disease (aGVHD) mice to further evaluate their therapeutic effect in vivo. Results: The hUC-MSCs at P3, P6, and P15 showed similar morphology, biomarker expression, and cytokine secretion. hUC-MSCs at P15 had advantages on adipogenic differentiation and some cytokine secretion such as IL-6 and VEGF, with disadvantages on cell proliferation, apoptosis, and osteogenic and chondrogenic differentiation potential. Based on the SNP data of 334,378 exons and bioinformatic analyses, we found the somatic point mutations could be divided into 96 subsets and formed 30 kinds of signatures but did not show correlation with risk of tumorigenesis, which was confirmed by the in vivo transplantation experiments. However, hUC-MSCs at P15 showed impaired hematologic supporting effect in vitro and declined therapeutic effect on aGVHD in vivo.

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Section: Discussionmentioning

confidence: 99%

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

et al. 2019

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“…PPARγ is considered a master regulator of adipogenic fate decision 21 . Our previous work demonstrated that PPARγ expression positively correlates with the adipogenic capacity of MSCs with different tissue origins 22 . In this study, we further validated the regulatory role of PPARγ with its two specific shRNAs in the adipogenesis of BM-MSCs.…”

Section: Resultsmentioning

confidence: 54%

PPAR Gamma-Regulated MicroRNA 199a-5p Underlies Bone Marrow Adiposity in Aplastic Anemia

Zhang

Liu

Dou

et al. 2019

Molecular Therapy - Nucleic Acids

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Increased propensity of bone marrow-derived mesenchymal stem cells (BM-MSCs) toward adipogenic differentiation has been implicated in the fatty bone marrow and defective hematopoiesis of aplastic anemia (AA). However, the underlying molecular mechanism remains to be investigated. In this study, we found that microRNA 199a-5p (miR-199a-5p) exhibits significantly higher expression in AA BM-MSCs compared with the normal control and is demonstrated to facilitate adipogenic differentiation of BM-MSCs through lentivirus-mediated miR-199a overexpression. Mechanistic investigation reveals that miR-199a-5p could be regulated by PPAR gamma (PPARg) in a transcription-independent manner and regulates adipogenic differentiation by targeting the expression of transforming growth factor beta induced (TGFBI), which is subsequently validated as a negative regulator of adipogenesis. Besides, the positive correlation between PPARg and miR-199a-5p expression as well as the inverse relationship between miR-199a-5p and TGFBI expression in normal and AA BM-MSCs was observed. Altogether, our work demonstrates that PPARg-regulated miR-199a-5p promotes adipogenesis of BM-MSCs by inhibiting TGFBI expression, which might be a novel mechanism underlying the bone marrow adiposity in AA, and provides promising therapeutic targets for AA treatment.

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“…Adipogenic differentiation was performed according to the method described elsewhere with minor modifications . The MSCs were seeded into 12‐well plates.…”

Section: Methodsmentioning

confidence: 99%

Levamisole suppresses adipogenesis of aplastic anaemia‐derived bone marrow mesenchymal stem cells through ZFP36L1‐PPARGC1B axis

Liu

et al. 2018

J Cellular Molecular Medi

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Aplastic anaemia (AA) is a life‐threatening hematopoietic disorder characterized by hypoplasia and pancytopenia with increasing fat cells in the bone marrow (BM). The BM‐derived mesenchymal stem cells (MSCs) from AA are more susceptible to be induced into adipogenic differentiation compared with that from control, which may be causatively associated with the fatty BM and defective hematopoiesis of AA. Here in this study, we first demonstrated that levamisole displayed a significant suppressive effect on the in vitro adipogenic differentiation of AA BM‐MSCs. Mechanistic investigation revealed that levamisole could increase the expression of ZFP36L1 which was subsequently demonstrated to function as a negative regulator of adipogenic differentiation of AA BM‐MSCs through lentivirus‐mediated ZFP36L1 knock‐down and overexpression assay. Peroxisome proliferator‐activated receptor gamma coactivator 1 beta (PPARGC1B) whose 3′‐untranslated region bears adenine‐uridine‐rich elements was verified as a direct downstream target of ZFP36L1, and knock‐down of PPARGC1B impaired the adipogenesis of AA BM‐MSCs. Collectively, our work demonstrated that ZFP36L1‐mediated post‐transcriptional control of PPARGC1B expression underlies the suppressive effect of levamisole on the adipogenic differentiation of AA BM‐MSCs, which not only provides novel therapeutic targets for alleviating the BM fatty phenomenon of AA patients, but also lays the theoretical and experimental foundation for the clinical application of levamisole in AA therapy.

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miR-301b~miR-130b—PPARγ axis underlies the adipogenic capacity of mesenchymal stem cells with different tissue origins

Cited by 28 publications

References 45 publications

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

Systematic comparison of hUC-MSCs at various passages reveals the variations of signatures and therapeutic effect on acute graft-versus-host disease

PPAR Gamma-Regulated MicroRNA 199a-5p Underlies Bone Marrow Adiposity in Aplastic Anemia

Levamisole suppresses adipogenesis of aplastic anaemia‐derived bone marrow mesenchymal stem cells through ZFP36L1‐PPARGC1B axis

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